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In this JCO PO Article Insights episode, Miki Horiguchi provides a summary on the article, “TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing and explains what a non-inferiority trial is.
TRANSCRIPT
Miki Horiguchi: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Miki Horiguchi, an ASCO Journal’s Editorial Fellow. Today, I'll be providing a summary of the article titled "TARGET: A Randomized Non-Inferiority Trial of a Pre-Test, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing" by Dr. Stacy Loeb and colleagues.
To help you understand the TARGET study design, I'll first explain what a non-inferiority trial is.
One of the most common clinical trial designs we see in clinical papers is the superiority trial. A superiority trial is designed to demonstrate that a new treatment is superior to a control, such as a placebo or a standard treatment, in terms of a primary outcome that is relevant to the study's purpose. In a superiority trial, a statistical test is performed for the null hypothesis that there is no treatment difference between the two arms. If a significant p-value, which is conventionally less than 0.05 is observed, we consider that the probability that the null hypothesis being true is very low, and thus conclude that there is a treatment difference between the two arms. On the other hand, if the p-value is larger than 0.05, we cannot conclude that there is a treatment difference because the probability that the null hypothesis being true is not low enough. Here, it's very important for us to keep in mind that a non-significant p-value does not mean no difference between the two arms.
Therefore, if the study objective is to show that a new treatment has a similar treatment effect to a control treatment, the standard statistical testing approach used in a superiority trial is not appropriate. To meet this specific study objective, utilizing a non-inferiority test is more appropriate. The formulation of a hypothesis in a non-inferiority test is distinct from that in a superiority test. In essence, the null hypothesis is that the new treatment is inferior by more than the predefined margin, whereas the alternative hypothesis argues against this, suggesting that the new treatment is not inferior within this margin. A significant p-value from the non-inferiority test indicates support for the alternative hypothesis, implying that the new treatment is at least as effective as the control treatment considering the predefined margin of non-inferiority.
There are a couple of points to consider prior to designing a non-inferiority trial. The first is about the justification for using a non-inferiority study. The new treatment must offer a clear advantage other than the treatment effect, such as fewer side effects and lower cost, so that it can be a viable alternative to the control treatment as long as it maintains a certain level of treatment effect that is not inferior to the controls.
The second point is about the non-inferiority margin. The non-inferiority margin defines the threshold below which the new treatment is deemed non-inferior to the control. The selection of an appropriate margin is pivotal as it profoundly influences the power and sample size of the study, as well as the interpretation of the statistical test results. To ensure the study's objectives are met, the non-inferiority margin must be established during the study design phase. This decision should be informed by clinical expert opinions, findings from previous studies, or regulatory guidelines.
Now let me move on to the introduction of the TARGET study. The TARGET study was a multicenter, non-inferiority randomized trial to compare the effects of two types of interventions for pre-test genetic education in patients with prostate cancer. The authors developed a patient-driven, web-based education tool that consisted of nine modules with text and videos to deliver genetic testing education. They then assessed its non-inferiority to traditional genetic counseling and the decisional conflict about taking genetic testing. The primary endpoint was the change in the decisional conflict score between pre- and post-intervention. The authors estimated the difference in pre-post change of the score between the two arms and the corresponding one-sided 95% confidence interval. The non-inferiority of the web tool arm on the pre- post change of the score to the genetic counseling arm was assessed based on a pre-specified non-inferiority margin of 4. In this case, if the estimated upper confidence bound for the difference between the two arms is less than the non-inferiority margin, the study confirms the non-inferiority of the web tool to the genetic counseling in terms of the primary outcome.
The non-inferiority margin for this study was determined based on a previously conducted similar study. For the TARGET study, several factors underscore the appropriateness of using a non-inferiority trial. First, the web-based education model is likely to significantly increase convenience compared to traditional genetic counseling, which is delivered in person or through telehealth appointments with the genetic counselor. The introduction of the proposed web tool is expected to reduce logistical burdens for patients, such as those related to transportation and scheduling. Second, from the perspective of healthcare providers, the adoption of the proposed web tool could reduce the workload of genetic counselors, offering a potential solution for a shortage of counselors.
A total of 346 patients were randomly assigned in a 1:1 allocation to either of the two interventions. The primary analysis population was the modified intention-to-treat population, which included 153 on the web tool arm and 162 on the genetic counseling arm. The estimated difference in pre- post-change of the decisional conflict score between the two arms was -0.04 and the upper boundary of the corresponding confidence interval was 2.54, which was less than the predefined non-inferiority margin. The p-value for the non-inferiority test was 0.01. The authors reported results for the secondary endpoints, which included cancer genetics knowledge, attitude toward genetic testing, and satisfaction with genetic counseling. It was also reported that a total of 265 patients took genetic testing, and among the total, pathogenic variants were identified in 42 patients. The authors concluded that the study results support the use of a patient-driven web tool for expanding access to pre-test education for germline genetic testing among patients with prostate cancer. The authors also mentioned some limitations of this study, one of which is the limited racial and ethnic diversity among the study population. Some requirements to access the web-based tool, such as a computer and Wi-Fi access, may raise concerns about widening disparities in access to genetic services for cancer patients. Further studies to examine ways to address these limitations are needed.
Thank you for listening to JCO Precision Oncology Article Insights, and please tune in for the next topic. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all the ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO PO author Dr. Christian Rolfo shares insights into his JCO PO article, “Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.” Host Dr. Rafeh Naqash and Dr. Rolfo discuss how early liquid biopsy in aNSCLC in parallel with path dx is associated with shorter time to treatment.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stephenson Cancer Center, University of Oklahoma.
Today we are thrilled to be joined by Dr. Christian Rolfo, Associate Director of Clinical Research at the Center of Thoracic Oncology at the Tisch Cancer Institute at Mount Sinai Health System. He is also the lead author of the JCO Precision Oncology article entitled "Liquid Biopsy of Lung Cancer Before Pathological Diagnosis is Associated with Shorter Time to Treatment."
Our guest's disclosures will be linked in the transcript.
Christian, it's great to have you here. Welcome to our podcast and we are excited to learn about some of the interesting results from your study.
Dr. Christian Rolfo: Thank you very much, Rafeh. It's a pleasure to be here and discuss about liquid biopsy.
Dr. Rafeh Naqash: You have a very important role in different liquid biopsy consortiums. This is an initiative that you have been leading and spearheading for quite a while, and it's nice to see that it is becoming something of a phenomenon now on a global scale where liquid biopsies are being implemented more and more in earlier stages, especially. For the sake of our audience, which revolves around academic oncologists, community oncologists, trainees, and patient advocates or patients themselves, could you tell us a little bit about the background of what liquid biopsies are? And currently, how do we utilize them in the management of lung cancer or cancers in general?
Dr. Christian Rolfo: Liquid biopsy has been gaining importance over the years. We started to talk about liquid biopsy in 2009 when we started to see some correlations with EGFR mutations. In practicality, what we are doing is the most common or most applicable indication is to go for liquid biopsies from the blood, peripheral blood. So we are doing a blood draw and from there, what we are capturing is the DNA or fragments of DNA that are still in circulation. But the liquid biopsy definition is a little bit more broad and we can apply the concept of a minimally invasive approach to different fluids of the body, including pleural effusion, urine, and including CSF that is another indication, there, we are going to be a little bit more invasive than peripheral blood, but it is also an emerging tool that we will have to find specific indicators. In cancer, we started the history of liquid biopsy in advanced disease with the identification of biomarkers, and then from there, we are moving to other scenarios, including, nowadays, monitoring minimal residual disease and early detection. And that is applicable also for other tumors.
Dr. Rafeh Naqash: Thank you, Christian, for that summary. Now, as you've rightly pointed out, we have come to implement liquid biopsies more and more, both in the academic setting and the community setting. And this has definitely led to faster turnaround time in some ways compared to tissue. In this study that you have authored with the help of many other collaborators and Foundation Medicine Flatiron Health data, the goal here, from what I understand, was to look at liquid biopsies that were done before, resulted before the pathological diagnosis. Could you tell us a little bit more about the premise of this study, why you thought about this question and how did you try to implement that idea to get to some of the interesting results that you see here?
Dr. Christian Rolfo: Yeah, so what we are seeing generally in lung cancer and also in people with other tumors is that patients are having a journey and that they start seeing different doctors until they get a diagnosis. Generally, after the pathological diagnosis, if you don’t have an in-house technology that is doing reflex testing, generally, oncologists need to request for testing and that is taking time. So if we are looking for comprehensive days until a patients are able to get a molecular profiling before we start the treatment is sometimes very long. We are talking, in some cases, about months. So, how we can speed the process, that was the main question. We tried to include liquid biopsy in the staging procedures that we generally were doing when we have a clinical diagnosis of lung cancer. It’s either images that we are used to do, PET scans, MRIs, and other assessments, we want to include liquid biopsy there before the biopsy. And that's what we did. We were searching for this specific aim using the Flatiron Health Foundation Medicine electronic health records from 280 centers across the United States. We included a big number of patients in this analysis, more than 1000 patients for the first analysis.
Dr. Rafeh Naqash: That's phenomenal that you had real-world data from 200+ centers across the US. Of course, when you have patients on a clinical trial versus patients in the real-world, we all know that there are differences in terms of approaching, overseeing, and managing these individuals. So this data set is an extension of what we could see in the real-world setting.
Could you tell us a little bit about the number of patients that you eventually identified that had liquid biopsies done before pathological diagnosis? I think you have different cohorts here, a group that was before and a group that was after, and you compared several important metrics treatment-wise from what I see. Could you highlight those for our listeners?
Dr. Christian Rolfo: Yeah. So we were looking for patients who had a liquid biopsy CGP, comprehensive genomic profiling, ordered within 30 days pre diagnosis and post diagnosis. We focused on 5.2% of patients, which corresponded to 56 patients who ordered a liquid biopsy before diagnosis. The median time was eight days between the order and diagnosis and the range was between 1 to 28 days. And that was compared with 1020 patients who ordered a liquid biopsy after diagnosis. It is important to be clear that both cohorts had a similar stage and ctDNA tumor fraction. We can explain later what tumor fraction is, because it was done in addition with a paper that we just published last week. Liquid biopsy patients were consulted to have this CGP median one day after diagnosis, versus 25 days after for patients who had their diagnosis and their liquid biopsy later on. So, from these patients, the majority of the patients, 43% of LBx-Dx were positive for an National Comprehensive Cancer Network driver, and 32% had ctDNA TF >1% but were driver negative, so that is what we call presumed true negative. From here, maybe I can explain what is tumor fraction and, in general, how we use it.
Dr. Rafeh Naqash: I think that would be great for our listeners. We see this often in more and more liquid biopsy results nowadays, and I've tried to explain it to some of my fellows also. So, it would be nice if you explain for the sake of our listeners what tumor fraction is, what does it mean clinically, can you use it in a certain way, what biological relevance does it have.
Dr. Christian Rolfo: So we are analyzing another paper that came out this week in cancer research on the concept of tumor fraction and it’s a new definition. So what we are doing with tumor fraction is an algorithmic calculation or mathematical calculation on the amount of DNA of the cells also taking into consideration the math, the quantity of DNA present in the sample. So we are going very low in the sensitivity of this analysis and capturing there the real informative results of the ctDNA of the liquid biopsy. So in practicality, when you see a report that says the threshold that was established in this study was more than 1% or less than 1%, so patients who have a tumor fraction of more than 1%, we can really consider this liquid biopsy informative. And also in this next publication, we compared with tissue. In patients with a tumor fraction of more than 1%, were completely 100% correspondent with what we found in the reflected tumor tissue, the NGS. But what happened in patients with a tumor fraction of less than 1%, we can say that these patients are not informative. So we need to wait for the tissue biopsy result to come in because we were able to recuperate several patients that the liquid biopsy was negative with the tissue biopsy positive.
This is an important concept because we are distinguishing not only the informativeness of liquid biopsy, but also we can distinguish between patients who are considered not shedder based on what is considered a shedder. And that was a problem until this kind of introduction was a problem before with the technology because the technology wasn't very fast to distinguish the sensitivity or high sensitivity. Now, the sensitivity is no longer a problem. Maybe, there is really value of information in what we have in liquid biopsy, and using this mathematical help, we can get these patients distinguished and help more people. So that would be really interesting.
Dr. Rafeh Naqash: You touched on a few important concepts here, and one question I have, and I think there's no better person to answer this question. You're the right person to answer this question for our audience. Do you think when you have a liquid biopsy tumor fraction of less than 1%, and you have a tissue that is pending with an NGS, where tissue NGS has not resulted yet, but liquid biopsy results come in and tumor fraction is less than 1%. But let's say you have a non-smoker with a typical driver mutation and clinical characteristic positive individual in the clinic, and the tumor fraction is less than 1%. How much can you trust that liquid biopsy when the tumor fraction is less than 1%. Because do you think some of these driver mutations, like you mentioned, could be low shedders and you could miss a potentially actionable mutation on a liquid biopsy if the tumor fraction is less than 1%? Is that something that you've looked at or correlated or understood what would be the clinical meaning of that?
Dr. Christian Rolfo: Absolutely. So there are two concepts here. A liquid biopsy could be non-informative, and that is what we saw in this paper. So you have patients that have a liquid biopsy negative, and that we see in the clinic, a liquid biopsy negative tissue biopsy positive. That could be because the liquid biopsy is not informative, but it could be also that the patient, for some biological reason, and we don't have an answer about that, they are not shedding the ctDNA in the bloodstream, ctDNA that we can capture. What we saw in different studies, including one of the papers that we presented also in ASCO last year with a MET amplification and METex14, for example. In the study that was the VISION study using tepotinib, you see that patients who have a liquid biopsy negative are doing a better outcome compared to a patient who have a liquid biopsy positive. So I believe that we still have patients who are not shedders for some biological reason, that could be put in together with patients who have more bone metastasis than organ metastasis, or patients who have more in location, for example in the brain. These patients are difficult to capture in ctDNA due to some biological reasons. But also you have patients who are non-shedders. For the technicality of the parts of this tumor fraction analysis, it is really important to distinguish that and we will hear more and more. So, as you say, we have already some reports in some companies like Foundation are doing, but some others like to incorporate this tumor fraction. And several in-house technologies allow also to have this kind of mathematical calculation. So that is what we are facing now, to really understand better the power of liquid biopsy.
Dr. Rafeh Naqash: Now, some of the other things that your project or paper that you published with JCO PO does not necessarily cover is the payer aspect of this. Now, we've had more and more discussions, obviously, and more and more information has been highlighted with the payers that this is an important test and needs to be reimbursed, even though if you do tissue NGS, liquid biopsies are complementary to tissue. So taking both together is probably a better view of the overall tumor or the mutational status of the tumor. But one of the biggest holes in this whole process, and this is my personal experience, I want to know what you think, is that we can't order these tests when the patient is admitted to the hospital, and 50% or more patients end up getting diagnosed in the hospital during an inpatient stay. The average hospitalization for someone with lung cancer is five to seven days on average, and then another one to two weeks to get into the clinic to see an oncologist. So what would your thoughts be there? How can we improve things there in terms of, can we try to do something different so that the payers agree that, yes, you can send a liquid biopsy when the patient is admitted, because there's that 14-day Medicare rule? Has your team, or have you in particular, tried to navigate some of those issues, and what are your thoughts on how we can try to improve some of those conversations?
Dr. Christian Rolfo: Yeah, that's a really good question, because here we are talking about inequities in access to the technology and the results and it's crucial. Several of our patients, specifically in lung cancer, they are coming to our consultations or to the emergency with a very bad situation so they need to be admitted immediately. And as you say, they can be there for one month waiting for results or for recovery or for stabilization of their general condition before we can start. Several of these patients will have some biomarkers that we can target with treatment. So in other words, I will say that this is a stupid rule because we cannot have in 2024 these kinds of limitations to access to treatment when we have on one side, the FDA is doing a terrific job to get drugs approved in a very short time, and on the other side we have payers who are not understanding the concept of molecular or precision oncology.
So what we are trying to do in these cases, to be honest, is to navigate with the vendors and try to get this done. I generally send the samples because I consider that personally that it is a very crucial information. And in several cases, we have started targeted therapies while the patient is still admitted. So I think it's something that we need to put in a better effort, because already we are not doing enough for our patients, if you look at the data of the MYLUNG Consortium that was presented in ASCO some years ago on the testing performance in the community practice, 50% of the patients with lung cancer were tested there were only some in minority groups, African Americans, 39%. So I think we need to do better in education, but also from the payer side, it's really crucial that they understand this concept.
Advocacy groups have a lot of say here. They are also doing an important job on that. We are now launching with ISLC, ISLB, Lung Cancer Europe, and Longevity in a survey that is to make also the patients aware what is the importance of molecular profiling, tissue or liquid biopsy, it’s very important that you get something to treat the patient and select the right treatment. And even to say, there’ll be a whole other work in your case so that is really important.
Dr. Rafeh Naqash: Absolutely, I completely agree. We have made a lot of strides, but there is still a lot of room for improvement in terms of equity, access, and reimbursement.
Now, one of the things that I noticed in your paper, and you could tell me a little bit more about this, when you looked at the pre-diagnosed liquid biopsies, meaning before tissue diagnosis, 56 individuals there suspected to have lung cancer, community-based testing was identified in 53 individuals versus academic being three. This is very encouraging when you see something like this happening in the community. Did you look at that? Did you try to understand why or how that was the case? Because in a general community setting, I would think that community practices have a more complicated system of reimbursement because they are dependent on direct reimbursement, whereas in bigger academic centers, there’s some leeway here and there. So did you try to understand how they were able to order this before tissue, could you give us some insights there?
Dr. Christian Rolfo: Yes, I think it was not big in this specific question, but it's a very interesting topic. Because we, generally, in academia, will believe that we are doing the things in advance and we are more, compared with the practical and the general practitioners or the general colleagues in the community practice, we have more resources. But sometimes, and it's true, obviously, we have more resources in terms of research and more opportunities in terms of clinical trials in some cases. But I think we understood with this minimal example that there is an important interest among general oncologists in the community practice to get this done. And this is something we need to emphasize, because sometimes we are putting the blame on our colleagues that are outside the academic centers on this lack of testing, and it’s not really true sometimes. So this is a good point to start to work together and try to get more things done for our patients and try to get also the reality.
I think one of the problems we will have in the future that we can face right now is the lack of new figures in this molecular profiling. I am referring, for example, molecular nurses or personnel that is working and helping to get this done. We need to have more people that are working in this education for the patients in the access to treatment and access to the technology, but also to navigate better these problems with payers that sometimes in some patients that seem to be overwhelming. Because when you talk about the $100 that could be extra, it’s hard for some patients. So we need to be very conscious about that. So having a new figure in the hospitals and the community practices could help to test more patients.
Dr. Rafeh Naqash: And I think at the end of the day, the payers or the reimbursement mechanisms need to understand that genomics is part of the diagnosis these days. It's not ancillary, it’s not an addition, but it is part of the diagnosis. I'm pretty sure you have had similar instances where you get a confusing pathology result but then a genomic result points in a certain direction. You treat the patient in that direction, and then you see the patient benefiting in the tumor shrinking, which suggests that genomics is complementary to the path diagnosis. It’s not necessarily a surrogate.You can’t replace pathological diagnosis, but you can use genomics as a complementary diagnosis as part of the whole paradigm of treating the entire patient. So I think we definitely need more and more conversations like the ones that you’re having or your liquid biopsy consortium is having and then more education from the FDA. Of course, more legislation, more advocacy.
Going back to the paper, I did notice another interesting thing, which is, again, very encouraging is patients with lung cancer with a performance status of 2 or about had a decent proportion of testing done. Which, again, points out to the important concept of avoiding these preconceived biases that, “Hey. If somebody is not a great performance status, testing and finding something in that individual could potentially change a lot for the individual.” Do you have any personal examples from patients you have treated or seen in the clinic for our listeners where you identified something and maybe they were not doing as great initially, and then you identified something in liquid biopsy, treated them and it changed the entire course of their illness and whole trajectory for them?
Dr. Christian Rolfo: Being working in lung cancer for years, everyone has this kind of patient that we see that their performance state was very bad. Obviously, as a clinician, we need to identify why the performance is bad and is deteriorating. So we see some patients in lung cancer, some of them, they can have a very important comorbidity packet that is associated with lung cancer. So in patients who have a deterioration for lung cancer, and we find a driver help in some patients that were doing a kind of a weakness, and that is something that we see in several patients, specifically in patients living with leptomeningeal disease. In some cases, when we start to do drivers that have a big impact in the crossing the blood-brain barrier, I have a good response. I have patients that had an important recovery. So this is something we need to distinguish and sometimes when the patients seem very bad they say, “Okay, we go directly to targeted care or supportive care.” We try to test these patients as well because these patients have an important impact on the quality of life that we are treating. We will not be able to cure patients in this setting with targeted therapies, but we can certainly make an impact in the quality of life and also in our form of survival.
Dr. Rafeh Naqash: One of the other questions that comes up often when you’re in a multi display team, since most cancers these days are on the multi display decision making opportunities to treat the patient the best possible way is: Who orders the liquid biopsy? I remember from my fellowship several years back, our program director Paul Walker, who is, again, an amazing lung cancer thoracic oncologist, he had advocated that our endoscopic suite folks, the bronchoscopist, whether it was pulmonary, interventional pulmonology or CT surgeons, whoever did the bronchoscopy for the first time in the patient that they would send it whenever they see the patient from the bronchs. This was around six, seven years back. And I think Paul was a little ahead of his time and I didn’t necessarily understand the implications that this would have.
And now, as I progress in my own little career, I can see the vision that he had, which I think a lot of other sectors have tried to do, and I’m pretty sure you have a certain process, too. Is that something we should try to talk more and more about? Because, of course, when you do the bronch, then you get a diagnosis and the patient sees the oncologist. This whole process takes anywhere from two to three weeks, maybe even more for smaller centers. So, is that something that you’re doing or you see that you’re having more conversations that, “Hey. Whoever sees the patient first should be able to order the liquid biopsy.” It's not necessarily the medical oncologists, it doesn’t mean I love to order sequencing results or sequential tests, but it could cause a delay in the patient care. So, could you tell us a little bit more of that?
Dr. Christian Rolfo: So it's really important, this part, because we need to create in our institution flows that will have this very well organized. And ideally, in the ideal world will be that we have reflex tests coming from the pathologist, but it's not happened in several places, because we don't have our NGS at home, or we are sending to vendors, and sometimes we are not sending to them. So that is one of the aspects.
The second aspect, and that I think is still a problem in some treatment, is that we still have 24:30 cytologists coming out in place of covariances. And in our institution, we were working very hard with our interventional pulmonologists and interventional radiologists to get this quality of tissue appropriate, and we have a very good rate of success and issues in a very minimal quantity of patients. Obviously, some patients are very difficult to get samples, and we need to refer still with cytology. But in some cases, where our surgeons or our pulmonologists have sent in samples for NGS, and I think this is we are coordinating. “I will see this patient next week. Can you please start to order?” And here, our nurse practitioner, our nurses in the team are also playing an important role for the reason I insist in the idea to have new figures that could be these molecular navigators we can call, or molecular nurses that helping coordinate this, not only the coordination, but also in the discussion of molecular tumor boards. We did an experience like that some years ago at Maryland University, and actually it was a very important opportunity to decrease the number of quantities of issues and get the results done very quickly. So I think it's important to come to have conversations with our colleagues, pulmonologists, radiation radiologists, interventional radiologists, pulmonologists and pathologists to get this done very quickly.
Dr. Rafeh Naqash: I love the idea of molecular navigators. And of course, everybody in the current day and age, we’re having staffing issues, so getting a molecular navigator would be awesome, but I’m not necessarily sure how everybody would be able to implement it. But I think in the bigger picture, whether it’s molecular navigators or multi disciplinary nurse navigators in general, liaisons in general, I think we all can do a better job in trying to coordinate some of these testings. And we have tried to do that through our thoracic oncology group and of course, there’s a lot of progress that needs to be made, one step at a time.
Dr. Christian Rolfo: If somebody is interested in this topic on the International Society of Liquid Biopsy, we started with a project that is called a Certificate for Advanced Studies in Precision Oncology. So we are educating the healthcare team for all this process and trying to get practical insights to have this career later. Because I think it will be something that’s interesting for nurses or pharmacists to get this kind of career later or get another approach in their career.
Dr. Rafeh Naqash: Thank you so much, Christian.
Now, going to not the scientific part, which I think is the most interesting part of this conversation is to talk about you and your personal journey. Could you tell us a little bit about where you started, what your career has been like, how did you progress? Because you have a lot of junior faculty that listen to this and it's always good to take inspiration from people like yourself.
Dr. Christian Rolfo: Thank you. As you can hear my accent, it’s not from here. So I was born in Argentina, I did my medical degree there. And then I had the opportunity to get a scholarship in Italy. I went to Italy and I stayed there for seven years. I did my fellowship there again, and I started to know there precision oncologists. My journey started in sarcoma. And actually I was working in the group of Dr. Casali's group, a very well known sarcoma expert. And at that time we were running phase I trials for imatinib, I remember, known as GIST. I saw this kind of response and awakening of patients that were really in very bad condition, with only through this imatinib. Very little to treat that disease at that moment, a median overall survival of two months. So I started to be interested in that. Then I moved from there to Spain and met Dr. Rafael Rossell, who was my mentor. In Italy, I have also a mentor in breast cancer, Dr. Luca Gianni, one of the pioneers in breast cancer treatment. So knowing all these people and having the support of them, was really crucial.
So I think this is the first advice for junior faculty: try to choose your mentor, even if your mentor is not in your center. Like the case, for example, Rafael Rossell was not in my hospital, but he was my mentor. So having this kind of discussion, I did my PhD in EGFR mutation, at that time was the fashion, not immunotherapy, of the moment. And then from there, after eight years in Spain, I moved to Belgium. I have a short period of completing my training at MD Anderson and I went to Belgium to Antwerp University and that was the opportunity to become the Director of the phase I program in the Early Clinical Trials Unit. It was really exciting to see growing a unit, and now they continue at the center in Belgium. My colleagues that stayed there, they are doing a terrific job of continuing this idea. And from there I went to Baltimore, three years working at Maryland University being the Director of Thoracic Oncology and early clinical trials as well. Three years after, I moved to New York, and here doing this journey in clinical research, also being the Director of Clinical Research at the Center for Thoracic Oncology.
Life has put me in different places, different cultures, different opportunities. For me it was a really good journey to be in different countries, knowing different ways to see oncology as well, and immediately to work, because it was a shock coming from Belgium to the area of Baltimore where I had the reality to discuss peer to peer conversations and things that are not usually discussed in Europe. So it was really a very nice journey to learn, to have the capacity to adapt.
That is the other thing, my second advice, if I can give advice, but if you have the opportunity to go to some place, adaptation is the most important. So try to enjoy what you’re doing and try to enjoy and learn from the patients, hopefully, and contribute your knowledge as well.
Dr. Rafeh Naqash: Thank you so much, Christian. Two last questions. For all the places that you visited, what is your favorite place? And what is your favorite food?
Dr. Christian Rolfo: My favorite place to live, I have Italy in my heart. Obviously, Argentina is my place, family. But Italy is in my heart. And then Spain, Spain gave me my wife and my son. So I have very good memories there and it’s a very nice place. Obviously, I’m Argentinian, so for me it means meat in some places, Asado, that is a typical Argentinean one. But also, I am very eager to enjoy the pasta and paella, so we have several things. Anyway, here in New York, the pizza of New York is great. It is not Italian. This new way to make pizza from New York is fantastic.
Dr. Rafeh Naqash: I can try to see you’re trying to keep everybody happy in a politically correct way.
Dr. Christian Rolfo: I didn't mention Belgium, but we have chocolates there.
Dr. Rafeh Naqash: That is true. Every place is special and unique in different ways.
Christian, thank you so much. This was very entertaining and very informative for me and hopefully for the audience. Thank you so much for being a part of this conversation. And thank you so much for submitting your work to JCO PO. We hope you consider JCO PO for future research in this exciting area as well.
Dr. Christian Rolfo: Thank you. Thank you very much, Rafeh, for the opportunity. And JCO Precision Oncology is a really great forum to discuss precision medicine. Congratulations for all your work. The last, if you allow me to give an advertisement here. We have our Liquid Biopsy Congress, the ISLB, the annual conference will be in Denver from 20 to 25 November, so just before Thanksgiving day. So if you are able to go there, we will have a lot of discussion on liquid biopsy like we did today. Thank you very much.
Dr. Rafeh Naqash: Thank you so much for highlighting that, and hopefully, our listeners will try to register and be part of that meeting.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review. And be sure to subscribe so you never miss an episode. You can find all our shows at asco.org/podcasts.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO PO Article Insights episode, Fergus Keane provides a summary on "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice", by Papadopoulou, et al published January 25, 2024
TRANSCRIPT
The guest on this podcast episode has no disclosures to declare.
Fergus Keane: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Fergus Keane, an ASCO Editorial Fellow. Today, I will be providing a summary of the article entitled "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice" by Dr. Eirini Papadopoulou.
The mismatch repair pathway has gained interest in recent years due to advances in precision oncology, the widespread use of immune checkpoint blockade, and next-generation sequencing-based assays to identify microsatellite instability. The mismatch repair pathway has a key role in DNA repair and maintaining genomic stability. Tumor cells, which are MMR deficient are prone to mismatch errors in the microsatellite regions during DNA replication. Microsatellite instable, referred to as MSI-High tumors are observed across a variety of tumor types, most commonly colorectal and endometrial cancers.
Germline Lynch syndrome is caused by inactivating variants in one of five primary MMR genes, namely MSH2, MLH1, MSH6, PMS2, and EPCAM, and is associated with an autosomal dominant pattern of inheritance. Mismatch repair deficiency is observed in most tumors in individuals with Lynch syndrome and can also occur sporadically. In mismatch repair deficient colorectal cancer, sporadic cases are identified by BRAF V600E mutations or MLH1 gene promoter hypermethylation. The absence of both of these findings should raise suspicion for germline Lynch syndrome.
The aim of this study was to report the prevalence of microsatellite instability in a large cohort of patients in Europe, specifically Greek patients. In addition, the authors aimed to evaluate the proportion of patients with microsatellite instability referred for germline testing and what factors appeared to influence clinician decision to refer for germline testing. 4553 patients with metastatic cancer were included between January 2020 and April 2023. All patients were referred for MSI analysis, and at physician discretion, BRAF V600E and MLH1 gene methylation analyses were available. Approximately half of patients included had colorectal cancer. 5.27% of patients exhibited MSI-High in total, of whom 58% were female and 42% were male.
The rates of MSI-High cancers varied according to tumor type, but the highest rates observed in patients with endometrial cancer at 15.69%, gastric cancer at 8.54%, colorectal cancer at 7.4%, and urinary tract cancers at 4.55%. Of the MSI-High patients, with colorectal cancer identified, 24.85% had a BRAF V600E. Excluding these patients, 198 were eligible for genetic testing with a hereditary cancer panel. Of these, only 22.7% were actually referred for a hereditary panel. The median age at diagnosis in this group was 59 years, compared with 66 years for those who were not referred for germline analyses. The age at diagnosis and referral for genetic analyses were significantly correlated.
Beyond colorectal cancer, patients with other cancer types who were also referred for germline testing included nine patients with endometrial cancer, four with gastric cancer, two with ovarian cancer, one with breast cancer, and one with gallbladder cancer, and referral patterns differed by tumor type. Of patients with colorectal and endometrial cancer, 24.4% had a positive germline mismatch repair variant identified. Of note, while the median age of patients with a pathogenic or likely pathogenic germline result was 48.5 years, over 40% of patients with a pathogenic germline result were aged over 50 years, highlighting that age alone should not be the only criterion for consideration of a referral for germline analysis in such patients.
This study highlights some important points. First, MSI analysis is an important biomarker for a variety of tumor types, including colorectal, gastric, and endometrial cancer, but also less commonly associated cancer types. Second, only 22.73% of patients eligible for germline analyses were referred in this patient cohort, despite recommendations from international guidelines indicating that a proportion of patients with a possible familial predisposition syndrome may not be tested for same. Third, key features such as age at diagnosis and tumor type influence the clinical decision for referral for genetic analysis.
The authors conclude that the value of MSI testing as a potential screening tool for identification of patients with a higher risk for germline pathogenic variants may be underappreciated and highlights this important biomarker.
Thank you for listening to JCO Precision Oncology Article Insights, and please tune in for the next topic. Don't forget to give us a rating and review, and be sure to subscribe so that you don't miss an episode. You can find all ASCO shows at asco.org/podcasts
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO PO authors Lauren C. Leiman and Dr. Emma Alme share insights into their JCO PO article, “Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care”. Host Dr. Rafeh Naqash and guests discusses increasing access to liquid biopsy for cancer, reviewing the barriers and examining the proposed solutions.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor of Medicine at the OU Health Stephenson Cancer Center at the University of Oklahoma.
Today, we are excited to be joined by Lauren Leiman, Executive Director of BloodPAC, and Dr. Emma Alme, Public Policy Director at Guardant Health. They are both authors of the JCO Precision Oncology article titled "Recommendations for the Equitable and Widespread Implementation of Liquid Biopsy for Cancer Care."
Our guest disclosures will be linked in the transcript.
For the sake of this conversation, we will refer to each other using our first names. So, Lauren and Emma, welcome to the podcast and thank you for joining us today.
Lauren Leiman: Thank you for having us.
Dr. Emma Alme: Thank you so much.
Dr. Rafeh Naqash: So, this article is an opinion piece that addresses something that is emerging and current and tries to connect it to something that is futuristic also and hopefully, will address a lot of different needs relevant to patients with cancer. For starters, since our audience is pretty diverse, could you tell us what the BloodPAC is? Since the article is somewhat a combined piece from different stakeholders, could you explain what this BloodPAC Consortium is as an entity and what is its role for this BloodPAC?
Lauren Leiman: Sure, this is Lauren Leiman. The BloodPAC was formed almost seven years ago as an initial commitment to the White House Cancer Moonshot back in 2016. I was the head of external partnerships and had this idea with a colleague of mine, Dr. Jerry Lee: Could you accelerate the development and approval of liquid biopsy assays for cancer patient benefit if you were able to create some standards and frameworks for the field broadly, and also if you could aggregate data to support those standards and frameworks? So, we brought together about 20 different organizations across pharmaceutical companies, diagnostic partners, foundations funding in the space, government agencies, all to think through can we create these frameworks, are we willing to submit data. We were extremely successful in that first round, and by the end of 2016, we were able to have our first data deposit into- we built a BloodPAC Data Commons, which is housed in Chicago and was created by Dr. Bob Grossman up there.
In 2017, when it became clear that the last administration was not going to continue the White House Cancer Moonshot, we became an independent non-profit 501(c)(3). And we have grown substantially since that time from those original 20 different organizations to about 66 different organizations today, across all those areas again, including today, payers, which is very exciting. And we have added on to our mission statement one word that we will discuss today, which is very exciting, which is “accessibility”. After our five-year anniversary and even slightly before then, we decided that we really feel that we have been able to contribute, as a community, to accelerating the development and approval of these tests. But, in actuality if we don't get them into patients' hands, what is the point of all of our hard work? So, we added the word "accessibility." Today, we have these 66 different organizations that collaborate, essentially, to compete. They’re pulling together projects and deliverables in about ten different working group areas to contribute products to the liquid biopsy community to help accelerate those three things.
Dr. Rafeh Naqash: Thank you for explaining that. That seems like a very important initiative.
Now, when you say that you’re contributing data, does it mean that different companies and entities are contributing patient-level data so that you can pool that and assess what is the utilization, what is the utility, what is the payer-related aspects, coverage aspects. Is that all part of the initiative?
Lauren Leiman: It is. We started with the idea, which is kind of scary, I think, for a lot of different companies: Are you willing to submit your protocols essentially, pre-analytical data? I think, much to the FDA's surprise, I was kind of, “Of course, everyone should be willing to do this, they should absolutely do this, it’ll be really exciting. Why wouldn’t they?” And I think others were a little skeptical that these companies who are highly competitive including Emma's company, Guardant, would be willing to contribute data. And in fact, Guardant is probably one of the first ones, first two at the table to actually submit their data which was just extremely exciting. And the data was around mostly protocols and pre-analytical variables, what tube types are you using? As we moved on, our pharmaceutical partners did submit full clinical trials with deidentified patient data, which was extremely exciting.
Today, our Data Commons sits in two different areas or visibilities for our members. One is membership-only data that only our members can see, so have been been contributed by them potentially sometimes for certain projects we’re working on. And then we also have an open segment of our Data Commons that’s open to the public, that includes published data and studies that anyone can take a look at and see. Our goal is to continue to open up all of our data over time, so that anyone can take a look at it. We are, I think, the leading liquid biopsy repository.
As we move into the future though, I think because we are mostly an organization that has pharmaceutical companies and diagnostic partners, we are company driven, aggregating large sums of research data is not necessarily their goal. And so to try to identify an area of mutually beneficial interests for everyone, I do think that over the next year or two, you’ll see a potential shift or pivot in the use of Data Commons to where the industry is today which is probably, hopefully a little bit more coverage focused. How do we pivot from being a source of aggregated research to a source of identifying and approving the value of liquid biopsy to the full community? And again, that’s for the full spectrum all the way through payers and the coverage of these tests, which I do think would add a tremendous amount of value to everyone on the life cycle of this industry but would also add a tremendous amount of value for access in getting these tests into patients’ hands.
Dr. Rafeh Naqash: Of course, you importantly covered a bunch of different concepts. One is data democratization, which is extremely important in the current day and age for different people in the public domain if they have access to data, they can do a lot of interesting and important things and add to the overall understanding of what we know or don't know in this space of liquid biopsy utilization. And then, of course, the aspect of disparities and coverage assessments.
Now, going to Emma, for the sake of our listeners, some of them are trainees, and many of them are oncologists, perhaps many are patients. What is the current landscape for liquid biopsies? Where do we use them, and what are the general approaches and principles of where things stand?
Dr. Emma Alme: That's a great question, and it really spans the cancer care continuum. And I think the space where it's most established is in the advanced cancer stage for therapy selection. So that's where we actually have some even FDA approved assays for liquid biopsy, with Guardant 360 test being one of them. It's comprehensive genomic profiling to identify actionable biomarkers to get patients on targeted therapy. So that's where it's really been integral to precision medicine. And we're seeing an increase in utilization of liquid biopsy as the technology becomes more established. It's not just in cases where tissue is insufficient now. Most recently, we've seen NCCN guidelines and non-small cell lung cancer change for concurrent testing for liquid biopsies. So that's been an exciting trend in adoption.
And then as you move across the cancer care continuum, there's residual disease monitoring and response, where we can actually use ctDNA to look at a patient's response to therapy, even after surgery - is there still ctDNA there? Instead of just having imaging as an option, we can actually look sooner to see how the patient is responding and if there is still cancer present. So that's a really exciting place where we're seeing growth in liquid biopsy. And then moving even earlier, before a patient even has cancer, there's a tremendous opportunity for liquid biopsy in early cancer detection. I think that's something that has been previously discussed on this podcast and we see it a lot in popular media. But it's not just for multi-cancer, we have the opportunity for single cancer as well liquid biopsy tests in cancer screening.
That's a really exciting space, really thinking about the accessibility of these tests. Because a lot of cancer screening modalities today are hard for a lot of patients to access. And it requires going to a medical facility. So if the first step is a blood test, that really opens that up to communities that traditionally have been left out of screening. So I think there's a huge opportunity there, not just when we’re thinking about screening for cancers that don't have screening modalities currently, but also screening for those that do, where maybe a first non-invasive step can really open the door to patients who don’t have access.
So it's a long answer to say that, really, it's across the entire cancer care continuum. We see a lot of opportunity here for liquid biopsy to be a way to advance the field but also increase access for patients who have been left out of precision medicine.
Dr. Rafeh Naqash: I think access is definitely the focus here. And I can give you my example. So I do early phase drug development and I do a lot of research in liquid biopsies and ctDNA monitoring. In the center of care, I treat people with lung cancer also and there have been instances, probably about a year or a year and a half back, where a patient could not come to the clinic. The clinic wasn’t done and on my to-do list for that individual patient, I put in ctDNA testing just to remind me when I see the patient, to get it done. But the patient didn't make it to the clinic. Surprisingly enough, mobile phlebotomy was available. And later I came to know that this is something that can be done and provided to the patient at their home and you can still get the same results, which was very surprising in a good way. And it did help in making some treatment decisions for some patients who, sometimes in a state like Oklahoma, which is where I am based, we have a significant rural population and people drive six hours for some of our trials, especially the early phase trials. And then if you tell them, “Well, if you don't make this appointment, XYZ cannot get done,” it doesn't necessarily change things for them. So something of this sort definitely helps.
Now, going to Lauren, I noticed this interesting sentence in the article, "fork in the road," where you describe, based on the current practices and policies, in the direction that we're going in, we can either increase or deepen the divide and disparities or decrease it. Could you tell us a little bit more about what currently exists on the disparity side and how do you see us narrowing that gap in the near future and implementing something that is equitable?
Lauren Leiman: What's exciting about this paper is I think as we are talking about trying to condense this discussion down to something that’s really digestible for everyone in the community, there are six barriers that we’ve identified. And I also should start by saying the working group that we have within BloodPAC that wrote this paper is intended to look at two different areas. One is that broadly, liquid biopsy still isn't available for the majority of the population domestically here in the US so that’s a problem. In addition, it's clearly not available in underserved areas, and that's an even deeper divide. So we're kind of at this fork in the road because it's not broadly accessible to the majority of patients today. And so we have this moment in time where we're able to make a decision to bring everyone along with us, which is very exciting but also will take a lot of work. And these six barriers that the paper identifies, I think are very clearly articulated. They are: lack of uncertainty around test performance, the lack of familiarity with this technology, inconsistent payer coverage is an issue, mistrust of the medical establishment - especially in underserved areas, fear of discrimination in seeking this kind of technology, and the difficulty with terminology.
I think that the whole liquid biopsy community has a role to play in addressing these six areas. I think that BloodPAC, in particular, as a consortium and a collaborative process for 66 different organizations that work in the field, we have a role to play, most certainly in helping to address specifically some of these areas. We have working groups that specifically address reimbursement and policy, so that would obviously fall into payer coverage of these tests. We have working groups creating lexicons both in the molecular residual disease area, as well as our multi-cancer early detection areas. So creating terminology and lexicons that are consistent across the entire community and also digestible for patients, which is really important. And so mitigating these barriers is going to be a collaborative process across all stakeholders in the liquid biopsy field. And I think BloodPAC is uniquely positioned to address many of these because of our diverse stakeholders and membership, which is exciting. But I do think that this is the perfect moment in time now to start addressing these challenges, and we shouldn't wait much longer, as we think through how we can bring everyone along with us and make sure we're not leaving anyone behind.
Dr. Rafeh Naqash: As this entity or consortium, as you call it BloodPAC, has moved forward, this is a question for both of you, Emma and Lauren. Emma, I guess you can start. How were things five years back? What are some of the things that you have been able to achieve, and where do you potentially see the next five years?
Dr. Emma Alme: I think we have made a lot of strides on the coverage side when it comes to advanced cancer testing for liquid biopsy. By no means are we there by any stretch of imagination, but we're starting to see some coverage adoption, which does make a huge difference because at the end of the day, that’s so important to ensure equitable access. Especially when we're talking about a technology that has the potential to close some of the barriers in precision medicine because of the fact that you don’t need access to some of the medical facilities, as you pointed out earlier, rural patients don’t have access to. Because transportation is not necessarily a barrier here the way it is for some for some of these other treatment aspects. But if you don’t have consistent pay or coverage, that’s a place where you’re really going to see drop off in terms of patients not getting equitable care and not getting standard of care as liquid biopsy enters into that realm.
The increase we've seen in private payers adopting coverage, the way we see Medicare coverage for advanced cancer liquid biopsy, is encouraging. We've seen states adopt legislation to require coverage of biomarker testing, that’s passed in 15 states now, thanks to the work of the American Cancer Society and a broad coalition of stakeholders. I think that’s beginning to make a difference, but we have a long road to go. We still, on the MRD side, that’s just emerging. And so one space where we have some recommendations on this is continued evidence generation - continue to gather that clinical utility data that will support payer adoption increasing on the advanced cancer side, but then moving across that cancer care continuum to those other types of liquid biopsy tests. I think that’s hugely important and there’s a role for BloodPAC to play in that as well, especially in making sure that we bring everyone to the table to have these conversations on what is the evidence that, we need to generate, what should that look like, what are the standards to ensure that everyone feels confident in these tests. That’s one area that we’re really excited to see.
And I also think another space is on the diversity in clinical trials. It's so important to make sure that when we are bringing these tests to market, the data that we gather to support that is representative of all patients who can benefit. It is so important to make sure that the tests work, but also to build confidence in all of the people who are going to get these tests and feel like, “Okay. I know that this test works for patients that look like me, too.” And so that is something that at Guardant we are working really hard on. We read out our clinical trial, ECLIPSE, for our blood based test screening for colorectal cancer a little over a year ago, and we were really happy to be able to say that our trial was representative of the US population, particularly for Black Americans, where colorectal cancer incidence is increasing, 30% to 40% higher rates of mortality, in Black patients than White patients for CRC. So it’s especially important to make sure that the population is representative in the clinical trial of the patients who will benefit.
And I think we are seeing companies increasingly realize their responsibility in that space and it’s something that we can all really prioritize moving forward with things like making sure transportation is accessible to patients, making sure that clinical trial materials are accessible, culturally sensitive in a broad set of languages. There are a lot of different activities. You have mentioned mobile phlebotomy earlier, that can be incorporated into trials working with community centers and not just academic medical centers to ensure that the trials are taking place close to where patients live and work. This is a tractable problem and I think we’ve made a lot of headway in the five years. But looking to the future, there's still a lot more we can do together to ensure that work continues.
Dr. Rafeh Naqash: All excellent points. And I completely agree with you. Bringing the trial to the patient is more important and likely to lead to better outcomes than the patient driving six hours to a facility to come on for trial.
So, the question for Lauren that I have from a physician or scientist standpoint, is what gets covered or does not get covered is not necessarily that I know about in my daily clinic of 15-20 patients. What is the difference between different states having different coverage policies for something like this? If it's the same payer in state A and the same payer in state B, why is the coverage policy in state B different from that in state A? And what are some of the things we can do locally and at a national level to help bridge some of these disparities and gaps?
Lauren Leiman: I'm going to hand that question over to Emma. This is her bread and butter.
Dr. Emma Alme: That is such a great question, and I wish I had a more satisfactory answer for you. The reality is that when it comes to diagnostics, coverage is really a patchwork, compared to when we think about drugs whether it’s FDA approved, we expect to be covered. With diagnostics, it's really up to the insurer. And I keep going back to the advanced cancer space because that’s where we see the broadest coverage because it has been around the longest. But we see broad coverage from Medicare for these types of tests. But, for private payers, it's really a patchwork. We see a lot of payers only just starting to cover these tests, maybe where there's a CDX indication with an FDA-approved drug we see it, but not more broadly for tumor profiling. Especially not for the larger, more expensive comprehensive genomic profiling panels that are more expensive. I think you can extrapolate the obvious reasons why that might be. But, as this is being moving into NCCN guidelines, we see very slow adoption by some private payers.
And you touched on the legislation in different states. This coalition on American Cancer Society has been spearheading is trying to pass state-level legislation that will align coverage with a strong, robust set of evidence, and that’s an FDA-approved companion diagnostic indication, medicare coverage, whether it's an NCD National Coverage Determination, a Local Coverage Determination, or National Clinical Practice Guidelines like NCCN, so really a robust set of evidence. And so this is resonating with state legislators across the country where we are seeing that take off in 15 states. But the political climate is different in different states so there are differences in terms of which state will adopt this, some of the differences are in language that they put into this. But even now that these are passing, we're seeing differential implementation, some plans are not necessarily reading this legislation and saying, “Okay, I have to cover all the tests that Medicare covers.” They are thinking that maybe they have some agency to put on other medical necessity criteria. So I think there’s a lot that will play out on the individual state level to see how this nets out. But it’s really kind of how different insurance companies and plans are interpreting these mandates, are interpreting guidelines, etc.
But you touched on the differences between the states and one of the things that has actually been shown in data from the precision medicine coalition is that even when you change insurance coverage for one individual plan, it doesn’t necessarily translate into adoption in the direct correlation that you would expect. And part of that is because it’s such a patchwork and it’s so chaotic. Providers don’t necessarily know for their patients which plan will cover, which one won’t. They’re very hesitant to subject their patients to out of pocket costs and so you get providers being reticent to order liquid biopsy just because of this coverage landscape. And so there really is that need not just to go step by step but get broader coverage for these patients across the board.
And so I think the long term vision is can we get to a change at the federal level. That’s hard compared to the state level. It’s a long road ahead. That’s why I started this with I don’t have a satisfactory answer. There is still a lot of chaos ahead even though we made some progress along the way.
Dr. Rafeh Naqash: I completely agree. Lots of things to do together. But, in my daily role as a physician or a scientist, I come across situations where a patient's situation was denied for liquid biopsy, then the company went and appealed or insurance doesn’t want to pay for it, and then they ask for peer-to-peer review, which is a lot of time and energy on the provider’s side, the physician's side, even for as simple as a CAT scan for cancer, let alone a liquid biopsy. I started thinking at that time, is there a scenario where if I were ordering a Guardant or a foundation or any liquid biopsy for that matter, can they not provide additional support where I don’t have to do a peer to peer and I can spend time and energy concentrating on the more important patient issues that are right in front of me, rather than having to wait for an insurance company to call me at a certain time of the day where I may or may not be available and then having to reschedule the call and spend another 30 minutes to them explaining. So I don’t know if you guys on the other side of the aisle also think about some of these issues, but could that be a scenario that could potentially be implemented in the near future?
Dr. Emma Alme: Yes, absolutely. This is something that we at Guardant think about a lot. One of the challenges is that, as a laboratory offering liquid biopsy, you are an ancillary provider, and so I think you touched on it, a lot of this role falls to you as the physician to secure prior authorization and to be the patient’s advocate. And not all plans – this is often true for Medicare Advantage – allow the laboratory to be the one to, for example, initiate prior authorization and provide the medical necessity information to make sure that that test is approved by the insurance company, and then to be the advocate for that patient in appeal process as you mentioned. And I think there is a lot of education that needs to happen among policymakers to make some tweaks to this process to ensure that the patient can have access, that the laboratory can be involved in the process where it makes sense, to smooth out this process.
And exactly right, I think you touched on a place where it is a huge burden for providers. There are places where the laboratory is best equipped to move the patient through that process and there's a lot of red tape that we can help overcome. And that's not specific to liquid biopsy. I think that's true across the diagnostics industry. But you're exactly right that it is another hurdle to access is if this is a process that has a lot of red tape. So I'm pleased to hear you think about this the same way.
Dr. Rafeh Naqash: I'm glad you guys are having those conversations, having conversations is the first important step to make a change in the near future.
If there's a patient listening out there and that patient has gotten a recent bill of $5,000 for liquid biopsy, what are some of the steps that you would like to highlight for them from a patient standpoint so that they can advocate for themselves? And should they talk to the physician in the company? Should they directly approach the company to not have that additional financial toxicity in situations where it may not be covered?
Lauren Leiman: I would 100% encourage those patients to please reach out to the company. I can only speak for Guardant but we have a patient access program. Our team calls any patient that's going to have more than $100 out of pocket because our goal at Guardant is to make sure that patients have access to the testing they need to inform their treatment and get the best possible care. I think we're all aligned across these companies across both- like we want to make sure that we are lowering the burden for cancer patients. There's already so much stress on these patients initiating treatment. They don't need to have the added stress of battling insurance. So we're here to help and no patient should be on their own in that space. So please tell your patients to reach out to the company in those instances, but I would hope that they would already have gotten outreach from the company in the first place.
Dr. Rafeh Naqash: I often discuss with some of my colleagues about the financial burden of cancer care, unfortunately, that people tend to have. And I remember this scenario a couple of months back where a patient of mine, when I sat down in the clinic room, they had this big, thick folder with them. And after I finished the discussion about what was going on with the cancer, they said, "Could you help figure this out?" And they opened this folder. It had so many bills, and one of the bills was obviously a liquid biopsy bill. And that was my understanding, too, that there is a lot of resources available to these people. And eventually things worked out. The company took the cost of whatever was not being covered by the insurance. But again, you touched upon an aspect in the article about educating the physicians, the providers. I think definitely a lot of work needs to be done there so that the patients can advocate for themselves and the healthcare providers can advocate for the patients, too, like having those checks and balances and those resources present and in the institutions where these people get cared for or knowing what's the right way to channelize these issues and to whom within the companies, so that all of this gets taken care within a timely period, so that the patient doesn't come back with the same issue six months later, “I still have this bill,” that even if it's being sent to the patient or their family by mistake, it does add a lot of psychological pressure.
So I think a lot of things potentially need to be done in that space, and hopefully you guys are still doing that and continue to do that, make progress in that space to help mitigate and alleviate some of that patient level burden, which is extremely crucial in their care.
Lauren Leiman: I think what's interesting about what we're looking at now is BloodPAC is thinking through these financial challenges, the coverage challenges for someone who's probably made it to an academic center to access these tests to begin with. And so to go back a little bit in the conversation, I think there still are challenges, which I'd love to hear more about from the experience of a clinician. But we have talked about, does mobile phlebotomy access everyone? Is it capable of providing access for everyone? I don't know. There's new technologies that we are looking at, like home blood collection. Most of the companies that we work with right now, they're not getting enough quantity. The quantity isn't there. But is that something that we should be pursuing? Because as you've already said, people drive six hours, and sometimes you can't make that drive. And sometimes a mobile phlebotomy lab is not able to get those six hours away. There’s a limit on how far they can go. That's a huge challenge.
I'm also fascinated by the idea that if you were to eliminate coverage as an issue, so if we were to say we're offering tests for free, is there still the educational barrier, the understanding barrier that we are not putting enough emphasis on? I don't know the answer to that question. I think there is a large element to that, though. And I think that when you say education, I have asked colleagues, "Okay, guys, who are we educating? Are we educating the clinician on specific tests? Are we educating the community health worker somewhere else outside of an academic center? Are we educating the patients themselves? Do they need to really understand exactly what this kind of futuristic technology is and what it can do for them?" Those are a lot of permutations of what if, what if, what if, what is the barrier? And so to take a step back, the reality is for that big bucket of individuals that I talked about at first, yes, coverage is going to be the primary barrier for them. But if you were to remove that barrier for some individuals, I think you still have a lot of challenges left ahead of you, which is essentially what the paper is saying. But I think that that is the really big question that I still have in my mind. If we can eliminate coverage, what's left and how do we address it?
Dr. Rafeh Naqash: To that point, I would like to add also- you pointed out educational barriers and there's definitely educational barriers on the provider side also, physicians, whether it's academic or community, that's a different discussion altogether. And this is not just one example, but this is an example that I'm giving because there's several other examples similar I've seen where somebody gets a liquid biopsy done in the community setting, or maybe even in an academic setting somewhere else. And somebody like me who deals with some of these results, I do a lot of precision medicine, I do a lot of genomics, but that's not everybody's interest or forte. That's not something that everybody's necessarily interested in or I try to read each and every detail in a report and understand implications, and not everybody necessarily thinks that that's the best utilization of their time. And I have identified a lot of patients that have been in the system within our state or outside our state where liquid biopsy two years back showed a certain potential germline mutation with a very high variant allele frequency and never got any germline testing. And then I see the patient and I start connecting the dots and the patient gets germline testing done - patients is positive, children are positive, children get XYZ procedures done as part of surveillance or mitigation strategies to prevent future cancers, which again, prevention is cure. At the end of the day, you catch something earlier, as we all know, higher chances for cure.
So I think that part of education, we still need to do a lot more on educating the providers, the physicians, or making it somewhat easy, like is there a way that, well, if you have a potential finding of a germline mutation, let's say on a report, instead of just mentioning the potential of germline mutations, maybe we can go to the next level and offer free germline testing and free genetic counseling and make sure that you communicate with that provider versus the responsibility being on the provider or the physician that, “Hey, did you read this carefully? Did you miss something? Did you not miss something?” This is something I have come across and we’re actually doing a project right now looking at some of that and analyzing the data and the percentage is pretty significant, and hopefully, if and when the results of that project are published, you will understand how much of a difference it actually can make in the lives of patients and their families to catch something early.
Dr. Emma Alme: I think you raise a really good point and your example of germline testing along with tumor profiling is a good example of the kinds of questions that we'll encounter as liquid biopsy moves across that cancer care continuum. So I think we do have to be thinking about what kind of education will we be giving to providers for how they integrate, for example, MRD liquid biopsy testing with standard of care imaging, what does that patient management process look like? On the early cancer screening side, what happens when you get a positive test for a patient? What does that diagnostic workup look like? Especially when there isn't necessarily a standard of care screening pathway- isn't a diagnostic pathway. Whose responsibility is that? There are so many outstanding questions through how we think about provider education across this board that really will take all stakeholders together to really formulate what this looks like.
I think you raise a really good point. Right now, I think we all have more questions than answers, but I think it's an important place for us all to be working really hard on right now, to ensure that this doesn't roll out in a way where there is confusion, especially where the providers offering liquid biopsy, maybe primary care physicians who aren't necessarily, as you said, going to be well versed in the literature on liquid biopsy, thinking about these tests report the way that you are right now. There's a lot of work to be done there.
Dr. Rafeh Naqash: Absolutely. It was a pleasure talking to both of you about the science, logistics, and payer aspects. A couple of quick minutes on both of you as individuals. I like to start with you, Lauren, can you tell me briefly, what's your background? How did that background connect to what you're doing today? And what else have you learned in this process?
Lauren Leiman: Sure. I am Lauren Leiman. I’m the Executive Director of BlooPAC. My backgrounds are primarily in communications and business and developing collaborations that are mutually beneficial for all participants. I have worked in finance. I've worked in Africa for many years for an economist and really decided during that time that health care and health initiatives were really what interests me and ended up working in a melanoma foundation for many, many years, developing interesting collaborations between academic institutions and funding formats, and took that to the White House for the first White House Cancer Moonshot as the Head of External Partnerships, and work towards identifying collaborations between different government agencies and different companies, as well as straight corporate commitments to the Cancer Moonshot, which was “a decade of progress in half the time”, the mission statement.
And having worked in melanoma for a while and working at the Moonshot, I'd heard about this liquid biopsy technology. It's out there and I thought it was pretty cool. I have melanoma in my family, and was like, wouldn't it be really interesting if you could get your blood drawn and just tell me if I have melanoma as opposed to kind of scanning my body every six months? And my colleague Jerry Lee, at the time kind of dropped a ream of paper on my desk and said, “Read this.” So I'm neither MD nor PhD, I’m a lowly MBA, who went home and read through everything and came back and said, “You don’t have a science problem. You have the collaboration problem, you need to work together, you need to share your data and share your information, which was kind of the birthplace I guess for BloodPAC - could we again, aggregate our data, bringing together these experts in the field to help accelerate the development and approval and accessibility of these technologies. That is my background.
Again, an interest in things, going back to Africa and the time I spent there, I'm heavily interested in underserved populations, not just domestically but globally. My hope is that eventually BloodPAC starts really engaging in how do we increase access for all to these really exciting new tests? I do receive, BloodPAC and I as the executive director, receive calls probably once a month from different startups around the world saying, “Good luck with all your $500 test. I want a $5 test, how are we going to get there?” Which you know, I think is the absolute goal for everyone. But slowly but surely, I think we are going to work towards increasing access for all not just domestically here and not just underserved populations here in the US, but hopefully locally as well.
Dr. Rafeh Naqash: Thank you, Lauren. Same question to you, Emma. Could you tell us about your background and how it led to your current work and some of the things you learned?
Dr. Emma Alme: Absolutely, my background began on the science side. I did a PhD in biochemistry at UCSF University of California, San Francisco. About halfway through my PhD, which I think is a realization many have, I discovered that I loved talking about science and thinking about science and reading about science, but it would be okay if I didn't have to pick up a pipette again. At the time, I was so invigorated by all of the research going on around me but realized that, similar to what Lauren said, it wasn't the science that was the barrier in a lot of cases of this research really reaching patients and changing their care. There were so many policy barriers that were standing in the way of that that I felt like I really wanted to help tackle and so I was fortunate in the fact that there are a lot of fellowships out there for PhDs in science to move into policy roles and serve as science advisors, so I did a smattering of those all around DC. I worked at the National Academy of Science. I worked at NIH and then I went to Congress, where I was a Health Policy Fellow for Anna Eshoo and got to interact with so many different companies in the biotech space and learn about all of their amazing technology, including liquid biopsy that folks were working on where there again, were so many barriers to adoption, where there were policy solutions, and I got really excited to work on that. It was the perfect nexus of my background and biochemistry and genetics and health policy.
And so the opportunity came up to work on policy for Guardant who was really thinking about those issues. And so I jumped at the chance to spend all of my time thinking about how do we increase access for patients? How do we make sure that this innovation actually gets into their hands through changes in coverage and reimbursement? And also thinking about most of the things that we've been talking about today - diversity in clinical trials, how we brought in education for patients and providers. So it's been a really exciting space to work in. It's been super fun to get to help the Guardant work with BloodPAC and I think it's an amazing group of collaborators that brings me a little bit back to my academic roots in terms of enjoying the kind of conversations that all these folks have together as we think about standards. That's been a really exciting place for me to sit in the health policy world combining all of that experience together.
Dr. Rafeh Naqash: Thank you so much. It looks like all of you within the BloodPAC and perhaps outside the BloodPAC are people driven by a common vision and mission and hopefully will succeed in all of those things that you're trying to achieve. Thank you for giving us the opportunity to talk to you guys and thank you for publishing in JCO Precision Oncology. Hopefully we'll see more of your work with regards to implementation and some of the next steps that you're taking and perhaps even the data for some of these studies that you're combining together, within JCO Precision Oncology in the near future.
Dr. Emma Alme: Thank you so much for having us.
Lauren Leiman: Thank you.
Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don’t forget to give us a rating or review and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guests’ statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Leiman COIs:
Stock and Other Ownership Interests:
Company: Illumina
Company: Eli lilly
Alme COIs:
Employment:
Company: Guardant Health
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Company: Guardant Health -
In this JCO Precision Oncology Article Insights episode, Mitchell Elliot provides a summary on "Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial," by Krop, et al published on January 18th, 2024.
TRANSCRIPT
Mitchell Elliott: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Mitchell Elliott, an ASCO Journal Editorial Fellow. Today, I will be providing a summary of the article titled "Prediction of Benefit from Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial" by Dr. Ian Krop on behalf of the APHINITY Steering Committee and Investigators.
HER2 epidermal growth factor receptor 2 positive, or HER2 positive breast cancer is characterized by overexpression of the HER2 protein. HER2 is an extracellular receptor that binds with itself and other proteins on the cell surface to facilitate rapid growth and division of cancer cells. Historically, HER2 positive breast cancer carried a worse prognosis than other subtypes. Anti-HER2 therapy with the monoclonal antibody trastuzumab in combination with chemotherapy has been shown to significantly improve clinical outcomes. Pertuzumab, another anti-HER2 monoclonal antibody, binds to a different site on the HER2 protein and has been shown to further disrupt HER2 signaling and improve clinical outcomes.
Primary results from the APHINITY trial, this trial, served as the basis for dual HER2 blockade, combining trastuzumab and pertuzumab with chemotherapy in the adjuvant setting. This data helped establish dual HER2 blockade as the standard of care in many jurisdictions around the world. Understanding patients who do not derive benefit from the additional anti-HER2 therapy is paramount for delivering personalized and effective care while minimizing treatment-related side effects. Understanding the underlying biology of patients who do not drive a response may provide insight into areas of future drug development and integration of novel therapies into future clinical trials.
The clinical definition of HER2 positivity encompasses those that are most likely to have HER2-driven tumors, but previous work has demonstrated that this clinical-pathologic definition does not accurately reflect the molecular heterogeneity of this subtype. These authors completed a translational secondary analysis of the phase III APHINITY trial using nested case-control methods with RNA-seq data derived from primary tumors of patients enrolled in this trial. Both the MammaPrint and Blueprint classifiers are commercially available assays run on microarray data using previously published and validated gene sets. MammaPrint classifies tumors as high or low risk, while Blueprint classifies tumors into luminal, basal-like, or HER2 subtypes. Luminal A tumors are MammaPrint low risk luminal classification, while luminal B tumors are classified as MammaPrint high risk with conventional luminal classification.
In order to facilitate these analyses, RNA-seq data was converted into pseudo microarray-based sequencing using a bridge study from an independent cohort of 75 patients. Conventional Blueprint scores for luminal type, HER2 type, or basal type were calculated for each sample. The subtype with the highest score of the three was the conventional subtype reported for the tumor. The Blueprint subtype was further sub-stratified as a single-activated or dual-activated subtype. Single-activated samples represented the dominant enriched pathway in each tumor, while dual-activated subtypes were assigned if there was no statistical difference between the two dominant pathways.
The primary endpoint was invasive disease-free survival, IDFS, and was stratified by genomic subtype and treatment arm. IDFS was defined as the time from treatment random assignment until the date of first recurrence of ipsilateral invasive breast tumor, recurrence of ipsilateral local-regional invasive disease, distant disease recurrence, contralateral invasive breast cancer, or death from any cause. Patients without an event at the last follow-up date were censored. The median follow-up time was 45.4 months. 964 patients were evaluated for MammaPrint and Blueprint subtypes. One patient was excluded as they were low risk by MammaPrint. The final cohort included 963 patients in this nested case-control study with IHC/FISH-defined HER2 positive tumors. Two-thirds of the patients were hormone receptor positive. Most patients were over the age of 35, 83% had lymph node involvement, and 83% of patients received anthracycline-containing chemotherapy.
Blueprint classified 50% of patients as luminal B type, 28% as HER2 positive, and 22% as basal type. Most of the luminal B tumors were single-pathway activated, while only around 50% of HER2 type and basal type tumors had single-activated pathways. Similar clinical and treatment characteristics were observed between the conventional Blueprint subtypes as well as the single and dual-activated subtypes.
Nested case-control inverse probability-weighted corrected multivariate Cox regression analysis revealed no significant difference in IDFS among the different conventional Blueprint subtypes. Conventional Blueprint subtypes were also not prognostic of benefit from the addition of pertuzumab. The authors then investigated whether there was a significant difference in IDFS in patients with only single gene pathway activation. Interestingly, patients classified as Blueprint basal single-activated subtypes were more likely to have an IDFS event, with a hazard ratio of 1.69 and a 95% confidence interval of 1.12 to 2.54. This captures the worst prognosis of molecularly defined basal-like tumors, remembering that all of the patients included in this cohort were, by ASCO-CAP guidelines, HER2 positive. In comparing the benefit from the addition of pertuzumab amongst the patients with single-activated subtype, there was no significant improvement in IDFS events with the addition of pertuzumab. There was a non-significant numerical benefit with the addition of pertuzumab in HER2 single subtype, suggesting that patients with dominant HER2-related signaling may derive more benefit from this combination therapy.
To help account for confounding variables, multivariate analyses were pursued to correct for routine clinical factors such as age, nodal status, hormone receptor status, as well as the use of anthracycline in addition to the conventional and single-activated pathway subtypes. Of all the clinical factors included in these analyses, only nodal status was significantly associated with IDFS in all of the conventional and single-activated subtypes. This reflects the important consideration of both clinical and genomic risk in patient assessment, as both have strong implications on treatment outcomes.
In summary, Blueprint HER2 tumors, which consist of both single and dual pathway-activated tumors, did not clearly distinguish those who derived pertuzumab benefit. There was a further non-significant benefit noted in HER2 single pathway-activated tumors. This suggests that tumors with multiple mitogenic pathways may have an inferior response to HER2 targeted therapy compared to single-activated tumors.
Overall, this article presents further insight into the molecular heterogeneity within the clinical-pathologic defined HER2 positive breast cancer subtype. The use of a commercially available gene signature assay was able to distinguish a subset of patients with a worse overall clinical outcome regardless of treatment received. Further analyses are required to validate and assess the utility in deploying this strategy in the treatment of patients with early HER2 positive breast cancer, but there is a suggestion that the 80-gene signature may refine patient selection, optimize treatment planning, and improve long-term outcomes for this patient population.
Thank you for listening to JCO Precision Oncology Article Insights, and please tune in for the next topic. Don't forget to give us a rating and review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO PO author Dr. Eric Klein shares insights into his JCO PO article, “Performance of a Cell-Free DNA-Based Multi-Cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancers” Host Dr. Rafeh Naqash and Dr. Klein discuss how a multi-cancer detection test may facilitate workup and stratification of cancer risk in symptomatic individuals.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.
Today, we are excited to be joined by Dr. Eric Klein, Emirates Professor and Chair at the Glickman Urological and Kidney Institute at the Cleveland Clinic Lerner College of Medicine. Dr. Klein is also a distinguished scientist at Grail and author of the JCO Precision Oncology article titled "Performance of a Cell-free DNA-based Multi-cancer Detection Test in Individuals Presenting with Symptoms Suspicious for Cancer."
Our guest's disclosures will be linked in the transcript.
For the sake of our conversation today, we'll refer to each other using our first names. It's great to have you here today, Eric, and welcome to our podcast.
Dr. Eric Klein: Thanks, Rafeh. I'm happy to be here.
Dr. Rafeh Naqash: So today, we're going to try to delve into this very interesting paper. We've had a couple of very interesting podcasts on liquid biopsies, or plan to have a few more. And this is a different aspect of liquid biopsy assessment, and the context here is early cancer detection. Now, the story as it starts, is based on the methylation profile of cancer. Can you tell us, for the sake of our listeners, as we have a very broad audience ranging from trainees to community academic oncologists, what do you understand by methylation profile on a cancer?
Dr. Eric Klein: Sure. Happy to start with that. There are lots of cancer signals in the blood. Cancer cells secrete or otherwise supply the bloodstream with DNA that has methylation signals that are specific to cancer. That's a hallmark of cancer-specific mutations. You can look at chromosome fragments, you can look at proteins and mRNA and exosomes and that sort of thing. In Grail's development study, we focused on using methylation because that, as I mentioned, is a fundamental process. A fundamental property of cancer cells is altered methylation. And in our original development studies, that was the strongest signal, the one that allowed us to have the lowest limit of detection when cancer was present, and the one that allowed us to have the best predictive accuracy for the cancer signal origin. Some people think about that as predicting the tumor origin or the tumor type. And that's the basis of Grail's assay, a pan-cancer methylation profile.
Dr. Rafeh Naqash: Excellent. And now to understand some of the methodology that you used here, before we go into the details because there's a lot of sensitivity and specificity obviously associated with any cancer detection test, and you want a high sensitivity and specificity. And the idea here is that this would help in triaging patients appropriately using this non-invasive tool. Could you tell us the patient population that you were trying to enroll in this study? And I think there is, again, background to other studies that you have done using the Grail test. Could you put that into context of this specific study?
Dr. Eric Klein: Sure. The population in this particular publication was from substudy 3 of a much bigger study called the Circulating Cell-free Genome Atlas, or CCGA. That was a discovery, refinement, and validation study of this methylation-based signal. And in total, all three substudies together was about 15,000 people, and it was a case-control study. About 10,000 of the individuals enrolled had cancer and about 5000 were not known to have cancer and served as controls. In the first part of the study, substudy 1 of CCGA, we simply asked the question: In individuals with known cancer, could we detect a methylation-based signal? And the answer was ‘yes’. The second question was: In patients not known to have cancer, did we not see a signal? And by and large, the answer was ‘yes’. The second substudy was a refinement and validation of the original methylation-based test. And then this study, what we refer to colloquially as CCGA3, or substudy 3 of CCGA, was the final validation that underlies the methylation assay that is currently on the market.
So, in CCGA3, we determined what the performance characteristics of this test were in a case-control fashion, and what we found, importantly, was that the specificity was very high, at 99.5%, which means the false-positive rate is only half a percent. We found that the overall sensitivity for detecting cancer varied by stage, but when you included all stages 1 to 4, the overall sensitivity for detecting known cancers was about 51%. We found that the ability of this methylation-based test to predict the correct cancer signal origin was right around 90%. And finally, the final performance characteristic was really important, which is the positive predictive value. So in individuals who had a positive signal detected, the positive predictive value was 43%, which compares very favorably to existing screening tests, all of which are below 10%.
That was the background, and the development there was focused on eventually developing a test that will screen the general population, the asymptomatic population, at risk for developing cancer. This is a subset of CCGA3, or the substudy 3 of CCGA, where we looked at the performance characteristics of this test in individuals who had symptoms that could possibly be due to cancer and individuals who had underlying medical conditions that could result in a false positive, and individuals in particular over age 65, because the risk of cancer goes up over age 65.
Dr. Rafeh Naqash: Thank you for explaining that. So, again, going to some of the finer details in this study, you mentioned some very important numbers here, 99%, 63%, or something in that range for sensitivity and specificity. Could you explain a little more on that based on the cancer types? As you mentioned, stage 4, when I read the paper, has more true positives likely based on or related to how much cell-free DNA is released in the tumor. The tumor burden may be playing a role there. Could you explain that a little more for our listeners?
Dr. Eric Klein: A cancer that sheds cell-free DNA into the bloodstream is more likely to be aggressive, and that's been shown in multiple different studies using multiple different platforms. And the reason for that is that the ability to shed cell-free DNA into the bloodstream goes along with biologic processes that we know are related to tumor aggressiveness. So that's a higher mitotic rate, it's neovascularization or the angiogenic switch, it's the ability to be an invasive cancer. And so the fact that you can detect cell-free DNA in the bloodstream implies some degree of biologic aggressiveness, which is not to say that tumors that shed cell-free DNA into the bloodstream are not curable. They are, in fact, curable at the same rate as cancers in people who are not tested for cell-free DNA. We know that for sure. It's just a signal that is there for us to exploit for the detection of cancers in asymptomatic individuals. And the hope is when we screen the general population, the general asymptomatic population for cancer, as we do with mammography and colonoscopy and PSA and so forth, that we can detect cancers at earlier stages, when they are far easier to cure. So I mentioned in CCGA3 that the overall sensitivity across all stages for detecting the presence of known cancers was 51%. That varied from about 16% for stage 1 cancers to 40% for stage 2 cancers to over 80 and 90% for stage 3 and 4 cancers.
Dr. Rafeh Naqash: Right. And again, to provide more background to this, what we've come to understand gradually, as you mentioned, is that shedding is an important event in cancer trajectory. Do you think detection of cancers that are likely positive, driver mutation positive, have a lesser tendency to shed and maybe resulting in lesser tendency to earlier detection also, or is that not something that's true?
Dr. Eric Klein: No, I don't think it has anything to do with the presence of driver mutations. The methylation signal that we see is a reflection of the perturbation of methylation in normal cells. So normal cells turn genes on and off using methylation. That's well known. Cancer cells exploit that biologic process of methylation by - in a gross oversimplification, but in a way that makes it understandable - they use methylation to turn off all the genes that prevent cell growth and turn on all the genes that allow cells to proliferate and get all these other biologic properties that make them invasive and so forth. So it's really important to understand that the test that was used in this study and that was developed in CCGA3 measures a shared cancer signal across multiple different cancer types. In CCGA3, we were able to detect more than 50 different individual kinds of cancers. It's a shared cancer signal that is fundamental to the biology of cancers, not just a specific cancer, but cancers.
Dr. Rafeh Naqash: I see. I think what I was trying to say, basically was, when we do liquid biopsies in the regular standard of care clinic, and you're trying to assess VAFs or variant allele frequencies for a certain mutation, you tend to see some of these BRAFs or EGFRs that are very low VAF, and the data that I've seen is that you treat irrespective of the low VAF, if it's a driving mutation process. If your VAF is 0.1%, you still treat it with a targeted inhibitor. The context that I was trying to put into this is it all depends on shedding. So this liquid biopsy that we currently use, whether other platforms that are out there, if you're not shedding as much cell-free DNA or circulating tumor DNA, you're probably not going to catch that subclone or clone that is a driver. So, does that play a role in your test also? If you have, let's say, a lung cancer that is an EGFR stage 4, if the shedding is low, following a general conceptual context that these driver mutation-positive tumors do have less shedding in general than the non-driver mutation-positive, would you think that would somehow impact the detection using your test or your approach?
Dr. Eric Klein: So, generically speaking, any test that looks for a cancer signal in blood is going to have a lower limit of detection. So there are analytic variables that make it such that, if you have extremely low levels of cell-free DNA or your other target shed into the blood, it's not going to be detected by the test. That’s an analytical issue. Having said that, it's important to distinguish the fact that this test that we're developing isn't really a liquid biopsy. A liquid biopsy, really, if you think about it, is on patients who have known cancer, and you’re doing a biopsy of the blood to determine if you can see a signal in the blood. This test has been developed to screen asymptomatic individuals who are at elevated risk of cancer, who actually may not have cancer. So we don't really view it as a liquid biopsy. But conceptually, you are correct that every test is going to have an analytical lower limit of detection so that not every tumor that sheds minuscule amounts of cell-free DNA will be detected. But that's not really relevant to this particular paper, I would say. It’s not really relevant to the performance characteristics that we saw in this population.
Dr. Rafeh Naqash: Understood. Thank you for differentiating the usual liquid biopsy approach that we use currently in the clinic, and this approach, which is meant more for detection in asymptomatic individuals.
Going to some of the results, could you highlight some of the interesting findings that you had in this paper as far as performance is concerned?
Dr. Eric Klein: Sure. Let me put it in a clinical context because we were just discussing asymptomatic individuals. That's what the test is ultimately meant for - screening asymptomatic individuals. But a common problem in oncology is this: patients present to primary care physicians with vague or nonspecific symptoms. Someone with COPD, for example, who presents with a cough, the cough could be due to the COPD, but if they have an underlying lung cancer, the cough could also be due to the lung cancer. Or someone presents with GI symptoms, could be related to cancer, or it could be related to a whole host of other things. And so there is a challenge for primary care physicians to sort out who might have cancer and who does not, particularly if they present with vague symptoms. In fact, most cancer diagnoses in the United States and Great Britain are actually found by primary care providers.
In this paper, we looked retrospectively, after the fact, in CCGA3, the case-control study that we did, to see how this methylation-based test performed in individuals who had symptoms that could be associated with cancer, or could be due to cancer, or might not be, might be due to other things. What we found was that the performance characteristics were as good or better in this symptomatic population, where the physician is facing a diagnostic dilemma, as they were in the asymptomatic population. This is really important, specificity false negative rate across all the patients in the study was the same as it was in CCGA3. It was 99.5%. Again, the false positive rate was only 0.5%. We found, however, that overall sensitivity was better in the symptomatic population, and it was 64% instead of, or as compared to 43% in the asymptomatic population. That is not surprising because some patients who present with symptoms are more likely to have cancer.
We also looked at a subset of patients who had GI cancers because that’s a very, very common presenting symptom in primary care practice, and this test performs exceptionally well for detecting GI cancers. We found that the overall sensitivity was 84%. Finally, and importantly, in terms of the clinical utility of a blood-based test to detect cancer and direct a diagnostic workup, what we call the clinical signal origin accuracy - the likelihood or prediction that a positive signal was related to a particular tumor type - overall accuracy in this population was 90%. So if you had a cancer signal detected and you had a clinical signal of origin assigned to it, let’s say, the test came back with cancer signal detected, the CSO prediction was GI cancer, the overall accuracy in actually finding a GI cancer was 90%. Actually, it was a little higher for GI cancers, but overall, for all cancers, it was 90%.
Dr. Rafeh Naqash: You mentioned that GI cancers had a very high sensitivity, around 84% or so. Is that, again, related to the tumor shedding compared to some other tumor types?
Dr. Eric Klein: Yes, there is a broad range of shedding across tumor types. So if you look at our data from CCGA, cancers like thyroid, prostate, and kidney do not shed a lot of cell-free DNA into the bloodstream, whereas GI cancers, hematologic malignancies, ovarian and pancreatic cancers shed much more cell-free DNA, and therefore their sensitivity for detection of those cancers is better.
Dr. Rafeh Naqash: What would be the alternate approach? Your sensitivity here is 64%, which is pretty good, but it's not perfect. So the patients who potentially would be missed using this test, what would be the alternate approach capturing those patients also and hopefully avoiding a missed cancer diagnosis?
Dr. Eric Klein: Well, it would be whatever the standard workup is that a primary care physician orders for someone who has vague symptoms. So, he idea here was to develop this, what we call a diagnostic aid for cancer detection in the symptomatic population. The idea here is to make the workups more efficient and to lend a greater degree of certainty as to what the diagnostic pathway ought to be. So, if you have a patient with vague symptoms and you're not sure if they are due to cancer or not, you might order a pretty broad diagnostic evaluation that might not end up finding cancer. In fact, if you take all the patients in a primary care setting, only about 7% of those individuals have cancer. Whereas, if you have a blood test that has a sensitivity of 64% and a positive predictive value of 75%, and you did that blood test early in the diagnostic workup and it was positive, you can do a much more tailored and perhaps a more efficient evaluation in speeding the diagnostic resolution.
Dr. Rafeh Naqash: As you mentioned, perhaps avoid unnecessary testing, which adds to the overall cost burden in the healthcare field.
Dr. Eric Klein: Correct. This was tested in another study called SYMPLIFY, which was done in a similar population of patients as this study - symptomatic patients presenting with vague symptoms or GI symptoms or weight loss, fatigue, those sorts of things, to primary care practice in the UK. And that was a prospective study. And the performance characteristics were very similar to what we saw in this study, although the overall positive predictive value in that study was 75% if you look at all cancers. And that would be very useful to a primary care physician and a patient to know what the likelihood of their having cancer is at the time they present or within a few days of presenting.
Dr. Rafeh Naqash: Absolutely. And perhaps, to complement this approach with some of the other diagnostic approaches, maybe the possibility of detecting cancer earlier increases. So this is likely complementary and not necessarily the one-stop-shop.
Dr. Eric Klein: It's important to understand that even in the symptomatic population, this is a screening test. And so, like all screening tests, if you have a positive mammogram that shows a nodule, you need to have a diagnostic workup to prove whether or not you have cancer. This blood test does not make the diagnosis of cancer; it simply helps direct a diagnostic evaluation that’s necessary to confirm whether or not cancer is present or absent. That’s true for both the asymptomatic and symptomatic populations.
Dr. Rafeh Naqash: Could you tell us a little bit more about the CSO prediction in the general context of oncology and NGS, or the whole transcriptome sequencing that we do these days? We often see on a report that says,“What is the likely tumor of origin?” if you have an unclear primary. Can you explain that in the context of the approach that you guys use for CSO prediction? How does it differ from methylation versus mRNA prediction of tumor of origin or cell of origin?
Dr. Eric Klein: Methylation has a rich signal in it, and it can distinguish cancer cells from a non-cancer signal, and using a second algorithm, specific methylation patterns that are specific to given lineages can identify lung cancer versus colon cancer versus liver cancer.
Dr. Rafeh Naqash: Understood. Do you see this as becoming an approach that could be used, using, for example, urine or other sources that we can easily acquire versus blood?
Dr. Eric Klein: Possibly. There is a lot of work in the field looking at urine-based markers for cancers, particularly, obviously, urologic cancers. And so there are already some products on the market made by other companies using methylation and other specific mutation patterns, for example, in urine to detect bladder cancer and to determine bladder cancer aggressiveness. It is an area of active investigation.
Dr. Rafeh Naqash: This is definitely an exciting field, and the way the entire field of liquid biopsies in general is moving as it’s detecting cancers or identifying mutations, and then implementing appropriate approaches, whether it is more screening or more treatment and all the drugs, etc.
Are there any other interesting future approaches that you guys are planning as part of this paradigm shift that I envision will hopefully happen in the next few years?
Dr. Eric Klein: Yes, as a company, Grail is focused on using this methylation-based technology across the entire cancer spectrum. So that’s screening asymptomatic individuals, it’s helping to direct diagnostic workups in individuals who present with symptoms to primary care practice, and also in the post-diagnostic space and all the possible uses there. So the detection of minimal residual disease and the decision on whether or not additional treatment is necessary, predicting response to particular therapeutic agents, or even choosing the correct therapeutic agents. All of that is under development.
Dr. Rafeh Naqash: Definitely exciting. Now, the last portion of this podcast is specifically meant to highlight your career and know a little bit more about you. Could you tell us about your career trajectory and how you shifted focus towards a biomarker-driven approach?
Dr. Eric Klein: Sure. Biomarkers have been a part of my career for a long time. I am trained as a urologic oncologist and did my residency in urology at the Cleveland Clinic and a fellowship at Sloan Kettering. At the dawn of the molecular biology era, the lab I worked in bought one of the very first PerkinElmer RT PCR machines for $5,000. It took up a whole desktop. I got very interested in genomic science at that time. So I spent well over 30 years practicing urologic oncology at the Cleveland Clinic, primarily focusing on prostate cancer. In the course of my career, I had the opportunity to work on a number of blood-based, urine, and tissue-based biomarkers. I have always been interested in understanding how our ability to measure molecules in blood and urine can help improve patient outcomes either through a streamlined diagnostic process or understanding of the biology of the disease better, picking the appropriate therapy, and so forth.
In the course of that, I worked with someone at a company called Genomic Health in developing a biopsy-based RT PCR gene expression assay that helped select men for active surveillance. That individual subsequently joined Grail and he came knocking on my door in 2016 when Grail was just getting started to tell me about this exciting new technology. He said, “This isn't about urologic cancers in particular, but would you be interested in helping us accrue patients for this big clinical trial we're doing, CCGA, and determine if this technology would be useful in some way in helping patients.” And being the curious individual that I am, I said, “Sure.” And so I helped accrue lots of patients to CCGA. The results were shared, and I was quite excited by them and continued to work with the company on other studies, including PATHFINDER and some others, and eventually became a consultant for them.
When I reached what I thought was the end of my clinical career by choice, I decided to step away from clinical practice, I had the opportunity to join Grail as a scientist, and that's where it’s been. And what I would say, in the big picture, is this: as a surgeon, I was able to help a lot of patients on an individual basis. So I did about 10,000 major cancer operations in my career. So I helped those 10,000 people. As an academician, I was able to make certain observations and publish them in a way that taught people about different kinds of surgical techniques and how they may work better, and so I was able to expand my impact beyond the patients that I actually touched.
When I heard about and understood what Grail was trying to do, I thought, “Wow, if we could develop a screening test that detects lots of cancers that we don’t screen for - about 70% of all cancer deaths in the US are from cancers that we have no screening tests for - and if the screening population in the United States, individuals between ages 50 and 79, that’s how CMS defined screening populations, well over 100 million a year, if this works, think about the impact that that could have.” That is really why I got excited about it. It fit my scientific interest, and I could see the big picture.
Dr. Rafeh Naqash: Thank you for giving us some insights about your personal career. It is definitely a very interesting topic. I learned a lot, and hopefully, our listeners will find it equally interesting. Thank you again for being here today.
Dr. Eric Klein: My pleasure. Thank you for having me.
Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to rate and review this podcast, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
The guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not reflect the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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In this JCO Precision Oncology Article Insights episode, Miki Horiguchi provides a summary on “Clinical Trial Diversity: A Bend in the Arc Towards Justice”, by Tannenbaum, et al published on September 19, 2023 in JCO Precision Oncology. The editorial discusses the need for inclusion of under-represented groups in clinical trials. See the accompanying Original Report, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP),” by Vaidya, et al as well as an interview with co-author, Dr Mary Redman.
TRANSCRIPT
Hello and welcome to JCO Precision Oncology Article Insights. I’m your host Miki Horiguchi, an ASCO Journals Editorial Fellow. Today, I will be providing a summary of the article titled “Clinical Trial Diversity: A Bend in the Arc Toward Justice” by Drs. Susan Tannenbaum and Jennifer Miller. This editorial accompanies the article “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP)” by Dr. Vaidya and colleagues.
In the previous episode of this series, our Social Media Editor, Dr. Rafeh Naqash, interviewed Dr. Mary Redman, a Senior Author of the Lung-MAP article. Dr. Redman shared the background behind the Lung-MAP development, some highlights from her paper, and her career trajectory as a biostatistician. I strongly recommend listening to the interview if you haven’t done so. To begin I’ll provide a brief summary of the Lung-MAP information before discussing the editorial.
The Lung Cancer Master Protocol or Lung-MAP is a biomarker-driven master protocol that evaluates multiple molecularly targeted therapies for patients with advanced non-small cell lung cancers under a single trial infrastructure. Since Lung-MAP began enrolling patients in 2014, it has addressed the challenges of implementing precision medicine at oncology clinics and assuring equitable patient access to molecularly targeted therapies. In addition to meeting an unmet need in terms of treatment, Lung-MAP meets an unmet need in terms of accessibility to precision oncology clinical trials for all types of patients who get lung cancer in the United States. Specifically, Lung-MAP utilizes a public-private partnership that includes the National Cancer Institute’s National Clinical Trials Network, the SWOG Cancer Research Network, Friends of Cancer Research, the Foundation for the National Institutes of Health, Foundation Medicine, pharmaceutical companies, and lung cancer advocacy organizations. There are thousands of sites around the country that can offer Lung-MAP.
In the Lung-MAP article, the authors sought to examine whether Lung-MAP improves access to precision oncology clinical trials compared to conventional standalone trials. To this end, the authors compared accrual patterns by sociodemographic characteristics between Lung-MAP and a set of ten clinical trials for advanced non-small cell lung cancer conducted by the SWOG Cancer Research Network. The authors found that patients enrolled in Lung-MAP were more likely to be older, from rural or socioeconomically deprived areas, and with Medicaid or no insurance compared with conventional clinical trials. However, female patients and patients of Asian race or Hispanic ethnicity were underrepresented. The authors emphasized in their conclusion that further research examining participation barriers for underrepresented groups in precision oncology clinical trials is warranted.
In the associated editorial with the Lung-MAP article, Drs. Tannenbaum and Miller discuss some efforts to include diverse populations in clinical trials such as those of Lung-MAP and the continuing challenges we are facing.
The editorial begins with a striking example of an industry-funded trial, where pharmaceutical companies submitted a new drug for US Food and Drug Administration approval to treat patients with non-small cell lung cancer in the United States. However, the pivotal trial was conducted wholly in China, enrolling significantly younger patients than those with that type of cancer in the United States. There were no Black nor Hispanic-identifying patients and far more men than women in the trial. The product was not approved by the US FDA. Although the US FDA has approved many other products where the trials were unrepresentative , this example suggests that in order to capture elements in future patient populations in the United States, study samples need to include patients from under-represented groups as well.
The authors also introduced a recent study result that showed racially and ethnically under-represented patients, and their clinicians, are more likely to trust and use new medical products when the trials have enrolled a diverse population. This fact suggests that clinical trials that include a higher proportion of women and older adults, as well as patients from racially and ethnically under-represented groups, help to gain acceptance for the drug even after its approval.
The authors then introduced some efforts toward enhancing clinical trial diversity, including the National Institutes of Health Revitalization Act of 1993, the Institute of Medicine’s 2003 report, the US FDA’s 2020 guidance, and the innovative public-private collaboration of Lung-Map. While several studies suggested that clinical trials funded by the National Institute of Health have improved enrollment of patients from under-represented groups, industry-funded trials have still fallen short of these goals. Since industry-funded trials play a crucial role in developing novel drugs, industry must be held accountable for clinical trial diversity and make greater efforts to improve the situation. The authors introduced additional guidance toward this end. They include the US FDA’s 2022 new draft guidance to industry, recommending that sponsors of clinical trials submit a Race and Ethnicity Diversity Plan. Another is the Food and Drug Omnibus Reform Act of 2022 where the US FDA can require sponsors to have plans that include diverse populations in their clinical trials. These efforts are pivotal steps in the direction of making biomedical research more accessible and inclusive and lead to promoting health equity across the country.
Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. Don’t forget to give us a rating or review and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.
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JCO PO author Dr. Amit Mahipal shares insights into his JCO PO article, “Tumor Mutational Burden in Real-world Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.” Host Dr. Rafeh Naqash and Dr Mahipal discuss real world evidence of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma.
TRANSCRIPT
Dr. Rafeh Naqash: Welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center, University of Oklahoma. Today we are joined by Dr. Amit Mahipal, Professor of Medicine and Director of GI Oncology at the Case Western Reserve University in Seidman Cancer Center. Dr. Mahipal is also the author of the JCO Precision Oncology article titled "Tumor Mutational Burden in Real World Patients with Pancreatic Cancer: Genomic Alterations and Predictive Value of Immune Checkpoint Inhibitor Effectiveness."
Our guest disclosures will be linked in the transcript. For the sake of this conversation, we will refer to each other using our first names. So Amit, welcome to our podcast and thank you for joining us today.
Dr. Amit Mahipal: Thanks for having me here.
Dr. Rafeh Naqash: Excellent. We came across your article in JCO Precision Oncology and it really aroused my interest because the topic and the audience that it caters to is very important in the current times. Because immunotherapy generally is considered- pancreas cancer the graveyard in immunotherapy in essence, based on what I have seen or what I have encountered. And now you're the expert here who sees people with pancreas cancer or has done a lot of work in pancreas cancer research side. So can you tell us the context of this work and why you wanted to look at immune checkpoint inhibitors in pancreas cancer?
Dr. Amit Mahipal: Absolutely, Rafeh. As you mentioned, pancreatic cancer is considered a what we call "cold tumors." They don’t typically respond to immunotherapy. And when we talk to our patients or patient advocates, as you know, patients are very excited about immunotherapy. Immunotherapy has transformed the treatment for a lot of different cancers and not only has increased survival, but the quality of life is so much different than with chemotherapy. This work came from based on the KEYNOTE-158 trial, which was a tumor-agnostic trial which accrued patients who had TMB high tumor. What that means is that tumor mutation had more than 10 mutations per megabase. And what happens is because of that trial, more than 200 patient trial, the FDA actually approved this immunotherapy or pembrolizumab as a single agent pembrolizumab for any patient with a solid tumor who has high TMB. Again, tumor mutation burden, more than 10 mut/Mb.
This question comes in now. Does this apply to our pancreatic cancer patient groups? Especially as we know these are "cold tumors" that typically do not respond. There have been multiple trials looking at immunotherapy, single agent, dual immunotherapy agents, as well as combinations with chemotherapy, with somewhat very, very limited success. So that was kind of the basis. So we wanted to look at this retrospective kind of review of a big database to see how many patients we can find who have high TMB and see in that patient population is immunotherapy really active based on the FDA approval or is pancreatic cancer not a tumor where we should try immunotherapy unit as a selective group.
Dr. Rafeh Naqash: Thank you for that explanation. Taking a step back again, since you see these individuals with pancreatic cancer I imagine day in and day out in the space of drug development, what is the general current standard of care approach for individuals with pancreas cancer in your clinic? I'm talking about what are the most common approaches that you utilize that seem to be working or have FDA approvals in the pancreas cancer space.
Dr. Amit Mahipal: As with any tumor, the first thing is obviously staging. So depending on whether we're dealing with early stage or advanced stage and what are the goals of treatment. At this point, the only thing that can cure pancreatic cancer patients that would be considered conventional therapy is surgical resection. So any patient who is a candidate for surgical resection is in a different bucket compared to advanced patients. For early stage patients, we try to do what we call neoadjuvant treatment or neoadjuvant chemotherapy. We shrink the tumor or at least maintain it, look at the biology of the disease, and then take them to surgery, which typically involves a Whipple procedure if it's a head of the pancreatic mass.
Moving on to advanced patients, that’s where we know the goal of treatment is palliative to increase survival, but unfortunately, most of the times we cannot cure them. And there the standard of care options include systemic chemotherapy. We have two typical regimens that we use, one is called FOLFIRINOX, which is a three-drug regimen of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan. And another regimen is gemcitabine plus abraxane, which is a two-drug regimen of gemcitabine plus abraxane. These are considered the standard of care. Unfortunately, the median survival even with the best standard of care chemotherapy is only about a year, 12-13 months, depending on what trials we look at.
Dr. Rafeh Naqash: I still remember some of these regimens from my fellowship, where we had to decide which to give to each individual based on their performance status and clinical status, etc. But now I can see a lot of ongoing drug development in the space of pancreas cancer. I'm guessing that's why you wanted to assess both the molecular genomic landscape of pancreas cancer in this study and also look at the immune biomarker aspect. Could you tell us a little bit about the Foundation Medicine Clinical Genomic Database? How did you identify the patients, how many patients did you identify, what you narrowed down in the criteria, and the eventual sample size of what you were looking at?
Dr. Amit Mahipal: FoundationOne has a rich database. They have two or three things. One is a genomic database only. So in our clinical practice, I think it’s some sort of next-generation sequencing or mutational testing for all patients with advanced solid tumors. All of these goes into their database. All of the samples that are sent to FoundationOne that goes into their database where they know the diagnosis of the patient and the know the sequencing results of these patients. In addition, they also have a clinical database called Flatiron. Basically, they collaborated with them. Flatiron has about 280 or so cancer clinics throughout the country, so a lot of community settings and some academic sites as well. They did not only have a genomic database, but they actually have a clinical database. They have demographics, clinical features, baseline clinical features, comorbidities, what kind of treatment they received, what would be the stage of the cancer, how many months of treatment they received, and their overall survival, and so on. So from that perspective, the FoundationOne has access to this partnership with Flatiron, clinical genomic database where they have both clinical data as well as genomic database for a lot of these patients.
In our study, we only focused on patients with advanced pancreatic cancer. We excluded a lot of patients who did not have sequencing results available, they cannot be performed due to lack of tissue. So the first we talked about the genomic database and we found about about 21,932 patients, so almost 22,000 patients and there we had the sequencing and we also had the data on TMB or tumor mutational burden. So here, we classified them into two groups: high TMB and low TMB. High TMB was seen in 1.3% of the patients, and about 98.3% of the patients had low TMB. Here we looked at the genomic alterations between the two groups. So these are like our genomic group, so to speak of about 22,000 patients. And among them, as mentioned, that the clinical data was available for about 3300 patients or 3279 patients to be exact.
After excluding some of those patients, we found about 51 patients who received immunotherapy. And when we say immunotherapy, it is single agent immuno checkpoint inhibitor like pembrolizumab or nivolumab. And then we classified them into high TMB versus low TMB and then we also looked at patients with high TMB and compared them to who received immunotherapy versus other therapies. Just to recap, we had about 22,000 patients where we have the genomic database and about 3300 or so patients who we have both genomic and clinical data for this patients. One of the key findings was that high TMB was present in only 1.3% of the patients, or about 293 patients out of 21,932.
Dr. Rafeh Naqash: Definitely an interesting sample size that you had utilizing this resource, which, of course, is more or less real-world. It is important to gather real-world outcomes that you did.
So, going to the TMB story of this paper, where you looked at immune checkpoint inhibitor use in these individuals, was there a reason why some of the individuals with low TMB were also given immune checkpoint inhibitors? From my understanding, I did see some checkpoint inhibitor use there. What could be the explanation for that?
Dr. Amit Mahipal: So this data is from 2014 to 2022. So from the span of about eight or so years. And as you know, immune checkpoint inhibitors were approved in the last decade. And there were a lot of not only trials, but even in the non-trial setting, people had tried immune checkpoint inhibitors in, frankly, different tumor types because of the success in some of the common tumor types, like melanomas, lung cancer, and so on. So I agree, as of today, we probably would not use immune checkpoint inhibitors in patients with low TMB or MSS. But at that time, I think that information was not available. So people with low TMB and MSI-stable tumors also received immune checkpoint inhibitors. But those numbers are again low. So it's not very high numbers.
Dr. Rafeh Naqash: Understandable. That makes it a little more clear.
Now, you looked at the TMB aspect. I'm guessing you also looked at the MSI aspect of PDAC. What is your understanding, or what was your understanding before this study, and how did it enhance your understanding of the MSI aspect of PDAC? And I'm again guessing, since TMB high individuals are on the lower side percentage, so MSI high is likely to be low as well. Did you see any interaction between those MSI highs and the TMB highs on the PDAC side?
Dr. Amit Mahipal: Yeah, absolutely. So we are very excited in general about MSI-high tumors for solid tumors because of their response to immunotherapy. Although I would do a caveat because we still don't know how MSI-high pancreatic cancer responds although there have been some real-world, very, very small series as well. In this study, one of the things is, is high TMB totally driven by MSI-high? That's a question that comes up, and TMB high may not matter. It's only the MSI-high that might matter. So definitely when we look at this patient population, we found that the patients who were 35-36% of patients who were TMB high also had MSI-high patients. So we do expect MSI-high patients to have a higher TMB compared to MSS patients. But there were about 66 or two-thirds of the patients who did not have MSI-high tumors and still had high TMB, as defined by, again, ten mutations per megabase. So we did see patients with MSI-stable tumors who had high TMB. And I think that was one of our biggest questions. I think MSI-high patients, we all tend to think that we would try immunotherapy even if it's in pancreatic cancer. I think what is not clear, at least from the real-world or any of the trial data, is if we were to give MSI-stable patients who have high TMB, if we give immunotherapy, are there any responses or any disease control that we see? And that was one of the reasons for this study.
Dr. Rafeh Naqash: Now, one of the things that comes to mind, and again, I think you based it on the FDA approval for TMB high, which is ten mutations per megabase, as you defined earlier. I do a lot of biomarker research, and oftentimes you come across this aspect of binary versus a linear biomarker, in this case being TMB, where about ten, less than ten. Do you think, in general, an approach where you maybe have tertiles or quartiles or a biomarker, or perhaps a better approach in trying to stratify individuals who may or may not benefit from immunotherapy?
Dr. Amit Mahipal: That's a great point. I think when we use ten mutations per megabase as a biomarker, as a binary endpoint, do we apply it to all tumor types? I don't think that's a fair comparison, frankly speaking. We do know that high TMB, even in different tumor types, do tend to respond a little bit better to or do have better outcomes for patients treated with immune checkpoint inhibitors in different tumor types. But what that cutoff is not known in most of the tumor types. And also, one of the problems is how do you measure TMB and is it standard across different platforms? Like I'm just giving some names like FoundationOne, Tempus, Caris, and some obviously like MSKCC and some other university-owned panels as well. And frankly, I think if you look at different panels and if you send the same tumor tissue, you will get different measurements. So I think standardization is a problem as well.
In one of the studies involving cholangiocarcinoma, for example, we found that a TMB of 5 was enough to have an additive effect of immunotherapy, same with chemotherapy, so to speak. But again, this needs to be validated.
So you're absolutely correct. I don't know why we use the binary endpoint, but on the same token, the binary endpoint is easy to understand as a clinician. Like, “Hey, someone has this, do this, not this.” And when we look into a continuous range, I think the benefit obviously varies between high and low, different tertiles, and becomes somewhat challenging. How do you classify patients and what treatments to give? So I think in clinical decision-making, we like the cutoffs, but I think in reality, I don't know if the cutoff is a true representation. And maybe with the more use of AI or computing, we can just input some values, and then it can tell us what the best treatment option might be for the patient. But that's way in the future.
Dr. Rafeh Naqash: That would definitely be the futuristic approach of incorporating AI, machine learning perhaps, or even digital pathology slides in these individuals to ascertain which individuals benefit.
Going back to your paper, could you highlight some of the most important results that you identified as far as which individual is better, whether it was immunotherapy, and you've also looked at some of the mutation co-mutation status. Could you highlight that for our listeners?
Dr. Amit Mahipal: So the first thing we looked at was the genomic database of almost 22,000 patients, and then we classified them into high TMB and low TMB, with about 300 patients in the high TMB group and the rest in the low TMB group. And what we found was, talking about again in the genomic database, that patients who have high TMB actually have low KRAS mutation. So if we think about KRAS mutation, pancreatic cancer, almost 85% or so of patients have KRAS mutation who have pancreatic adenocarcinoma. So patients in this subgroup, so in the high TMB group, only about two-thirds of the patients had KRAS mutation, compared to 92% of the patients with low TMB who had KRAS mutation. So just giving that perspective. So KRAS mutation, which is the most common mutation in pancreatic cancer and is a driver mutation, their rates vary differ from the high TMB group versus the low TMB group.
And then in addition, in the high TMB group, we found higher rates of BRCA mutation, BRAF mutation, interestingly, and then obviously from the DNA damage repair genes like PALB2 mutation, MSH2 or MSH6, MLH1, and PMS2. So all these mismatch repair protein mutations were higher. As I mentioned before, one-third of the patients with high TMB also had MSI-high. So it's not a totally unexpected finding. I think the biggest finding was that we found more KRAS wild-type pancreatic adenocarcinoma in the high TMB group, almost a third. And those tend to have different targetable mutations like BRCA2, BRAF, and PALB2 mutations. So I think one of the interesting findings is that patients in the high TMB group actually tend to have KRAS wild-type or less KRAS mutations. So they're not necessarily KRAS-driven tumors, and they have a higher chance of having other targetable mutations like BRAF and so on, for which we have therapies for. So it's always something to keep in mind.
Dr. Rafeh Naqash: Would you think that from a DDR perspective, the mutations that you did identify that were more prevalent in individuals with high TMB, do you think that this is linked to perhaps more DNA damage, more replication stress, more neoantigens leaning toward more tumor mutation burden perhaps? Or is there a different explanation?
Dr. Amit Mahipal: For sure. As we said, MSI-high tumors have mutations in the DNA damage repair pathway and they definitely tend to have higher TMB. So I don’t think that is very surprising that we found PALB2, or other MMR genes like MSH2, MSH6, MLH1, and PMS2 at much higher rates. I think the interesting finding is the fact that the KRAS wild-type and having BRAF alterations at least that’s not suspected to definitely increase TMB. Although if we look at colorectal cancer, BRAF mutation and MSI are somewhat correlated to patients with BRAF mutations and to have high rates of MSI-high tumors. But that’s not the case in pancreatic cancer. We also found an increase in BRCA2 mutations as well. So I agree that the DNA damage pathway repair gene alteration is not unexpected because they tend to increase TMB, but I think the other mutations were interesting.
Dr. Rafeh Naqash: And I think one other aspect of this, which I’m pretty sure you would’ve thought about is the germline implications for some of these mutations where you could very well end up screening not only the individual patient, but also their family members and have measures in place that we’re trying to enhance screening opportunities there. In your current practice, you are at an academic center but I’m talking about in general with your experience, how common is it to sequence broad sequencing panels in individuals with pancreas cancer? The reason I asked that is I do a lot with lung cancer and even now despite having all those targets in lung cancer which sort of paved the pathway for targeted therapy in many tumor types, we still don’t see a full uptake for NGS Phase I drug development. And I get a lot of referrals from outside and I often see that it’s a limited gene panel. So what is your experience with pancreatic cancer?
Dr. Amit Mahipal: We kind of changed our practice. Similar to you, I’m involved in drug developments. I’ve been a big proponent of NGS for almost a decade now, when didn’t even have targeted therapies but these companies first came in and they’re like, “Okay. We’re very very low chance.” But now obviously, we transformed the treatment for a lot of different cancers. Especially lung cancer, you don’t sometimes even start treatment before you get an NGS panel like you said in situ. So what we’re finding, at least for pancreatic cancer, as you know, the targetable mutations are there but they are somewhat not that common, I would say, in the 10-15% range. So many people would get dissuaded and then it’s like, what’s the point of doing it?
But I think for those 10% to 15% of the patients, firstly we can really change their treatment course and their prognosis. Secondly, if you don’t do it and they cannot go in a different clinical trials, now we have trials targeting KRAS G12C, but not only that, KRAS G12D which is the most common mutation we see in pancreatic cancer and so on. So it’s becoming very very important. One thing, at least with our practice we adopted last two or three years is sending liquid biopsies or liquid based NGS or blood-based NGS testing. Otherwise, what’s happening I would send a solid tumor NGS from the tissue. And pancreatic cancer as you know has sometimes a very small amount of tissue obtained from FNA. And inevitably after four weeks, we’ll get the result that there’s not enough tumor to do NGS testing. And then the patient comes one or two months later and then we order the test, and that just delays everything.
So now we adopted a practice where we are trying to send both blood based NGS and solid tumor NGS at the same time the first time of diagnosis when we see the oncologist for the first time. And that has really increased the rate of NGS testing results for our patient population. And it’s not 100%, even in blood-based NGS, sometimes they may not be able to find enough circulating tumor cells to do this blood-based NGS testing, but at least they’re having these. But you’re correct. I think we still see about one third of the patients who had not had NGS testing or referred for phase I clinical trial and have gone through more than two or three line of therapies which is unfortunate for our patients.
Dr. Rafeh Naqash: That's a very interesting perspective on how important it is to sequence these individuals. As you said, it may not be that all of them may benefit, but the ones that have those important alterations, especially BRCA, PALB, and KRAS could benefit from novel precision medicine-based approaches.
A question that came to my mind, I saw that you were trying to look at MYC and turmeric low tumors as well. So what is the role of MYC in the context of these individuals? Is there any drug development that’s going on? Because I see small cell lung cancer. MYC is an important target there. These are two different tumors, but it looks like there was a hint of some correlation with respect to some of the findings that you showed. Is that something that you’re currently looking at or planning to look at?
Dr. Amit Mahipal: I think that if we just talk about MYC in general, it is present at somewhat lower rate. I think we found MYC amplification in about 5% or so of TMB-low patients who had that and not really seen in the TMB-high patients. So right now, I am not aware of any trials targeting MYC in pancreatic cancer. But as you said, if it’s successful in lung cancer, maybe that’s when we can transform into the pancreatic cancer group.
Dr. Rafeh Naqash: Of course we can all learn from each other's specialties.We learned a lot from melanoma with respect to therapy. Hopefully, other fields can also benefit from each other’s experiences in the space of drug development.
Thank you so much for this interesting discussion. The last few questions are more or less about you as an individual researcher. So could you tell us briefly on your career trajectory and what led you into the space of GI oncology, pancreas cancer, even for that matter, drug development? And some of the advice that you may want to give to listeners who are trainees or early career individuals?
Dr. Amit Mahipal: Sure. So I have gone through some different institutions. During my fellowship, that’s when I really decided that I wanted to do GI oncology. Prior to that, I actually have a Masters in Public Health, where I learned about epidemiological research and how to design clinical trials, how to design cohort studies. My focus was on, actually there was somewhat a lot, but one of my mentors was working on colorectal cancer, and they had this huge database called the Iowa Women's Health Study Database of 100,000 patients. So that's where I started by clearly getting into colorectal cancer and GI cancer in general and how to learn from this database, how to mine these databases, how to do analyses, which seems easy but is actually quite complicated.
During my fellowship, I think the key to it is finding a good mentor during the fellowship. And I worked with one of the top GI oncologists in the country who’s practicing. And I worked under her and learned a lot not only from the clinic side but also from the research perspective and how sometimes you’ll come up with the ideas during the clinic itself.Like, “Hey, this patient had this and why aren’t we looking into this.” And she would even do some of the therapies based on phase II trials and she was a part of a lot of these trials and learning from those experiences.
And following my fellowship, I joined Moffitt Cancer Center, where I led the phase I program there. So I was heavily involved in drug development programs, all training programs I’ve been to, NIH in Bethesda, an observership in the CTEP program, and also did the ASCO/AACR Vail workshop, where you really learned a lot in just like one week. So those are kind of opportunities present for fellows and even the early investigators and attendings as well in the first few years can go there, have your proposal. And really they are the world experts in trial design and they’ll talk about how to design trials, how to add collaborators, improve your trial, and basically learn the whole protocol in a week so to speak.
And then I was at Moffitt Cancer Center for about five, six years. My home was GI so I did both GI oncology as well as phase I. And in terms of the GI oncology, my main focus was pancreatic cancer and liver tumors. Then I was at Mayo Clinic in Rochester for about seven or so years. I kind of did the same thing and solidified my career at GI oncology, looking at liver tumors, and pancreatic cancer and then being a part of the phase I division program. And now, most recently, about a year or so ago, I joined Case Western to lead the GI program here.
Dr. Rafeh Naqash: Are the winters in Cleveland better than the winters in Minnesota?
Dr. Amit Mahipal: For sure. I always say, you don't know cold until you go to Minnesota. It's a different kind of cold. I'm sure people in Dakota might say the same thing, but the cold in Minnesota is very brutal and different compared to any other place I've been to.
Dr. Rafeh Naqash: Well, it was great learning about you. Thank you so much for spending this time with us and for sharing your work with our journal. We hope you'll continue to do the same in the near future.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascopubs.org/podcasts.
Dr. Amit Mahipal: Thank you for having me here, Rafeh. Good luck. Take care.
Dr. Rafeh Naqash: Thank you so much.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
The guests on this podcast express their own opinions, experiences, and conclusions. Their statements do not necessarily express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Dr. Mahipal:
Consulting or Advisory Role:
QED Therapeutics
AstraZeneca/MedImmune
Taiho OncologySpeakers' Bureau:
AstraZenecaResearch Funding:
Taiho Pharmaceutical" -
JCO PO author Dr. Mary Redman shares insights into her JCO PO article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP)” Host Dr. Rafeh Naqash and Dr. Redman discuss the background of LungMAP and how it was developed to accelerate drug development and biomarker-driven therapies in lung cancer. Dr. Redman shares the initiatives undertaken to increase participant diversity in LungMAP and invites junior investigators to get involved in the project.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Stevenson Cancer Center. Today I'm delighted to be joined by Dr. Mary Redman, Professor of the Clinical Research Division at the Fred Hutch Cancer Center and also Senior Author of the JCO Precision Oncology article, “Representativeness of Patients Enrolled in the Lung Cancer Master Protocol” or the Lung-MAP.
Our guest disclosures will be linked in the transcript.
Dr. Rafeh Naqash: Dr. Redman, welcome to the podcast, and thank you for joining us today.
Dr. Mary Redman: Thank you very much for the invitation.
Dr. Rafeh Naqash: And for the sake of this podcast, we'll just use each other's first names. If that's okay with you.
Dr. Mary Redman: Please.
Dr. Rafeh Naqash: And since you and I know each other through the lung working group, we've worked on some things, or planning to work on some things, this article was something that I came across recently that you published with some very well-known folks in the field of lung cancer. And I wanted to utilize the first few minutes of this discussion to understand what was the background behind Lung-MAP because I think it's very important for people to understand why this kind of an approach was started in the first place and how it has successfully created a mechanism for master protocol. So, if you could dive a little deeper into that for us, since you've been there, you've done that, and it would help our listeners understand the genesis or the origination of this whole process of Lung-MAP.
Dr. Mary Redman: Happy to do so. So, Lung-MAP, the original concept goes back to February of 2012. And in February of 2012, the Thoracic Malignancy Steering Committee, the FDA and the NCI had a workshop. And the focus of the workshop was how we could accelerate drug development in lung cancer, and in particular, how we could accelerate biomarker driven therapies within lung cancer. And the outcome of that meeting was that master protocols or studies that set up infrastructures to evaluate multiple therapies, all within one infrastructure, were the way to go. And so born out of that, there were three master protocols. The Lung-MAP trial, the ALCHEMIST trials to evaluate studies in adjuvant therapy setting, and then the MATCH trial, which, of course, isn't just in lung cancer, it looks across different cancer types and looks on biomarker targets that transcend across.
So, when the Lung-MAP trial was being thought of, the idea was that while in non-squamous, non-small cell lung cancer, we had seen some advances with targeted therapies, that squamous cell lung cancer had essentially no targeted therapies that had been successfully evaluated. And therefore, there was an unmet need that squamous cell lung cancer being a more aggressive form of lung cancer than non-squamous lung cancers, and in particular in the second line setting, after patients had received platinum-based therapy, there was pretty much nothing other than docetaxel.
And so, the study was initially conceived of by Vassiliki Papadimitrakopoulou, who was at MD Anderson at the time and Roy Herbst who we had at Yale. And so therefore, we thought second line squamous cell lung cancer was an unmet need and that we could potentially have targeted therapies, given now that we had the genome atlas, the TCGA understanding of what all the potential biomarkers or targets that exist in squamous cell cancer. Concurrently, we also had the developments and improvements in next-gen sequencing. So, the technology improved for us to be able to detect these different genomic alterations that were present in these cancers.
So, all of that together - an unmet need of an aggressive cancer, a better understanding of the biology and the potential to have these targeted therapies - led to the development of Lung-MAP. But in addition, what we had seen and I think most of you who have studied cancers across the country know, patients who live in urban areas or are financially more well off are more able to access therapies, whereas patients who are less well off, more rural areas, and then just in general, different race ethnicities, didn't have the access that other patients from other settings had. And so, when we conceived of Lung-MAP, it wasn't just about meeting the unmet need in terms of treatment, it was also about an unmet need in terms of accessibility of these types of studies for all types of patients who get lung cancer. And so, utilizing the National Clinical Trials Network system that has sites all over the country, I think there's something like 2500 sites around the country, which include community oncology sites and of course academic sites.
Dr. Rafeh Naqash: Excellent. Thank you so much Mary, for explaining that. Now, as you highlighted, this dates back to 2011-2012, when things were just picking up from a broad sequencing platform standpoint, rather than limited gene testing, which has been more and more, there's been more and more uptick of NGS, especially in the space of lung cancer. So, you and several others came up with this idea and eventually implemented it. And there's a significant process of thinking about something and implementing something. So, what were some of the challenges that you encountered in this process and successfully circumvented or dealt with appropriately over these years, some of the lessons or some of the processes that you were able to understand and navigate around.
Dr. Mary Redman: We could spend the next hour probably talking on that topic. Anytime that you're setting up a big infrastructure, and I really do think the best way to describe Lung-MAP and a master protocol is that it's an infrastructure because the goal is to set up something where we can bring in new studies and so that everything is modular. And you complete one study, you add a new one. Things can be added while things are ongoing. And by things, I mean studies evaluating investigational therapies.
And so, anytime you're setting up an infrastructure that's never been done before, well, first of all, the complexities of different partners that had never worked together, so just understanding how best to work together, the infrastructure in terms of how to build it within our systems, the statistical and data management center had many complexities. The infrastructure in terms of how our systems at the statistical and data management center spoke to the NCI had challenges. How the NCI evaluated this protocol that had all these different studies that were coming and going. The studies oftentimes involved therapies that were very new in their development. And so oftentimes you'd have some new safety signal that came up which required a rapid amendment. And how do you do that when you have this infrastructure, and you don't want to stop one thing for other studies to be moving forward. And that because it's a public-private partnership and the pharmaceutical partners that are partially supporting financially and scientifically, some of these studies, learning to work with them, they have a little bit more say because they are more financially involved with the studies than a study that's typically funded by the NCI. And maybe the company is only supplying drug. So, contracting had its challenges, budgets, how do we actually budget things appropriately in this new infrastructure? I talked about all of that. And then a challenge about running such a study is how do you educate the sites so that when they're approaching patients, how can they talk to a patient about, “You're going to have your tissues submitted to be tested, and then on the basis of that tumor testing you're going to be assigned to get to an investigational treatment study.” And how do you describe all of that?
Dr. Rafeh Naqash: So definitely lots of lessons and experiences that you and your team have had. And the way I describe or look at Lung-MAP is one of those success stories that has redefined the way to run clinical trials from an NCTN and a SWOG cognitive group network standpoint. And going to this paper that you have published in this, your Precision Oncology, there's one aspect of clinical trials where we are always very focused on responses and survival and other clinical outcomes data. And then there is this important component that you and your team have looked at is, what is the distribution of the different kind of clinical trial participants? What kind of people are we getting in? What kind of people are we trying to cater to, and what is the unmet need gap that we still have not completely met? Could you tell us how this project started, the idea behind this project, and then some of the results that you can highlight for us today?
Dr. Mary Redman: So, Lung-MAP also has a company advisory board, and we meet with them either quarterly or biannually. And one of the conversations that we were having with our industry partners or collaborators was especially after the FDA came out with some of their work saying, we think it's really important that industry does better that they enroll a more representative patient population in their studies. You see some of these studies in lung cancer with 1% or a very small percentage of Black participants, for example, whereas the US population has significantly higher levels. And so, one of the major objectives, as I said about Lung-MAP, was to enroll a more representative patient population to provide access. And as part of these conversations, we kept saying, “Well, we've done a better job.” And I was thinking, well, we actually could evaluate how we have done.
And so, in thinking about that, I proposed within some of the researchers that are part of the SWOG Statistical and Data Management Center that we look at this question in particular, I approached Dr. Riha Vaidya, who is here at Fred Hutch with me, and she's a Health Economist with this idea. And she was very excited to look at this. And my initial thought was just to look at race, ethnicity, gender. And she took it one step further where she wanted to look at not only that, but also area deprivation index and then rural versus urban. So, getting at some of those other very important aspects of representativeness when we think about patient populations. And so that was how it came about.
Dr. Rafeh Naqash: Going back to some of the interesting things that you and the authors have done, is not only looked at the gender, age, but also looked at the socio-demographic representativeness. Now, there's definitely some things that you guys looked at and that Lung-MAP study did better on, and some things where maybe there's more room for improvement. Could you highlight some of those results for us today?
Dr. Mary Redman: Happily. And one thing I think that it's important if one goes and looks at this paper, and as I talk through the results, so Lung-MAP opened to enrolling patients in June of 2014. And from June of 2014 to January of 2019, we exclusively enrolled patients with squamous cell histology. And then in 2019, we expanded the study to enroll all histologic types of non-small cell lung cancer. And so, in this paper that's published here in JCO Precision Oncology, we compare our patient population and Lung Map to other patients enrolled within advanced non-small cell lung cancer trials. So that's all-histologic types. And then we compared it to the SEER population, the US population evaluated by SEER. And that also is all histologic types of non-small cell lung cancer.
And so, one of the major results, as you pointed out, is that while we did well in certain areas, for example, we did not enroll as many females as the other SWOG trials and then the US population. And I think that is probably, I would attribute all of that to being the case that squamous cell lung cancer patients tend to be more male than female. So therefore, those results, I don't know that if we looked at only the data since 2019, we might actually see that we were comparable. Going through the results, as you were just asking about, compared to previous SWOG trials, we did better in terms of enrolling older patients, not as well as the SEER data. Some of the challenge is I'm not 100% clear that we'll ever be able to get perfectly there, in part because Lung-MAP, for the majority of the time, only enrolled patients who had performance status 0 or 1, and older patients tend to have higher performance status, and so they might just not have been eligible. And I do think, especially with these investigational treatments, particularly with immunotherapies, for safety reasons, we do need to enroll patients with performance status 0 or 1.
We talked about the female sex versus male sex percentages and that our numbers were smaller. But if you look at SWOG trials versus SEER trials, they're pretty much identical numbers. So, I think that if we just looked at the later part of Lung-MAP, you'd see that they match. In terms of race ethnicity, the earlier part of Lung-MAP, we enrolled close to 15% of patients of nonwhite race or ethnicity. Historically, SWOG trials were slightly higher, but in the US population, it's around 21.5%, based on this year's data. And so, we did better than industry sponsored trials. So, if you look at those data, but there's definitely room for improvement. And that just in part, has to do with getting more sites, better outreach, more education, and better access.
And so, I think we have an accrual enhancement committee that does include patient advocacy groups. And I think that that is just going to be an area that we need to continue to work on. And then, as you mentioned, that we did better in terms of enrolling more patients from rural areas. We enrolled more patients from socioeconomically deprived neighborhoods, and more patients that were using Medicaid or no insurance for those who are under 65.
Dr. Rafeh Naqash: Absolutely. I think those are very important results. Me, as somebody who sees people on clinical trials, both phase I and late phase, of the questions that I get commonly asked if somebody refers a patient from the community is, “Am I going to be treated on a placebo?” It's one of those common things. And the second question ends up being like, “Is my insurance going to cover some of the costs associated?” And I think understanding those concepts, whether it's from an educational standpoint or a financial barrier standpoint, is extremely important in clinical trials because at the end of the day, these are things that people use as metrics for enrolling or not enrolling themselves on a clinical trial. There are certain aspects or sensitivities associated with enrolling people, let's say, of Native American ethnicity or American Indian ethnicity, where outreach is extremely important. From a Lung-MAP standpoint, could you talk about some of the outreach initiatives that are being implemented or have already been implemented to potentially help decrease this gap of representation?
Dr. Mary Redman: I think that one of the major- and this isn't exactly outreach, but to start out with one of the things that we have, in addition, I mentioned that we had an accrual enhancement committee. We also have a site coordinators committee. And when we set up the site coordinators committee, we make certain that we have representation from the geographic regions within the country and different types of sites. And the major goal for our site coordinators committee is to give us input about how it is to implement Lung-MAP within their own institutions. And so, we want to be able to overcome any type of barriers or perceived barriers that are out there, and we want to hear it directly from those people who are working closely to enroll the patients. And so that's been a key part of everything that we've done. And so, part of that is that we've just developed educational materials. We have modified the protocol based on input that we've received from them. So that's, I think, been a major approach that we have used to try to reach more patients.
We do have a newsletter that we put out. The accrual enhancement committee has also contacted different sites to really have more conversations, one on one, just more, I guess, almost like focus type groups where you try to understand, really understanding what's coming on, what are the challenges from their perspectives. And then we've had webinars where we try, and we've had hundreds of attendees for these webinars, where we let the sites have direct access to those of us who are running the study to ask their questions. So those have been our major approaches. And I think that we're always trying to figure out how we can do better.
Dr. Rafeh Naqash: I agree with you, and I think as both physicians, providers, and the clinical trial staff as such become more and more cognizant of increasing diversity, these conversations end up happening earlier and earlier in an individual's patient's journey, where trying to see feasibility, trying to see financial aspects, getting a patient enrolled on a clinical trial gets evaluated earlier and earlier. And hopefully, with some of the measures that the SWOG or the Lung-MAP group is implementing, these percentages will see more spike in the long run for better clinical trial enrollment approach.
So, Mary, now going to the science part of Lung-MAP for maybe some of the fellows or the investigators, early career investigators, who might be listening to this podcast, could you briefly explain what is the process of getting involved in Lung-MAP? Because for me, as a junior faculty a few years back, I was a fellow, and I remember at that point I hardly had any knowledge of corporate groups. SWOG, for example, was one of those that I'd heard about, but didn't necessarily know how to get involved. So, for trainees, for junior faculty, could you briefly say, what's the process? What does it involve? How would somebody propose something to Lung-MAP?
Dr. Mary Redman: Yeah, thank you for that question. And I really do hope that this actually is a way to get people to understand, and we'd love to have more engagement from more junior faculty and that's a major objective for the study. Because this infrastructure is in place, we are actually well suited to be able to mentor and bring junior faculty in. And so, the process is basically, you contact any of us that are in leadership within Lung-MAP and talk to us and we'll see if we can figure out a way. If you have an idea of a new study, wonderful. Our drug selection committee chair is Saima Waqar. She's a member of ASCO as well. I mean, one could find her and send her a note. The study chairs for Lung-MAP are Hoss Borghaei and Karen Reckamp. You can send them a note. You can send me an email, maryredman@fredhutch, and we will make certain that you are engaged and brought into the direct conversations that would lead to something.
So, it would be wonderful to have more junior faculty proposing ideas and leading sub studies, being a sub study chair. Each of our sub studies, as I mentioned before, are conducted independently, and then you are responsible for the development, conduct of the trial and writing of the paper and presenting. And so, we want all of that to happen. But we also would love to have ideas. If you think of this infrastructure as just being an amazing resource of data, we are happy to and would love to receive proposals for data analysis that could result in publication and presentation as well. So, if there's something that somebody sees as a question that they think we could answer, again, contact any of us and we will happily figure out a way how to work with you. We have a great team and a lot of capacity to be able to work with new people.
Dr. Rafeh Naqash: Thanks, Mary. And for all those listeners, trainees listening, you did get Mary's email, so try to send her an email, and hopefully she won't be complaining that there was a lot of requests. But I think all things considered, the Lung-MAP is a great data resource. As you mentioned, it's a great resource for junior investigators who are trying to build a career around clinical trials, precision medicine, and it's also a great resource, as you've shown, regarding diversity equity research from a clinical trial standpoint. So, I think it has all the components that are needed to run and create some interesting questions and answer those questions using the data set.
So now, Mary, going to the last part of the discussion here, one of the key components, we try to ask a few questions of the investigator, which in this case is yourself. Could you tell us briefly about your career trajectory, how you ended up doing what you're doing now, and what are some of the things that you've learned from and maybe advice to all the junior people listening to this podcast?
Dr. Mary Redman: Wow. Okay. Well, so if you hadn't already guessed, I'm a biostatistician. I started out in mathematics as an undergrad and then learned about biostatistics and thought that it sounded perfect for me. After I finished my doctorate, I did a year of postdoc and was starting to look for faculty positions. And if you haven't already inferred, I am a Seattle native. And so, when a position became available at the Fred Hutchinson Cancer Center here in Seattle, I applied for it, and the job happened to be with the SWOG Statistical Center. And so, you probably already guessed as well that I got the job. And so, I have been here at Fred Hutch since 2005. And when I joined Fred Hutch and the SWOG Statistical Center, which is co-located here and at Cancer Research and Biostatistics, just a mile west across Lake Union here in Seattle, the person who had been the lead statistician for the Lung Cancer Committee in SWOG, John Crowley, he was also the director of the SWOG Statistical Center and had been doing that for over 20 years, and he was ready to take some things off of his plate. And so, when I joined, they thought that I would be a great fit for the lung committee, in part because I had shown an ability to work with vibrant personalities, let's just say, which the lung community has in spades.
And so, when I started in the lung committee, David Gandara was the chair of the lung committee. And so, I worked for many, many years very closely with David, and we established a very close and really wonderful working relationship. And I learned a lot from him. I learned a lot from a lot of the other lung cancer researchers in the country and around the world. I pretty quickly became involved with the International Association for the Study of Lung Cancer and have attended most of the World Congress on Lung Cancer meetings and have gotten to know people around there. So as a biostatistician, obviously, I enjoy my mathematical and statistical skills, but I also just really enjoy learning and thinking about what I can bring to the problem where I come from a certain point of view and I love collaborating with the other people doing clinical research, in particular in lung cancer. And basically, my focus has always been on doing the best to answer our questions the most efficiently and effectively so that we can move the field forward and help people live longer.
Dr. Rafeh Naqash: Thank you so much, Mary, for your time and giving us insights into your professional and personal journey.
Also, thank you for listening to this JCO Precision Oncology conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO PO author Dr. Sanjeevani Arora shares insights into her JCO PO article, “Exploring Stakeholders’ Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings from a Clinical Practice Survey” Host Dr. Rafeh Naqash and Dr. Arora discuss germline genetic testing for all colorectal cancer (CRC) patients and advantages and barriers of implementing universal germline testing (UGT).
TRANSCRIPT
Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, social media editor for JCO Precision Oncology and assistant professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.
Today we're excited to be joined by Dr. Sanjeevani Arora, assistant professor at Fox Chase Cancer Center, and author of the JCO Precision Oncology article, Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.
At the time of this recording, our guest’s disclosures will be linked in the transcript. Dr. Arora, welcome to our podcast and thank you for joining me today.
Sanjeevani Arora: Hi, thank you so much for having me. It's a pleasure to be here.
Rafeh Naqash: As it happens, you were in Vegas for your meeting, which is relevant to this publication since this was, I believe, presented at the meeting as well. Is that correct?
Sanjeevani Arora: Yes.
Rafeh Naqash: Great. So, Dr. Arora, for background purposes, could you tell us what is the main theme of this project and what was the reasoning for doing this project in this important space of germline testing for colorectal cancer?
Sanjeevani Arora: So, we were interested in understanding what the stakeholder's perspectives would be for support as well as implementation of universal germline testing in all colorectal cancer patients. We know that colorectal cancer is one of the leading types of cancers in the United States as well as in the world.
And from what we understand is that the prevalence of mutations that would increase risk of colorectal cancer, that can vary in an unselected population, so somewhere about 15%. The criteria, however, to identify who might be harboring a variant that would predispose to colorectal cancer, there are various methods to do that.
However, I think an important point to consider here is that many patients who harbor such variants do not meet established criteria for genetic testing. The problem with that is that that is a missed opportunity to not only manage a patient who may carry such variations, so that can impact their clinical management as well as in their family as well.
So, missed opportunity for risk reduction and early detection with enhanced surveillance. So, really if you think about this is based on these, the NCCN itself has now recommended universal germline testing for individuals who are diagnosed with colorectal cancer who are younger than 50 years of age.
And in June 2022, they also suggested to consider testing for those who are older than 50 years of age. But in spite of this, there is lack of data from stakeholders and lack of data on advantage of and barriers to implementing universal germline testing at different clinical practices.
So, this was really the main reason why for us to go ahead and do this study so that we can understand what the challenges are related to universal germline testing and especially coming from the stakeholders and also to try to understand what the overall broad support is from the stakeholders.
Rafeh Naqash: Thank you so much for that explanation. I personally work in the early phase clinical trial space. So, for me, genomics makes a huge difference for people with cancer and not just from a testing standpoint, but also from a target standpoint drug discovery standpoint.
And I think as I've gradually progressed in my career, I have felt that catching individuals with germline predispositions can make a huge difference for their families, especially. Prevention is better than cure in most respects.
So, this is a very relevant and a very timely topic. And outside of this study, from a logistics perspective, could you tell us, since our listeners are not just academic clinicians or geneticists, but perhaps a bunch of them are probably community oncologists also and hopefully other disciplines that are not in the academic setting, how does it work for you in your current setup at Fox Chase of how people get this germline testing, people with colorectal cancer?
Sanjeevani Arora: The main challenge here is trying to, at least in terms of the perspectives of genetic counselors, is that currently they see all patients and eventually if there is implementation of universal setting in the way, they will perhaps only end up seeing those who truly are at high risk. So, that would really be a huge change in their own practice as well, like who they're seeing in the clinic.
In terms of how this could be implemented, obviously there are multiple challenges here. So, for example, it would go on from not only just the who would order and who would consent, but also then who would be disclosing the results because there would be a big demand for this.
So, the idea would be trying to really streamline if non-genetics providers could get the training to be involved in this. So, this system can be streamlined, I should say, that genetic providers would be more involved in the phase where they are truly required. So, perhaps that would be in the result disclosures or on a case-by-case basis.
Rafeh Naqash: I think you bring an important point as far as testing and who is responsible for discussing the implications of the results. And I know you touched into that aspect in your survey. Could you elaborate a little more on the results section side of what you found that had clinical relevance or meaningfulness from your survey standpoint?
Sanjeevani Arora: So, when we surveyed our respondents on support for the kind of providers who could be involved in ordering and consent for universal germline testing, the majority obviously supported genetics providers. So, here genetics providers were genetic counselors, medical genetics geneticists and genetic nurses.
However, there was also broad support for medical oncologists, gastroenterologists, and surgeons. There was even a minor part of our respondents also supported other providers as well. So, it's good to see that while there is broad support for genetics providers, there is room for other providers to be involved in this aspect of universal germline testing in a program.
We also looked at the opinions and how and when genetics education should be provided in such a program for universal germline testing. The majority of our respondents, said that pre-test genetic education is necessary. So, they all felt that this is an important aspect of a universal germline testing program.
However, there were nuances on what materials could be provided as well as who could potentially be involved in this. So, based on what the respondents said in their survey, it looks like this could be a good place for non-provider staff to be involved in this.
However, when we also asked them what the non-genetics providers in the knowledge that they have potentially when we directly ask them this, do they have the knowledge to consent for genetic testing? Going back to the consent point, again, the majority did not agree with this. However, there was a percent that also felt that they do have this knowledge, but when we asked them that if they have the knowledge to disclose results, there was a strong disagreement there.
So, there definitely is room for non-genetics providers to get the right training or to be involved in this aspect if needed. But it looks like at least for the consent, there is more support.
Rafeh Naqash: So, the more one thinks about this topic from a broader perspective, not just colorectal cancer but other tumor types. What comes to my mind as you have elaborated in your discussion and in your survey, is the education part of it that you just mentioned about.
If you were to think out of the box, do you think that the NIH has a potential role in creating mechanisms to help facilitate some of that? Since I think the bigger question comes back to funding at the end of the day. Institutions need to invest time, energy, resources in trying to educate and expand on this aspect of genetic testing, which I think is immensely important for individuals with strong family history of cancer, or even find out that they don't have high risk features, but they end up having some germline variants that are potentially actionable for them or their family.
So, have you as part of your association, the CGA, been able to think on some of those lines to get a stakeholder like the NIH to help facilitate fund some of these educational initiatives at institutions? Perhaps maybe to start with NCI-Designated institutions and then expand in the community.
Sanjeevani Arora: I think NIH would have a big role in this or NIH as well as other funding agencies because I think this effort for a universal germline testing program in academic centers and then eventually going on to community-based centers or maybe both at the same time, this will require a collaborative effort between genetics and non-genetics providers that we identify is going to be really very important going forward.
So, there is not only a big role for the institutions and the community itself, but also for the NIH as you mentioned, where this would be really necessary to really help us identify who is a high-risk individual and when the pre-test education and other post-test is required.
Rafeh Naqash: I think because in the bigger picture it does play out into the amount of funding that a government agency like the NIH spends in individuals with advanced cancer, which they could potentially prevent if some of these programs are well implemented early on and help with reducing morbidity and mortality when these events do happen later on.
But I guess these are discussions beyond the scope of this project in this podcast, but I was just thinking from an out of the box perspective, could that be an opportunity that your group can perhaps work with the NIH on? So, going back to the project, the publication, tell us a little bit more about the genes that were tested. You talk about the single gene versus the multi-gene panel. Could you elaborate a little more on that and what are the advantages of one or the other?
Sanjeevani Arora: We did survey our respondents on what they thought would be the best way to move forward in a universal germline testing program. And you can see that the majority really supported a standardized multi cancer gene panel. And I thought that was really interesting because if you look at the data here is that while 46% support that, there's also a smaller majority, about 26% that only support colorectal and some common cancer genes.
So, in terms of the large multi cancer gene panels, so this would be not only just the colorectal cancer genes, so these would be high risk, moderate risk or limited evidence, colorectal cancer genes, plus it would be all other genes that we test currently for hereditary cancer types. So, this would be a lot of data that would come about in a universal germline testing program.
And then I think the idea would be how would this be managed? Because many of the genes currently, we don't understand if they would increase colorectal cancer is, so how would be manage the risk for perhaps other cancer types if there is a positive result? I think that's something to think about.
The other would be how would the variance of uncertain significance would they be reported and how would that work about? So, those two would be really important as well to think about going forward in such a program.
Rafeh Naqash:
Now from a cancer standpoint, my experience with germline testing has been when I see individuals for clinical trials especially, and I do broad next generation sequencing the tumor tissue or on blood and identify something that has a very high variant allele frequency that triggers a question in my mind whether this is germline.
Unfortunately, these days we don't do a great job in taking history from the individual where you ask them about family history extensively. Some clinicians are better in this perspective than others, but I think there's a gap there.
And then you go back to the patient, you ask them whether they have a history, had a recent individual recently that had uveal melanoma, and then I identified a very high variant allele frequency in a gene called BAP1, which you might be aware of. And then went back to the patient asked them and they said, well yes, they have family history of mesothelioma, family history of this cancer that cancer, and that triggered germline testing, which was positive.
So, from your perspective, since a bunch of these individuals would have first-line contact, I would imagine with oncologists, mostly medical oncologists rather than surgeons, what should one look out for? Let's say a program does not have universal germline testing implemented yet.
If me or my colleagues sees an individual with colorectal cancer, what would be the three or four red flags that we should consider to focus on germline testing in those individuals? Let's say we're in the community and I'm someone who's not necessarily on the genomic side, I'm a clinician treating colorectal cancer. What would some of those things be that should prompt me to consider germline testing in that individual with colorectal cancer? From your perspective.
Sanjeevani Arora: Once the universal germline testing program is implemented, and you wouldn't necessarily need those questions actually, but without such a program, obviously family history is a major red flag that is very important to consider.
And another would be, for example, in terms of tumor set testing for Lynch, if there is any mutations in Lynch genes or MSI High that could at least trigger test if that came from the germline.
Rafeh Naqash: I think those are important points. And in the clinical setting it does often happen that you see so many individuals and sometimes some of this thought process can get lost in translation.
But I think it's important to emphasize, like you pointed out, asking for family history if the universal program for testing of these individual’s not implemented, then inquiring on family history and these days we see a lot of young onset colorectal cancers. Interestingly enough, my colleagues talk about it all the time and I think those aspects of it should ideally prompt people to go for germline testing.
Now, from an implementation standpoint, you also looked at that in your respondents which individuals would be the ideal candidates for this testing. Could you elaborate on that?
Sanjeevani Arora: Which individuals would the ideal candidates, I mean, I think the idea here was what is the support overall for testing everybody? So, the idea is to move away from having certain criteria.
Now it would be the NCCN recommends testing any colorectal cancer patient who is younger than 50 years for a germline multi-gene panel testing. And then the consideration is for those who are older than 50, I hope the NCCN will eventually decide to recommend it for all. But this way there would be no need for any criteria as such, but just test all patients.
Rafeh Naqash: I absolutely agree with you, and I think organizations such as NCCN, NCGA should ideally partner on creating some of this framework so that everybody's on the same page. Because I think that does play into the fact that how payers consider reimbursement for some of this testing. Did you encounter that in your respondents as one of the reasons why it could be challenging to implement universal germline testing, from a payer standpoint, insurance standpoint?
Sanjeevani Arora: One of the things that we did factor into the survey as one of the barriers that ... so, we had about 11 questions for what the clinical practice barriers would be in a universal germline testing program. And this was one of the questions that the respondents did majorly agree on that the insurance may not cover the cost of testing for all patients. So, I think obviously the things do have to modify in terms of coverage guidelines to include all patients.
Rafeh Naqash: Right. Because that again plays into logistics of ordering this for individuals and those individuals not having to see several thousand dollars bills resulting in financial toxicity. So, Ithink having these discussions, in your collaborative group is leading, I think extremely important from that perspective.
What would be the next step for this? You did the survey, you understood what are the pros, the cons, the limitations, the benefits, what is the next step that your group is planning to take to implement some of this, create the second stage for some of this work, if there is something that you would like to highlight.
Sanjeevani Arora: In terms of just in general speaking about this, I think as we finished this survey and we got it through publishing this, some of the things that we thought about and not necessarily that we may be doing this as a group or it might be just individuals, but just to talk about what we think could be the next steps here is obviously, this survey, the stakeholders here were those who are experts in hereditary GI cancers.
The idea would be to also see what the thoughts are for those who are not, because they would be big stakeholders in this as well. So, it would be good to understand what they also perceive as the barriers associated with this and how we could get this implemented and also see what their support is. So, I think that's one thing.
The other thing that's I think really important to point out here is that we don't have patient perspectives on a universal germline testing program. And what do they think about this? What do they perceive could be potential barriers even for them? I think that would be very important so that there is really a real uptake in the real world. I think that's very important to do, that the patient focus is very important.
Now, I'm not sure if we would be doing this, I would love to do this, but I think it's really important to really consider that going forward.
Another thought that I had that was based on a question that I got asked when I presented this at the CGA-IGC meeting in Vegas just last week was that how one of the things that was pointed out were that the majority of our respondents were, and I've already kind of touched on this too, were genetics providers.
So, perhaps the results could be for some of the perceived barriers for how non-genetics providers could be involved, could be skewed because the survey majorly had results from genetics providers. So, I think again, just pointing out that there is a real need for collaborative efforts between genetics and non-genetics providers to understand where are the areas that they could need help so that this could be realized.
Rafeh Naqash: Absolutely. I think as you pointed out there are definitely limitations associated, but I think your work and this publication lays some very important groundwork to initiate the discussion, at least. It's understood that community providers take care of at least 60% of individuals. There's maybe more with cancer.
So, having stakeholders from different aspects is important, but can be challenging also since your group is just starting this work. So, I think the patient perspective, the community perspective is definitely important and hopefully that'd be something that you and your group can further work on and hopefully in the years to come, maybe publish it again in JCOPO as you did this time.
Sanjeevani Arora: Yeah, that would be the hope to really get even broader perspectives. Yeah.
Rafeh Naqash: So, Dr. Arora, a couple of quick questions on you as a researcher now since you've touched upon your work. Could you tell us a little bit about your background, your professional background, your interest in genetics and your current role at your institution?
Sanjeevani Arora: So, my background, I have a PhD in biochemistry and cancer biology, as a postdoc I really expanded into molecular genetics. That's what really led for me to work in this area. So, currently I have a research lab at Fox Chase Cancer Center, and I'm in the Cancer Prevention and Control program. And a major part of my research program is looking at the genetics of colorectal cancer. And I'm very interested in understanding what could be the other genetic risk factors that is really leading to this alarming rise in incidents, especially in the young population.
So, that's one of the aspects of my work that I'm interested in. But another aspect of my work that I'm working on is looking at are there genetic factors in the germline that could potentially impact how individuals respond to their treatment? And so, yeah, I do have a big stake in knowing more about overall genetics of colorectal cancer.
Rafeh Naqash: Excellent. Well, thank you so much. It was great talking to you about this topic and hopefully our listeners find this interesting as well.
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JCO PO author Dr. Bryson Katona shares insights into his JCO PO article, “Outcomes of the IMMray PanCan-dTM test in High-Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.” Host Dr. Rafeh Naqash and Dr. Katona discuss IMMray PanCan-d: A Blood-based Test for Early Detection of Pancreatic Cancer.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO Precision Oncology articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.
Today, we are thrilled to be joined by Dr. Bryson Katona, Director of Gastrointestinal Cancer Genetics Program and Assistant Professor of Medicine at University of Pennsylvania Abramson Cancer Center, and also lead author of the JCO Precision Oncology article, “Outcomes of the IMMray PanCan-d tm Test in High Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.”
At the time of this recording, our guest disclosures will be linked in the transcript.
One of the other unique things about this article is that this will be a concurrent podium presentation at the 2023 CGA-IDC Meeting and also concurrent publication in JCO Precision Oncology. Bryson, welcome to our podcast and thank you for joining us today.
Dr. Bryson Katona: Thank you so much for the invitation and I'm looking forward to discussing the findings of our recent study.
Dr. Rafeh Naqash: So, one of the unique things about this topic or this publication is surveillance, which we often talk about a lot in lung cancer, breast cancer, colorectal cancer, but not so much in pancreas cancer. For a listener who might be a community oncologist or for a trainee out there, fellow, who may not be as specialized in cancer genetics, what are the kinds of individuals that you would screen for pancreatic cancer? What are the high risk populations where there's a decent pretest probability that you could catch something early? And what are the implications of catching something early in people with pancreas cancer?
Dr. Bryson Katona: The whole field of pancreatic cancer screening and high risk individuals, which we'll refer to as pancreatic surveillance, has just been an area of increasing growth and increasing data over the last five years or so. For individuals that we would consider pancreatic cancer surveillance in, really, we try to target those individuals that have a lifetime risk of pancreatic cancer of about 5% or more. And so those fall in two main groups. So one of those groups are individuals that would have what we would define as familial pancreatic cancer. That's where there's a very strong family history of pancreatic cancer without a known genetic susceptibility. And so by strong family history, what we typically refer to is having two members of that family with pancreatic cancer. And those two members of the family have to be directly related to one another, and your patient would then have to be directly related to one of those individuals. So, say your patient has a father and a brother or a mother and a maternal grandfather. Those would kind of fit the criteria.
The other big group of patients that we consider doing pancreatic cancer surveillance in are those with genetic susceptibility to pancreatic cancer. And this can come in multiple different forms. Some more of the common cancer risk syndromes, such as Lynch Syndrome, and carriers of a BRCA1 or BRCA2 mutation. Typically in the presence of one family member with pancreatic cancer, those individuals could be eligible for surveillance. But there are other rarer syndromes as well, such as carriers of an ATM or PALB2 mutation, individuals with Peutz-Jeghers syndrome or hereditary pancreatitis as well.
Dr. Rafeh Naqash: My understanding of these mutations is they have to be germline in these individuals. Could you shed a little more light on germline mutations, what they are, how potentially to recognize them? Because in the current setup, at least, most patients with advanced cancer get next generation sequencing, which is not the same as germline testing. So, for somebody who sees these reports, I do early phase clinical trials primarily and do a lot of sequencing, and find a lot of interesting things which lead to germline testing in individuals, could you shed some light on the differences between NGS testing and germline testing, since you do this day in and day out? And in what scenarios would you test for germline things that could lead to downstream implications for individuals?
Dr. Bryson Katona: Oftentimes, this is a point of some confusion or uncertainty. And so when we think about germline testing, basically we're looking for gene mutations that are going to be present in every cell throughout the body. When patients who have a tumor undergo somatic sequencing of that tumor, of course, we expect to find lots of gene mutations in the cancer itself. But then, typically, if there is a mutation in all cells in the body or i.e., a germline mutation, that mutation will oftentimes be picked up in the cancer as well. And so I think when you're looking at somatic sequencing reports, sometimes some of these mutations that you see in there in cancer predisposition genes may not be a cancer specific gene mutation, but may be germline and may merit kind of more additional testing. That's always one way that we can identify individuals that if one of these gene mutations is picked up on the somatic sequencing, they can get referred.
Now, if we think about the population who may not have cancer yet but may have a strong family history, in those cases, those individuals are typically getting referred directly for germline testing since they don't have any tumor or anything like that that has been tested. So that also is another opportunity where, ideally, we would identify all these gene mutations in the ideal world just because we, of course, like to know about these before an individual actually does develop any cancer.
Dr. Rafeh Naqash: I think the important point you brought out is doing this before the individual develops cancer is a huge opportunity for us in the cancer field to improve outcomes for certain cancers. As you pointed out in your paper, like pancreas cancer, survival outcomes in the later stages are not that great, and we haven't had any significant breakthroughs in treatments. Could you tell us a little bit more about how pancreas cancer screening could help change some of those aspects where you could see an opportunity where individuals who get screened timely, diagnosed timely, could also benefit in the long term?
Dr. Bryson Katona: For pancreatic cancer, really, we know that if it can be detected at stage 1, that's really our only opportunity to meaningfully intervene and impact survival. And so when we talk about screening for pancreas cancer, basically our goal is that we either want to find very high risk lesions that are almost at the stage of cancer, or potentially stage 1 pancreatic adenocarcinomas. We know that for stage 1 disease, especially stage 1a, a five year survival is over 80%. And once you get to stage 2 disease, the five-year survival decreases dramatically. And so I think that if we're going to screen patients, really, our goal should be to detect these cancers at stage 1, where there's an opportunity for surgical intervention. Even stage 2 pancreatic cancers or any that are not surgically resectable, our ability to cure these patients essentially evaporates, and so really, screening should be done to detect things at a time when we can surgically intervene.
Dr. Rafeh Naqash: In your program, from a practical standpoint at UPenn, is it the cancer geneticist, or is it the medical oncologist who makes the referral and determines need? Or how do you go about it so that other programs or individuals who might be listening to it would understand how a screening program for pancreas cancer actually works?
Dr. Bryson Katona: I pretty much serve as the referral point for all of our pancreatic cancer early detection studies. We have a great collaborative group here and a lot of our oncologists who may be following these carriers with genetic susceptibility, oftentimes, if the patient is very convinced and wanting to go forward with screening, the oncologist will just order the screening tests themselves, and then me and my team will enroll individuals in studies once they come in for screening. So patients who are interested in screening oftentimes will come in for a full office appointment to really discuss the pros and the cons of screening and decide if this is something that they want to pursue themselves. Regardless of how patients get into the process, whether they get directly referred from oncologists or they come through our high risk pancreatic clinic through which I see patients, it's important that these individuals be offered the opportunity to enroll in pancreatic cancer early detection studies as really capturing data on all individuals who are getting screened is really our only hope of continuing to move this field forward.
Dr. Rafeh Naqash: I totally agree, and I think, as you mentioned in the manuscript, EUS, MRIs are decent tests, but nevertheless, one is invasive, the other one is probably not cheap, may not even be available outside of North America to a large extent. So you definitely need something that's easy, less invasive, perhaps can be implemented in a broader scale.
Now, from a payer standpoint in the current landscape, do payers actually reimburse for pancreas cancer screening? Is that something that is easy to come by, or do you actually end up requiring, like, peer to peer prior auth, which is something that has become a theme, an unfortunate theme in the oncology space these days. What is your experience with the pancreas cancer screening aspect?
Dr. Bryson Katona: I think that the landscape has been getting much more favorable towards payer reimbursement. Since the National Conference of Cancer Network, or NCCM, guidelines have included pancreatic cancer screening in one of their high risk guidelines, individuals who meet those criteria, we really haven't been having any issues getting their screening covered. Now, of course, there can be copays and deductibles and things like that that may still provide a financial barrier, but the insurance companies have fortunately been much more amenable to covering the screening procedures.
But you make a great point that doing an annual EUS or MRI is a pretty involved endeavor. It's expensive, it's time intensive. And in the pancreatic cancer screening space, what the studies have shown is that you probably have to screen 100 or a little bit over 100 individuals in order to find a high risk lesion. So you end up doing a lot of screening to identify a very small minority of individuals who will develop a high risk lesion. And I think that's important as well because even in these high risk populations, pancreatic cancer is still not an incredibly common cancer. It's still diagnosed at a fairly low rate. So, any individual who is undergoing screening, I think they have to be ready to embark on a long journey where they're sticking to this annually, but in the majority of cases, we will not identify a high risk lesion.
Dr. Rafeh Naqash: And from a genetic susceptibility, germline susceptibility standpoint, is there an age cut off where you mandate that these individuals should have pancreas cancer screening? Let's say if somebody's a BRCA1 or BRCA2, or is it irrespective of the age?
Dr. Bryson Katona: We know pancreas cancer is a cancer that affects older individuals. And so typically for the gene mutation carrier, so for like the BRCA1s and 2s and Lynch syndromes, those individuals in whom we're doing screening, usually we say to start at around age 50. 50 may still be a little bit on the early side, and the only reason we would ever consider starting earlier than 50 was if there was a very young pancreatic cancer in the family. One of the more difficult discussions to have with patients is when should they stop screening? And we don't have a really great answer for that, but I think that each year that we do screening, we always address that or think about those factors with patients.
Technically, a patient who would not be a surgical candidate, if a pancreatic cancer were to be identified, that individual probably should continue to screen, but that ends up being a very individualized decision between the patient and the provider. Now, apart from the BRCA1 and 2 and Lynch and those type of high risk patients, there is the familial pancreatic cancer patients where there's no known genetic mutation. Those individuals, we typically start around age 50 as well. Some of the rare syndromes, such as Peutz-Jeghers syndrome, and carriers of a CDKN2A mutation, we would start at earlier ages, but those syndromes are overall fairly rare.
Dr. Rafeh Naqash: Going to another aspect of biomarkers in the pancreas cancer setting, something that we regularly, routinely do. In fact, I was on service a couple of weeks back. A fellow of mine saw a patient with pancreas mass, he ordered a CA 19-9, and it was kind of elevated. You mentioned some very important aspects of limitations associated with this CA 19-9. Could you elucidate a little more about some of those aspects?
Dr. Bryson Katona: Definitely. So finding a biomarker, a blood based biomarker that we could use for pancreatic cancer early detection would really be the holy grail and would solve so many issues that come up in the field. And so CA 19-9 has definitely been the one that has been studied the most in this space. With CA 19-9, we know that it's a good marker for pancreas cancer once it develops. The issues that arise in the pre cancer stage when it's used as more of a screening type tool, is that, one, 10% to 20% of patients actually are Lewis antigen null and don't express CA 19-9. And so you have a pretty decent amount of at risk individuals who are not going to express CA 19-9 to begin with.
And then I think the other thing that makes it very difficult is the differing baseline levels of CA 19-9 that can be present. An individual who has a CA 19-9 that's checked and say it's 5 or 10 above the upper limit of normal, that could just be their baseline level or that could be something of concern. And oftentimes in those situations, it's a lot of worry and angst for the patient, but then also a lot of worry and angst for the provider as well, and individuals just don't quite know what the next best step is for evaluation in that case.
There is some data that's come out of Hopkins recently showing that there are a few genes where there are certain genetic mutations that may alter one's level, baseline level of CA 19-9. And so that may be a potential way to personalize or individualize what someone's baseline CA 19-9 level should be. But that's, of course, still kind of in the experimental stage and not something that's ready for widespread practice yet.
Dr. Rafeh Naqash: And the other biomarker, as you've based the study around is the IMMray PanCan-d ™ test. Seems like a composite biomarker. Could you tell us a little more about what constitutes this biomarker and what are the different parameters associated with it?
Dr. Bryson Katona: The IMMray PanCan-d test, really just to give a little history on it. So this was the first commercially available pancreas cancer specific blood-based test. This was commercially available to patients starting in late 2021 and through the summer of this year 2023. This particular test looked at 18 protein biomarkers and in addition also factored in the level of CA 19-9. And basically what it would result in, it would give four possible results. It would either give a positive or a negative result, but also had the potential to give a borderline result. And then the fourth possibility was via test not performed result. And those were primarily for the individuals who were CA 19-9 non-expressors. Again, this was really the first commercially available pancreas screening blood based test that was available.
Just for listeners, the company has, based on, I guess, their first 18 months worth of data, they temporarily pulled it off of the market to reevaluate some of the parameters. But while it was on the market, we were fortunate enough to collect this real world data. And I think that the data that we collected through this study really allowed us to learn some really important lessons about how a pancreas specific blood based biomarker, how it should work, and what are some important components of this biomarker that really need to be addressed in future versions of this test, but then also in future blood based pancreatic cancer biomarkers that are developed down the road as well.
Dr. Rafeh Naqash: Bryson, can you tell us a little bit about the inclusion exclusion for this study, the kind of individuals that you incorporated in the study, and then we can go on to some of the results?
Dr. Bryson Katona: Sure. So for this study, what we did was we ran an IMMray PanCan-d test on individuals who were coming in for their normal, their regular pancreatic cancer surveillance. So these were high risk individuals, lifetime risk of pancreatic cancer of 5% or higher who were already enrolled in a surveillance program. And so we had had baseline imaging of their pancreas. And in addition to those individuals who were offered this test, who were undergoing surveillance, we also spiked in several patients that had a known diagnosis of pancreatic cancer. And this was done such that the company was blinded to the results of who had a known diagnosis of pancreatic cancer. So what this did was it provided us really with the first real world data on the use of this test in clinical practice and also, because we utilized some spike in samples, allowed us to utilize and calculate some performance metrics of this particular pancreatic cancer early detection test.
Dr. Rafeh Naqash: And some of the important metrics that you mentioned in the manuscript is this test having a very high negative predictive value, but a low to medium positive predictive value, partly from some of the testing aspects related to some of the results. So could you tell us a little bit more why the negative predictive value was so high, but the positive predictive value was not as high? And what are the things that could be done in the near future to perhaps improve upon the positive predictive value?
Dr. Bryson Katona: Yeah, you're right. As you do mention, the negative predictive value was very strong. The issue with the positive predictive value came out of the fact that this test had a borderline result that was used. And when you have the option of not just a positive result or a negative result, but you have a test that can offer this borderline result, how this borderline result is characterized can really alter the performance characteristics. So just to give some numbers, about 7% of the patients who had the test performed came back with a borderline result.
Now, if people were comfortable with just brushing off the borderline result and not doing anything additional, then that would be fine, that wouldn't be a problem. But I think most providers, and probably most patients as well, if they see a borderline result, they're probably not going to be okay with just brushing it off and they're going to want to either do some additional testing, whether that be additional blood testing or potentially a sooner imaging study. And so, although it's a borderline, it's not a true positive, it's in the borderline region, I think it's probably going to raise a level of concern enough that most people are probably going to act on it like it may actually be a positive test. And so how those were characterized, the borderlines, it really altered the performance characteristics. And if you considered those borderlines to actually be positive tests, given that people are probably going to want to act on those results differently, it made the positive producing value of the IMMray PanCan-d very suboptimal.
And I think that probably is one of the most important lessons that we learned from looking at this data is that any future pancreatic cancer early detection tests probably should not have a borderline result and should be designed so that it either comes back as a positive or a negative without having kind of that ambiguity of a borderline result in the middle.
Dr. Rafeh Naqash: I think this is an aspect that touches every aspect, every side of biomarker assessment. One size does not fit all. There's a lot of borderline results we get. I do a lot of immunotherapy. Of course, immunotherapy biomarkers is a huge thing and so far we have not been able to narrow down something that is just one sole marker.
Now from a pancreas cancer standpoint, I think in your data set you had a few individuals with IPMNs, a few with pancreatic adenocarcinomas, and a couple, I think, with neuroendocrine tumors. Do you think that actually impacts the type of the lesion, actually impacts the outcome or the positive predictive value associated with the test?
Dr. Bryson Katona: We did find a couple incidental pancreatic neuroendocrine tumors in these patients. The test itself was not designed. It was designed and trained on pancreatic adenocarcinomas. And so the tests in the patients with pancreatic neuroendocrine tumors did not come back as positive or borderline. And then in terms of IPMNs, IPMNs are so incredibly common. I mean, most series have shown that probably around 30% of individuals who are undergoing pancreatic cancer surveillance have an IPMN that's identified. And so again, I don't think it was trained to necessarily pick those up. Although talking to patients about the frequency of IPMNs on surveillance is really important because I always counsel patients that you have about a 30% chance or that something's going to be found in your pancreas. Granted, most of these are inconsequential and just things that we continue to monitor, but they are found incredibly frequently.
Dr. Rafeh Naqash: And one of the other aspects I guess, is you mentioned this as a limitation in your manuscript, is the fact that the study had a majority of individuals that were of Caucasian ancestry or ethnic ancestry. So from an ethnicity standpoint or racial diversity standpoint, is there a plan to incorporate other ethnicities in a bigger, broader data set to validate whether a similar pattern of high NPV negative predictive value could be identified in non Caucasian individuals also?
Dr. Bryson Katona: That's a great point and at this point, unfortunately, it's not an issue that is specific to this particular study, but it is one that affects really the entire literature in the pancreatic cancer early detection space. Diversity amongst individuals who are undergoing pancreatic cancer surveillance enrolled in these pancreatic cancer surveillance studies is really limited. So most of the data that we have on outcomes of pancreatic cancer surveillance really in all of the major publications is primarily limited to individuals who identify as white. And so this is an area where the whole field I think needs to think of ways and create new innovative ways to get more diverse populations into surveillance. And so again, I think until we fix the bigger problem of getting more diverse populations into surveillance, we won't have populations big enough to validate this particular test on those individuals.
So I think one other point that is really important that came out of this data was having a pancreatic cancer early detection test that requires CA 19-9 to be expressed is also a major limitation. In this particular study that we did, we found that about 14% of our high risk individuals got a ‘test not performed’ result back because they were not CA 19-9 expressors. And with 10 to 20% of the general population not expressing CA 19-9, that really limits the individuals that would potentially be eligible for this type of a test. And so I think one of the other lessons that we learned from this is that any type of pancreatic cancer early detection test that is developed in the future, I think it ideally needs to be developed such that it can be run regardless of CA 19-9 expression. Otherwise you run the risk of developing a test that up to a fifth of at risk individuals may not even be able to benefit from.
Dr. Rafeh Naqash: I think those are very important points, and as the biomarker field advances, I think taking into account, one, different races ethnicities because biomarker expression could be different based on genetic ancestry, and then taking into account the fact that, for example, for pancreas cancer, as you mentioned specifically, CA 19-9 may not be a universally expressed biomarker. So trying to overcome some of those limitations by designing things that are more universal is probably the way to go and I guess more to come in this field. So Dr. Katona, what is next for this project to perhaps expand on this pilot proof of principle project into a bigger, broader population or a validation cohort of some subtype?
Dr. Bryson Katona: Immunovia, who is the company that developed the IMMray PanCan-d test, they're working to retool this test to hopefully release a second generation test in the near future. And I think that the hope will be that the second generation test will not have some of the issues such as dependence on CA 19-9 and use of a borderline result that this first version had. So we'll certainly be excited to help test and validate a second line test once it comes out.
And I think that just the pancreatic cancer biomarker field is an exciting one. I know there's several other commercial tests that are also currently being developed a little bit earlier in the development stage, but it's exciting to see so much effort and research being put into this area of just really great need. And so I'm really excited to see where the field goes over the next couple of years.
Dr. Rafeh Naqash: A couple of quick questions about yourself. Tell us a little bit about your journey, what led you into this specific field and how have things gone for you as an early career investigator in the last several years?
Dr. Bryson Katona: Great. Yeah, I'm a physician scientist, so I see high-risk individuals in the clinic. I have a basic science lab and I run a lot of clinical research and early detection studies. Really, I knew I was interested in digestive cancers very early on and as a gastroenterologist, I found that I could probably have the most impact in the early detection space. And so ever since I was a fellow, this has been kind of my area of interest and expertise and I think taking the highest risk individuals, so those with strong family histories, those with genetic predisposition, I think you really have the opportunity to make the biggest impact with early detection strategies. And so that was one thing that always really motivated me in this field.
Dr. Rafeh Naqash: Bryson, thank you so much for indulging with us. Thank you for choosing JCO Precision Oncology as one of the destinations, the final destination for your work and hopefully, more to see from you and your group in the near future. Congratulations on your concurrent publication presentation and the podcast, and thank you again for joining us.
Dr. Bryson Katona: Thank you so much for the opportunity. It's been a great discussion.
Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
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JCO PO author Dr. Jens Rueter Chief Medical Officer at The Jackson Laboratory and Medical Director of the Maine Cancer Genomics Initiative, shares insights into his JCO PO article, “The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.” Host Dr. Rafeh Naqash and Dr. Rueter discuss this successful initiative for patients and its implementation for access to precision oncology in rural settings.
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center. Today we are joined by Dr. Jens Rueter, Chief Medical Officer at The Jackson Laboratory and Medical Director at the Maine Cancer Genomics Initiative. Dr. Rueter is also the Associate Director for Regional Translational Partnerships at the Jackson Cancer Center and the lead author of the JCO Precision Oncology article titled “The Maine Cancer Genomics Initiative: Implementing a Community Cancer Genomics Program Across an Entire Rural State.”
Full disclosures for our guest will be linked in the transcript and can be found on the article's publication page.
Welcome to our podcast and thank you for joining us today, Dr. Rueter.
Dr. Jens Rueter: Well, thanks for having me. It's a pleasure to be here.
Dr. Rafeh Naqash: For the sake of this podcast, we'll refer to each other using our first name if that's okay with you.
Dr. Jens Rueter: That's great.
Dr. Rafeh Naqash: So this article that your group published in JCO Precision Oncology has significant implications. It has broad outreach. It incorporates an aspect of Precision Oncology that is very important for not only academia but also from a community outreach perspective, which is one of the reasons why I chose this as one of our podcast highlights. So to start off, I would really be interested to know what are the current barriers to the implementation of Precision Oncology, especially in rural settings versus urban settings, that can impact cancer mortality.
Dr. Jens Rueter: Yeah, that's a great question. Let me just go back a little bit in time here. When we first started with the Maine Cancer Genomics Initiative back in 2016, the problems were actually even more significant than they are today. Back in those days, I would say even access to testing was a problem in rural areas. And I think that is still the first thing to consider when thinking about barriers. Back in 2016, there were only a handful of testing companies. There were issues with reimbursement or patient out-of-pocket costs. So I think that's the first barrier. I would say that that has significantly changed in the last six years. There are more testing companies available. It appears that the out-of-pocket expenses for patients have dramatically decreased or the systems programs have improved. There are still some barriers, but I think it's a much smaller part of the population.
The second barrier to implementation, though, which remains to this day, and in fact, I would argue has actually become more complicated, is a quick and comprehensive, yet fast and deliverable interpretation of the test reports. The test reports contain a lot of information. It's often 20 to 30 pages long, multiple sections, and really understanding how to utilize that information for clinical care is a very significant issue for clinicians to this day. So that's the second barrier.
And I think then the third barrier that is still ongoing and I think, especially in rural areas, is the access to treatments through either a clinical trial or even through off-label prescriptions, that both of those require a lot of infrastructure, and that still remains a significant issue to this day.
Dr. Rafeh Naqash: You touched up on some very important aspects and one being understanding of genomic reports and this has been something that I talk to fellows all the know. I finished fellowship a few years back. At that time, NGS testing was becoming more and more prevalent, even though, as you mentioned in your paper, CMS coverage for this didn't start until 2018, 2019 approximately. And from a phase one trial standpoint, which is what I do, I have probably a little more exposure to genomics and precision medicine than perhaps some of our community colleagues. But it does come up often when we get referrals from outside sites. We're trying to look through the report and see something that stands out, whether it's a varying allele frequency that's high enough to warrant testing, germline testing, or some other targets that were identified a few years back but probably were not acted upon.
So you had this very interesting approach, a three-pronged approach is what I understood, of how you tried to tackle this within your main precision oncology program. Before we go there, could you tell us what was the idea behind establishing something like this? Because I imagine bringing it to fruition is something much more complicated, but the idea is where it starts. So I imagine, like, you probably had a conversation with some of your colleagues or somebody else noticed this as a barrier in the clinic and came up with this sort of an approach. Could you touch upon that for the sake of our listeners?
Dr. Jens Rueter: Yes. So back in 2016, or actually in 2015, when we started conceptualizing the Maine Cancer Genomics Initiative, the idea was to look at Maine as a state, as a very rural state. The Jackson Laboratory is an NCI-designated basic science cancer center in the state, the only NCI-designated cancer center in the state. And we feel like there is an obligation, if you will, to the state to do good for all of Maine. So it's a community approach that we felt was important. And we realized then at the time that, again, that testing genomic tumor testing, or NGS testing while available, was not being used effectively in the community. So I think those two ideas essentially made us think and believe that we should take the lead in starting such a program.
We felt that we had actually one significant advantage in that we are a non-patient care organization. So the Jackson Laboratory, even though we have an NCI-designated cancer center, we don't see patients at Jax. So we were not a competitor, if you will, for patients in the state. So we were an honest broker. We were sort of a neutral Switzerland, if you will, in Maine, and were able to convene the entire community around this concept. Even though Maine is a small state, there are a number of healthcare systems that are actually competing with each other for patients in certain areas. And when we sort of started this program, we said, look, we want to work with everyone, and it's important for us to work with everyone, and we want to include even the smaller, truly rural critical access hospitals that have small, very small oncology practices. They're just as important to us as the larger centers. So I think that was sort of the community idea behind this and this is what really started it all. And then also, again, the fact that testing was such an issue, it also happened that at the time, Jax had just started we had just started our own clinical laboratory, our own CLIA certified laboratory. So we felt like we actually had the expertise to bring a test to the community that would then engage them to utilize the technology more effectively. And that's how we proceeded with this.
Dr. Rafeh Naqash: Excellent. And I totally agree that this inclusive stakeholder approach that you had was probably one of the elements for success in this kind of an approach and led to a significant impact in the lives of patients. You mentioned three things that you targeted or three things that you identified and tried to implement as part of this Precision Oncology program. Could you tell us about those briefly, what they were, and why they were important to be included in this approach?
Dr. Jens Rueter: Yes, absolutely. So the first and most important one and most impactful one was that we developed a genomic tumor board program through this initiative, which again we had a centralized yet hub-and-spoke type approach where we said, “Okay, we are going to organize these for all of the practices, for all of the studies. The patients that are enrolled in our study protocol, we will organize these and basically create an environment where we call on national experts from around the country and, in fact, around the world at this point, that call in and provide input on the different cases that the physicians had enrolled.” We left it up to the physicians to decide which cases they wanted to present because they had some patients that they enrolled where they felt like they didn't necessarily have to present the case. So there was a lot of buy-in for these genomic tumor boards because we really discussed cases that were probably the most challenging ones and the most relevant ones.
So I think the genomic tumor board program was really the most significant development and the most significant infrastructure that we built. And in fact, the work that we did in Maine actually enabled us to design a cluster randomized study that we're now running through the SWOG Cancer Research Network. I'm leading that effort with a collaborator from Columbia in New York, actually, Meghna Trivedi. And so that was really a great success, and we will hopefully in a few years know if this approach actually leads to changes in some patient outcomes. We have some indication that it does from our own work, but we will see that in a more rigorous fashion.
The second pillar, if you will, the second part of the approach was that we have a dedicated clinical education group at JAX. So JAX Laboratories, as I said, a basic science cancer center, but we also have essentially an entire group dedicated to genomic education. And part of that group is focused on clinical genomics education. So we have a modular online program that clinicians can access, not just the physicians, but also the nurses and other people, other members of the patient care team. And in fact, in addition to the online program, we ran a few virtual educational sessions specifically for nurses, which we actually found was, nurses and clinical research coordinators were really one of the most important keys to success as well, that we get them on board and enable them to better understand the complexities of testing.
And then the third aspect, of course, was that we did provide the testing as well as part of this initiative, which we saw as kind of a method to really engage clinicians and take the pressure off the clinicians. “What if I order this testing? Are patients going to come back with significant out-of-pocket expenses?” Again, that was particularly relevant back in 2016, 2017, before the CMS coverage decision. So those three aspects were really what drove this program.
Dr. Rafeh Naqash: Excellent. Now what I gather is for something like this to come to a full functional state, you need a team and you need funding. So how did you define or identify the core group of people that were most important for this initiative? And what was the funding source? Because these days, nothing gets done without the appropriate level of funding. So I wanted to ask you and see how you manage some of those logistical issues.
Dr. Jens Rueter: Great question. So this whole program was really enabled by a large philanthropic grant, or donation, if you will, from a foundation called the Harold Alfond Foundation. It's a very large philanthropic organization in New England, and they're very Maine-focused. They have historical or family ties actually to Maine, and it's very important to them to bring Maine sort of to the forefront, sort of out of the rural disadvantage, and turn that into an advantage, which is why they agreed to provide funding for this program. And I agree with you that that is a critical step. This program was always in between a traditional research program that could be funded by an NIH grant, for example. I think that initially you need some startup funding first to get this going, and then later on, as you can develop more concise research questions, I think you can also apply for NIH funding for something like this. But certainly, philanthropy goes a long way here. So that was sort of the funding source, and, I think, very important.
Now, in terms of the team, that's actually a great question. You need a few different functions represented here. So I think, first of all, having some clinical expertise is important. So I was actually specifically hired to JAX for this program. I'm a medical oncologist. I actually still have a small practice in Maine as well, but I was in full practice before I joined JAX. And I was hired specifically for this purpose so I could engage with the community and sort of understand my colleagues over the state. You need a very good and rigorous program manager, someone who can really– It's a complex project that there are many aspects you need to consider and you really need someone that kind of keeps track of all the different activities and makes sure that things are moving in the right direction.
Since we are a research organization, we decided to roll this out on a study protocol. So we hired a clinical research manager that would basically disseminate and enable the study protocol and make sure that it's actually done correctly. Even though it was a low-risk observational study, we still wanted to make sure that we collect good data on the patients and the number of publications that we've been able to produce from this initiative, I think, speak to the quality of the data. And then as the program has evolved, we have actually added on a couple of other key functions within the program, and actually one of them pertains specifically to the genomic tumor boards, which again, I think are really critical to this. So you really need one dedicated person to organize these and coordinate these. It's a lot of scheduling. There's a lot of, as you know, from your own clinical practice, clinicians have very specific schedules, and if you really want to make this successful, you really need to make sure that everyone's schedules are accounted for.
And then we also recently added another function to our program, another individual who is a genomic navigator. Actually, we call it the genomic navigator. And I think that this individual, her job is if there are additional questions, for example, after genomic tumor board, or if there are just some very specific about a test report from the entire- it could be from anyone on the team, the physicians, the nurses, the research coordinators, she can help identify some additional answers to some additional questions. She can also help clinicians if they're interested in finding a clinical trial for the patient or find some supporting evidence for off-label drugs, for example, she can provide them with additional references. We have crafted documents that basically summarize the available evidence that exists for using a specific drug in association with a genomic marker. So I think genomic navigators are also very important, and I think there are some other individuals on my team now, but I think those are the core functions that you really should consider.
Dr. Rafeh Naqash: Thank you for giving us a detailed explanation of the team that I'm pretty sure has expanded over the last few years as you've tried to expand this program concurrently.
Now, going from the team to the platform, I was kind of interested to know a little more about the sequencing platform generally, as from my clinic, I do FoundationOne, or ERUS testing, or Tempus testing, etc., and I'm not very well versed with some of the platforms used. Could you tell us a little bit more about what these platforms are? How big the panels are from a DNA standpoint? And I see you did test for some RNA fusions as well. So could you tell us how that came about?
Dr. Jens Rueter: So when we first started the initiative, we started with a single assay that we ran through the Jackson Laboratory, and it was at the time a fairly contemporary test. It looked at both SNVs, insertions, deletions, and so forth on the DNA level and on copy number variants as well. And it was 212, at the time, 212 cancer-related genes. It was a homegrown panel if you will. This was back in 2017, 2018, and we also had a fusion assay that looked at RNA already at the time. So we were already kind of ahead of the curve at that point because, at the time, many assays were still just looking at DNA for fusion. So we already figured that it would be better to look at the RNA level. And then we sort of grew the panel from there.
The last panel that we used specifically for this first phase of the initiative had grown to 501 genes. It was already done on a specific platform. I think it was one of the Illumina platforms at the time. So we figured the off-the-shelf solutions weren't necessarily the right approach. We also added in tumor mutational burden. We added in MSI. We did not yet have at the time LOH or HRD assessment, but we certainly offered TMB and MSI. And we had the usual sort of commodity testing for PDL-1, which we actually sent out because it wasn't necessarily what we do in-house. So that was during the program as it is described in the manuscript.
I will say we continue this program. We're continuing the genomic tumor boards now. We've never stopped. We just continued after the study was over. We offer it essentially as a service now to the community, as an educational service if you will, and we now actually work with any test reports that the physicians provide. Again, I think the landscape has shifted dramatically and the testing itself doesn't seem to be as much of a barrier anymore. So we look at a lot of Tempus reports, KRAS foundation, every now and then we'll have something that's a little bit more unique, I would say.
There are obviously many other sequencing companies out there and we've actually found that this is– For our genomic tumor boards, we actually developed a template that is non-branded, that is just trying to put every test into the same table, front table, which I think has actually been very helpful for the clinicians because, again, sometimes you just can't find all of the relevant information on the front page. And we comb through every report and try to find every addendum that may have been generated and all kind of collate it in one single slide if you will, so that the clinicians have it right there and then we kind of talk it through as well. So that's essentially the evolution of the testing over the last six, seven years.
Dr. Rafeh Naqash: So this more or less sounds like a very state-of-the-art, contemporary approach that was available more or less to other clinicians at that time. 200 gene panel seems pretty extensive for 2018, 2019 and, as you probably know, things have gone to whole exome at this point, but I think you seem to be doing what was most appropriate at that time.
Now, going to the results between 2017 to 2020, your precision oncology program enrolled around 1600 people. The results were simple but very impactful, is how I describe it. Could you tell us some of the highlights from the results, what you identified, both from an implementation standpoint, participation standpoint, and from an impact at an individual patient's level?
Dr. Jens Rueter: Yeah, I'm happy to do that. So, I think the most important for us, the most important metric was that we were able to, over time, engage all practices and engage all– When we finished with the initiative, at that point, every physician, every oncologist in the state had actually been enrolled in our program as a study participant, which was actually one of the unique features, by the way, of our program: we said we were going to study both the physicians and the clinicians. So we had enrolled on our study 100% of the oncologists. It took us about 18 months to get to all the practices, which I think is an important metric for anyone who wants to pursue something similar. You have to always keep in mind that, even if you come in with a fairly solid proposal and something that is clearly of benefit to patients, every institution that you work with, it's going to take a while before you can get all the agreements signed and the IRB issues settled.
So it took us about 18 months, which I think is still fairly quick actually. And we listed the enrollment as well, the enrollment curve of patients in the paper. And it certainly did take some ramp-up in the very beginning, but then we really very quickly sort of ramped up to a steady state after about a year or so. We discussed about a little bit less than, about a third of the cases actually, at our genomic tumor boards. Almost three-quarters of the physicians actually participated in the genomic tumor boards as well. We ran around 200 GTBs throughout the initiative, and we're currently looking at the clinical outcomes of these patients. It's currently under review what the clinical outcomes were, but I can already say that we are sort of, I would argue, in about the same place in terms of patients that actually went on a genome-match therapy as many other publications in that venue. And it is actually, as you can probably imagine, rather complicated to define what a genome-match therapy actually is. And that will be coming out soon, hopefully soon.
So the other findings are also quite interesting and they have been published in other publications over the last few years. So at baseline, for example, we actually asked the patients, “What are your expectations? What are you expecting from this enrollment, from the tumor testing?” And we actually identified that the patient expectations were very high, which I think is important, an important finding - can be explained partially by precision oncology, it's a buzzword right now, and patients have certainly picked up on this and there are a lot of very high expectations in that it's going to change your outcomes. And physicians also at baseline felt quite confident, actually. There was a fairly good spread, but most of them felt quite confident that they would be able to utilize the information and actually explain it to their patients. They felt mch less confident, very on-point, in my opinion, that they would be able to put the patients on a targeted therapy or that their practice would have the infrastructure to support putting patients on therapy. So those are some of the other findings that we've identified over the last few years overall.
Dr. Rafeh Naqash: Thank you. And just on a side note, I was looking at Figure 4, which shows the number of cases per physician, and one physician particularly stands out with 120+ cases.
Dr. Jens Rueter: Yes.
Dr. Rafeh Naqash: Did that individual physician get any kudos after doing this excellent job?
Dr. Jens Rueter: Yes, actually this physician did. That's actually a really good point that you're bringing up. That's another important finding that I found quite fascinating, actually, that everyone is kind of the same at baseline. We offer the same thing to everyone. And you can see in Figure 4 in the paper that there is a significant spread in terms of how many patients each physician enrolled and also how many they presented at a genomic tumor board. And certainly that one physician is a very engaged member. We have a steering committee that we implemented very early on. That physician is also on our steering committee. And this really has contributed a lot of insights into what has worked well and maybe what hasn't worked so well. So it is a rather fascinating statistic, I agree.
Dr. Rafeh Naqash: One of the things I also noticed from your summary was that the uptake of the genomic testing and being part of this initiative was more for rural areas than for urban areas. And I was trying to understand why perhaps one of the reasons could be that it does help the community physicians in that setting. Was that what you saw, or was there another side to it that perhaps may not necessarily be explained in this manuscript?
Dr. Jens Rueter: Yeah. So, first of all, just to be very clear that the highest enrollment in rural areas was per capita so that’s an important distinction in my opinion. So, it obviously goes that the more rural areas are more densely populated. And what’s actually behind this is that the physicians that were working in those rural areas also just happen to be really engaged in the program and find a lot of value, especially, in the genomic tumor boards. So it was really very much a personable motivation. I would say, though, that the larger issue behind this, or the larger interpretation of these findings is that, especially at that time, I would argue that the– In Maine, you can always see that everything kind of moves from the south all the way to the north. It takes a little bit of time and it’s the same in pretty much anything, but in medicine as well. And so, I think at that time, the NGS testing just wasn’t really used all that much in the more rural areas. So I think the fact that we provided it– And again, there’s also less infrastructure at these smaller hospitals or smaller practices. So running through the hoops of getting prior authorizations and still managing potential out-of-pocket expenses just aren’t there and these were things back in the day for sure that were barriers.
So I think us coming in and saying, “Look, all you have to do is you mention to your patients that there is this program called the Maine Cancer Genomics Initiative, and if you’re interested, someone will contact you from the Jackson Lab and talk to you more about the study and see if you want to participate.” That’s all they needed to do. And then everything else kind of went from there. I think that is really probably one of the reasons why we had such a significant accrual in those more rural areas.
Dr. Rafeh Naqash: Amazing. And one of the things that I am very dreadful of is ‘tissue being the issue’ where, despite the biopsy, despite everything you do, the pathologist comes back. Or you send the tissue to the sequencing company, they come back saying, not enough tumor cells. What were some of the things that you did or your group did to help the people involved in this process understand why tissue matters? Because that can add to further delays in treatment. So I'm very curious to know what some of those things were that you tried to help everybody understand from an educational perspective.
Dr. Jens Rueter: We noticed that very much in the beginning, especially, of the program, so after about two or three months, we realized that there were a significant number of tissue failures and we realized we needed to address that. And we did that both by internal as well as external processes. So we actually looked back at our assay and said, "Look, maybe our requirements for DNA input are just too high. We need to rethink that and maybe there's a way to improve the laboratory processing so that we can actually work with less DNA." So I think that's a very important lesson.
And interestingly enough, I think this is still an issue to this day in a certain way with any of the testing laboratories, and we can get back to that in just a second. But I think the other aspect that was important here was, again, getting on the phone or on a Zoom call or whatever it was at the time, and really talk to the pathologist, talk to the clinicians, talk about, when you order a test, for example, think about beforehand as you're identifying the right specimen. Is this actually potentially enough tissue? If it's an FNA, maybe it's not enough. But if it's a good core biopsy, that's probably the better specimen. So that's certainly on the ordering physician side, but then also on the pathologist side, it was actually quite interesting. And one of the larger pathology practices in the state actually implemented something very smart, I think, as they sign out cases, and I think they do this universally on any case, as a pathologist signs out the case, he will actually indicate on the report which block should be used for sequencing. And they will actually indicate a tumor cell percentage, which I think is an excellent small step, but very impactful because it will reduce frustration on the side of the clinician, if a block is sent with not enough tissue, it will facilitate the workflow between the place where the tissue is stored, for example, and where it's cut, and it makes everything a lot simpler. And I think those are the kinds of things that you really have to think about.
I think in the contemporary times now where it's become quite common for testing companies to weed out samples that have 20% or 30% neoplastic content. What's interesting there, though, is that I feel like sometimes they're almost a little bit optimistic. They're always very clear on the disclosures in the report. They will say that there was a low tumor cell purity and some of the results should be interpreted with caution. But again, I'm not sure that clinicians are actually reading the fine print. So the example has kind of flipped a little bit that nowadays you're getting a lot more information than you did six, seven years ago. But you have to understand better as to how the information was derived.
Dr. Rafeh Naqash: I couldn't agree with you more as far as noting down in the pathology specimen which specimen is the most appropriate for NGS. It's a small thing to do, but I think it makes a huge impact when the research team or the nurses are actually trying to identify what specimen to send.
So now, Jens, coming to the last portion, I'd really like you to summarize in 30 seconds what are the future directions from this program? Where does it stand right now? And what are some of the things that you're trying to add on to the current format?
Dr. Jens Rueter: Where we stand is we're continuing to run our genomic tumor boards in the state of Maine. And as I mentioned earlier, we're also running a national study where we're running an additional GTB per week just to really see how impactful it is on patient outcomes. In the future, we need to improve the processes. We need to streamline the processes with genomic tumor boards, involve more technology to scale it, essentially, and make it more broadly available. And lastly, what's really important is we also need to think more closely about treatment options and enabling rural areas to have more access to clinical trials. And I hope that with the current post-pandemic thinking, that we can actually enable that with technologies, with virtual visits, with virtual consent, and so forth. And then, one other point, we also need to educate patients so that they know what to ask for when they're meeting with the oncologist.
Dr. Rafeh Naqash: Thank you so much.
Now the last portion, a minute or two is going to be dedicated to you specifically. So, Jens, tell us a little bit about your career trajectory. Where did you start? You mentioned earlier that you did or currently do practice clinical oncology. And how did you get into the field of precision medicine that culminated into developing such an impactful program?
Dr. Jens Rueter: We moved to Maine in 2010 after I completed my Hem/Onc Fellowship at the University of Pennsylvania, where I'd actually done quite a lot of translational and bench research. We came to practice. We moved to Bangor, and practiced here. And the Jackson Laboratory is really just on the road from where we are. We're at Mount Desert Island, right next to Acadia National Park, and I started collaborating with some of the scientists. Actually, early on, we built a tissue bank at the Northern Light Hospital here to facilitate translational research. And then when the funding became available, I received a call from the then CEO of Jackson Laboratory, and h, Ed Liu, and he said, "Jens, we're thinking about running this program and would you be interested?" And so that's how I joined JAX. And that's really when I started. I saw at the time already this gap that was widening and I saw how complicated it is to practice rural oncology. And I really saw this as a great opportunity to bring the field forward, to bring Maine forward, and to really address one of the major disparities that still exist to this day.
Prior to that, I spent quite a bit of time doing, as I said, bench research at the University of Pennsylvania. I also did my internal medicine residency at Tulane, and I always thought I was going to be a traditional physician-scientist. I actually feel great about this opportunity because I think it's addressing one of the major issues in contemporary oncology. So that's sort of how I got here. I'm originally from Germany, I went to medical school in Germany, did some research there, and then came to the United States about 20 years ago now for my postgraduate training, and I've stayed here ever since.
Dr. Rafeh Naqash: Excellent. Sounds like you're the right person for this job, with both a clinical translational bench kind of experience and having worked in different settings.
So thank you once again, Jens, for being a part of this conversation. I think at least I learned a lot. Hopefully, our listeners will find it equally interesting, intriguing, and perhaps implement some of the things that you have accomplished as part of this initiative.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Bio:
Jens Rueter, M.D. is the Chief Medical Officer of The Jackson Laboratory and Medical Director for the Maine Cancer Genomics Initiative.
Guest COIs:
No Disclosures
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JCO PO author Dr. Apar K. Ganti shares insights into his JCO PO article, “Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.” Host Dr. Rafeh Naqash and Dr. Ganti discuss clinical decision-making regarding biopsy; HER2 amplification, mutation, and targeted therapy; drug combinations; and aspects of the TAPUR and DESTINY-Lung studies. Click here to read the article!
TRANSCRIPT
Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the University of Oklahoma Stephenson Cancer Center.
Today we are joined by Dr. Apar Kishor Ganti. Dr. Ganti is a Professor of Medicine and associate director of clinical research at the Fred and Pamela Buffett Cancer Center at the University of Nebraska Medical Center. He's also a staff physician at the VA Nebraska Western Iowa Healthcare System. Dr. Ganti is the lead author of the JCO Precision Oncology article titled "Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study," which is also the TAPUR Study.
Dr. Ganti, thank you so much for joining us today.
Dr. Apar Kishor Ganti: Thank you for having me. I'm happy to be here.
Dr. Abdul Rafeh Naqash: For starters, Dr. Ganti, this is one of the trials from the TAPUR Basket study. So I wanted to take this opportunity since this is an ASCO initiative that has been there for a few years now. Could you tell us a little bit of background about the TAPUR initiative, what kind of trials are being run or have been run, and how it all started, basically?
Dr. Apar Kishor Ganti: The TAPUR Study or the Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial which evaluates the anti-tumor activity of commercially available targeted agents in patients with advanced cancers and tumors that have potentially actionable genomic alterations, like mutations, amplifications, etc. And this has multiple arms in multiple malignancies, using drugs that are currently approved in different indications and not necessarily approved for the indication that's being studied. But there's preclinical data that suggests that that particular drug may potentially be active in patients whose tumors harbor those mutations. For example, this present study that we conducted utilized a combination of pertuzumab and trastuzumab, both of which are FDA-approved for the treatment of patients with HER2-positive breast cancers. And we analyzed the efficacy of the combination of these two drugs in patients with lung cancer who had either a HER2 mutation or an amplification of HER2.
Dr. Abdul Rafeh Naqash: Thank you so much for giving us that background. Going to this study specifically, which is one of the very interesting TAPUR studies, what I'm reminded of especially is NCI-MATCH, for example, which runs on a similar premise to this study, where we've seen some successes and some not as exciting combination approach successes that is what we would have wanted to see.
For lung cancer specifically, as you and I both know and perhaps many of the listeners know, there's a lot of actionable drivers that have target therapies that are approved, could you touch on some of those to give a background on where the field currently lies and what are some of the important steps with respect to obtaining next generation sequencing, perhaps in patients. So what your practice is and what you would recommend for these individuals?
Dr. Apar Kishor Ganti: Certainly, non-small cell lung cancer, or non-squamous non-small cell lung cancer, to be more precise, seems to be the poster child for next-generation sequencing. And the importance of NGS testing cannot be overemphasized in these patients. For example, right now we have multiple different drivers that have drugs approved for the management of these patients. The first among them, obviously, was EGFR or epidermal growth factor receptor. And that has been followed fairly successfully by targeting ALK, ROS1, now, more recently, RET, MET, KRAS, and HER2. So if you look at lung adenocarcinomas, almost half of the patients will have a tumor with a mutation that is targetable. And so it's very important to make sure that these patients are tested for, before initiating any therapy. What makes it more important is that the standard of care for patients with non-small cell lung cancer without driver mutations is either immunotherapy or chemoimmunotherapy. And we have found that if a patient has a driver mutation, especially EGFR or ALK, even if their PD-L1 expression is extremely high, their response to checkpoint inhibitors is negligible. And so it is important to make sure that we understand what their molecular status is before starting any treatment in these patients. And I think the key point here is that every patient with advanced non-small cell lung cancer should have next generation sequencing studies done prior to initiation of treatment.
Dr. Abdul Rafeh Naqash: Absolutely. And in your practice, Dr. Ganti, do you tend to do liquid biopsies concurrently when you get a new individual with a diagnosis of lung cancer, or do you do it at some other time point?
Dr. Apar Kishor Ganti: Liquid biopsies, I tend to get them, but not as frequently as some would like. I tend to believe more in tumor biopsies, and I would get liquid biopsies only in the setting where a tumor biopsy is not feasible or if I feel that the patient needs treatment more rapidly than can be expected if I got a tissue biopsy. Liquid biopsies, in my opinion, are good, but they're very dependent on the tumor fraction that is present in the sample that you send. As you very well know, not all patients who have a driver mutation necessarily shed the mutation into the blood. And therefore, even if a patient has a driver mutation in a tumor, there is a small chance that the liquid biopsy may not detect it. So I tend to be more in favor of getting tumor biopsies for next-generation sequencing. In situations where the tumor fraction is high, the concordance between tumor biopsies and liquid biopsies is fairly good.
Dr. Abdul Rafeh Naqash: Thank you so much for that very important clinical decision-making thought process. At least in my practice, when tissue is often the issue, as you very well know, where you don't either have enough tumor cells or the biopsy is just enough to tell you whether it is squamous or non-squamous and not enough for any further sequencing, I try to get liquid biopsies whenever feasible and appropriate so that at least we can rule out some of the driver alterations before I put a patient on immunotherapies, due to the concern for subsequent toxicities if there are driver alterations. But I totally agree, I think tissue is definitely the standard, gold standard. And if you have overlapping mutations in tissue and liquid, then obviously it increases your confidence of treating that individual with that targeted therapy. But in general, tissue definitely, at least we should try to emphasize, and I try to do this often when I get a call from a community oncologist. I'm pretty sure you do the same where we ask for multigene broad gene testing NGS, so that especially when you have HER2 mutations, for example, you won't necessarily capture those as you show on your study here.
Now, going to your study, Dr. Ganti, could you tell us a little bit more about HER2 mutations and amplifications? And there's different levels of evidence where amplification may not lead to expression or expression may not lead to amplification. And then there is a separate category of HER2 mutations. And a lot of what we know for HER2 is from breast cancer. And recently, in the last two to three years now, is for lung cancer also. Could you tell us about how the field is shaping from a HER2 mutational landscape, an amplification landscape, in the lung cancer field?
Dr. Apar Kishor Ganti: As you rightly said, most of our knowledge from HER2 is from the breast cancer world. And frankly, I think we've been spoiled by the data on breast cancer. So, unlike in breast cancer, lung cancer seems to have a much lower frequency of HER2 alterations. And while in breast cancer, HER2 amplification seems to be important and predictive for response to HER2-targeted agents, in lung cancer, we see a combination of mutations and amplifications. So, in a large TCGA study, mutations in HER2 seem to occur in about 2% of all lung cancers. And amplification seems to be occurring in approximately a similar proportion of different patients. So, they seem to be mutually exclusive as best as we can tell.
And, unlike in breast cancer, where HER2 amplification seems to be directly associated with protein over-expression and response to tumor, the data in lung are much less robust. And so, it is not necessarily that an amplification will translate into a prediction of response to a HER2-targeted agent. And we and certain other studies have shown that patients who have HER2 amplification may not respond as well to HER2-targeted therapy as opposed to, for example, patients with HER2 mutations. So, that seems to be the discrepancy in HER2 amplification and HER2 mutations when you look at lung cancer versus breast cancer. And that's another reason why we are doing the TAPUR study at the various arms because what works in one specific cancer with the same mutation or same abnormality may not necessarily work in other cancers.
Dr. Abdul Rafeh Naqash: Absolutely. Thank you for indulging into that side of things. Now, going back to your trial, could you tell us a little bit of background on the eligibility criteria, how you chose some of the different mutations? What were the levels of evidence for some of those mutations from a pathogenicity standpoint, and then what were your endpoints, since this is a clinical trial with a Simon two-stage design?
Dr. Apar Kishor Ganti: Patients who were eligible for the trial included all patients with advanced lung cancer who did not have another FDA-approved treatment or were not candidates for another treatment. They all should have been 18 years or older at the time of diagnosis and have lung cancer with either ERBB2 amplification or we looked at 13 specific mutations, insertions, or deletions, and, if the patient had any of those abnormalities identified by any clear approved next-generation sequencing testing platform, then they would be eligible for the study. We chose these because of how frequently these specific mutations occurred in lung cancer and other cancers. And so, these 13 abnormalities were chosen from the host of HER2 mutations that you can see. Patients should not have received a previous HER2 inhibitor, obviously, and their LV ejection fraction should be normal because of the known risk of decreasing cardiac function with HER2-targeted therapy. They were treated with pertuzumab every three weeks and then combined with trastuzumab. Trastuzumab was given at a loading dose, initially of 8 milligrams per kilogram, and in subsequent cycles, we used 6 milligrams per kilogram. The dose of pertuzumab was a flat dose of 840 milligrams for the first dose and 420 milligrams for subsequent doses.
We continued the treatment till progression or excessive toxicity or patient withdrawal of consent. The endpoints were disease control, which we defined as objective response or stable disease for at least 16 weeks duration. Other endpoints were progression-free survival, overall survival, duration of response, and, of course, safety. We used a Simon two-stage design, as you said. The null hypothesis was that the disease control rate would be 15%, alternative hypothesis was 35%, the power was 85%, alpha was at 10%. So, if in the first stage, less than two out of ten patients had disease control, then the cohort would be closed for futility. If two patients or more had disease control of the first 10, then we expanded to an additional 18 patients for a total study size of 28. So, as far as safety analysis, any patient who received even a single dose of treatment was included in that safety analysis.
Dr. Abdul Rafeh Naqash: Thank you so much for giving us those details about the cohort. Going to the mutation or the amplifications, I'm looking at the cohort, so it seems like more or less, to some extent, there was an equal distribution of the mutations. 50% of individuals had mutations and then around 45%, 43% had amplifications. Did that play into your expectation of how the cohort did in terms of responses or the primary endpoints that you had set? Did you see differences based on those findings of mutations versus amplifications.
Dr. Apar Kishor Ganti: Yes, we did. The disease control rate was 37%, with an overall response rate of 11%. And when you looked at patients who had a partial response, which is three patients, all of them had ERBB2 mutation. And of the patients who had stable disease, only two patients out of seven had an amplification. Five patients had the mutation. So, again, this was similar to what we had expected, that based on previous studies, patients with mutation tend to respond better than patients with alterations.
Dr. Abdul Rafeh Naqash: Definitely. And going to one of the striking figures that you have in this manuscript, of course, you have the waterfall plot, and then you have the swimmer's plot and the spider plot. I'm very intrigued personally by the spider plot, which is the Figure 3 in your paper, especially with this individual that had this long, durable partial response. I believe this was the same individual with the mutation. I believe it was this 776 insertion. Was there anything, any other aspect that could have contributed to this response, or does this mutation, does it have any strong preclinical data of why the activity offer to direct therapy might be more pronounced in this mutation that you came across?
Dr. Apar Kishor Ganti: Not to my knowledge. I don't think we found anything specific or different about this particular patient compared to the others. So, as far as the mutation itself is concerned, it's a fairly common mutation, the G776 insertion. It is one of the most common mutations seen in lung cancer, and studies have shown that patients with the mutation tend to respond. But why this patient responded so long, it's difficult to say. I wish we were able to find out, but unfortunately, we were not able to.
Dr. Abdul Rafeh Naqash: Sure. Another question that I wanted to ask you since this falls into the precision medicine basket study questions. Does TAPUR have a different endpoint for different sub-studies? Because I vaguely remember coming across another paper where I believe a 16-week disease control was also the endpoint. So, is that something universal in TAPUR, or is it specific for specific tumor types and different combination approaches?
Dr. Apar Kishor Ganti: I believe that this is a more generalized feature of the TAPUR study, the stable disease for 16 weeks as a marker of response. Of course, different arms have additional endpoints, but I think this is one of the more common ones.
Dr. Abdul Rafeh Naqash: Now, there has been some work, as you very well pointed out in your paper as well, from others related to HER2 mutations, especially the DESTINY-Lung study. Could you tell us a little bit about that for listeners who may not be well aware of the DESTINY study with trastuzumab deruxtecan targeting the HER2 mutations?
Dr. Apar Kishor Ganti: So, DESTINY-Lung01 was a study of patients with ERBB2 mutated lung cancer. That study just looked at mutation-positive patients as opposed to what we did, looking at both mutation and amplification. And that study showed an overall response rate of 55%, which was much higher and led to the approval of fam- trastuzumab-deruxtecan in this group of patients. And so, one of the differences between our study and trastuzumab deruxtecan DESTINY-Lung01 study, is that our study included patients with both mutations and amplification and our study did not include any cytotoxic drug. And I believe that was one of the big differences, which may make the results of our study intriguing and potentially useful to patients who may not be able to tolerate a cytotoxic agent. Because, as you know, fam-trastuzumab-deruxtecan has the cytotoxic binder. It's an ADC and has been known to have some toxicities. And the thing about lung cancer is that these patients are relatively frail and may not be able to tolerate it. And so, that's one of the major differences, a portion at least for this combination, even though the response rates are much smaller than what we see with fam-trastuzumab-deruxtecan.
Dr. Abdul Rafeh Naqash: And from your practice, have you started using this combination from your study as a potential approach for individuals who may not be candidates for trastuzumab deruxtecan in your clinic?
Dr. Apar Kishor Ganti: I have not as yet because I have not come across a patient who would be eligible for this combination. In my practice, as we have TAPUR open, we have the tucatinib-trastuzumab arm that opened after this arm closed. So my priority is to try and enroll patients onto that cohort. And so I currently have one patient on that. And as you know, this is not a very common alteration, so we don't have as many patients with this. But definitely, this would be a combination that I would put patients on if I felt that they were not a candidate for fam-trastuzumab-deruxtecan.
Dr. Abdul Rafeh Naqash: So, Dr. Ganti, what's the next step after this since your study didn't meet some of its endpoints? What are you planning, or is there a plan to expand on this through the TAPUR mechanism?
Dr. Apar Kishor Ganti: Right now, I don't think that there's a mechanism through TAPUR to expand this particular cohort because there is also another cohort that opened subsequently with tucatinib and trastuzumab. But I think it would not be unreasonable to study this combination in patients who are not candidates for fam-trastuzumab because of the differences in toxicity. So that would be where I would potentially see a role for this particular combination, and I think it should be studied in that setting.
Dr. Abdul Rafeh Naqash: Excellent. Now, I try to dedicate a section of this conversation for provocative discussions that may not be addressed in your paper, but I still like to get insights from experts in the field such as yourself. So comparing it to the NCI-MATCH or some other precision medicine-based initiatives, we do often see that mutations that we think might be driving the process don't necessarily lead to really high or really promising responses to targeted therapies. So in this case, do you think, from a futuristic standpoint, a proteomic-based assay, since I think you work in the proteomic space as well, that would be an interesting way to look at whether signaling actually is altered from a mutation or an amplification, suggesting that that is driving the process, so would be a more attractive target than just looking at a mutational signature?
Dr. Apar Kishor Ganti: I think definitely that should be the way we should be looking at these kinds of studies, because even in this study, even if you look at fam-trastuzumab-deruxtecan and the DESTINY-Lung01 study, we have patients who have definite, identified drivers, and even there, only about half of the patients responded. It was much smaller in our study. But basically what I'm getting at is with the best of the drugs that we have today, only half of our patients respond with HER-2 mutations, for example. So I would definitely favor a more integrated approach to identifying those patients who would be candidates for these targeted agents and not just simply relying on a specific mutation.
Since we are being provocative, I would go one step further and say, “Hey, we have AI. And there are currently AI-based technologies which look at the entire next-generation sequencing profile and try to identify which drugs could potentially be effective in those patients based on a complete understanding of their entire tumor genetic profile, rather than just looking at one or two, or three mutations.” So that, I think, would be a much more robust approach through precision medicine. So, like you just said, that patient that we had who had a prolonged response, we don't know why he or she had a prolonged response. And maybe if we identified a pathway or pathways which were overexpressed or more active in that particular tumor setting, we would be able to identify better targets and better approaches for those patients. So I think that is the way to go in the future.
Dr. Abdul Rafeh Naqash: Excellent. Thanks for indulging into that provocative discussion and hopefully maybe five years down the line when we meet again or run across each other at ASCO, we will say, “Oh, it did actually happen, that multiomics is being used in a way that is suited for the need of the patient.” So matching the right patient to the right therapy at the right time.
So, Dr. Ganti, the last section is going to be dedicated to you as an individual. So you've had a very successful, brilliant career as a clinical trialist and as a lung cancer expert. Tell us, for the sake of our listeners and perhaps some of the early career junior investigators, what your career trajectory has been briefly, and what are some of the things that you felt were successful that could provide advice and insights to people who are earlier in their careers and trying to emulate what perhaps you have done or you are doing?
Dr. Apar Kishor Ganti: Well, that is a big one. I never thought of myself as being a role model for anyone, far less someone who's at the beginning of their career. But what I have always mentioned to students and residents and fellows is basically there is no substitute for hard work. Luck plays some role in this because you need to be at the right place at the right time for some of it, but hard work definitely will pay off. And the other thing that is important is not to get disheartened if your first clinical trial gets rejected or concept gets rejected, or if your first grant gets unscored. That is part of life, and persisting is probably the best way to continue.
Also, continuing to believe in yourself. I've seen a lot of folks, especially once they get into their second or third year after fellowship when things are not going the way they want to, they start to wonder, “Am I suited for this job? Am I the right person? Am I doing this correctly? Should I be doing something else?” And I think it's just a matter of time before they will find success. And also, the other thing is, if one particular approach does not work, there are always other ways that you can look at. So, for example, if you extend a bunch of clinical trial concepts that do not work out, you could potentially look at other ways of answering questions. For example, you could do retrospective analyses, come up with provocative, hypothetical generating questions that could be answered in the future in a prospective study. So there are lots of avenues to do that. And I think I was benefited by my mentors who helped me see this relatively early in my career.
Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Ganti, for all those valuable insights that you've learned over your career and hopefully will help some of the listeners. Before we finish, I'm going to ask you three rapid-fire questions that hopefully will let our listeners--give them a little bit of a sneak peek into you as a person. And you get like five seconds for each question. And they're not complicated questions. My first question to you is what is your favorite food?
Dr. Apar Kishor Ganti: Thai food.
Dr. Abdul Rafeh Naqash: What is your favorite place to go for vacation?
Dr. Apar Kishor Ganti: South Africa.
Dr. Abdul Rafeh Naqash: And what is your favorite hobby?
Dr. Apar Kishor Ganti: Reading.
Dr. Abdul Rafeh Naqash: Well, thank you so much again, Dr. Ganti. This was a very interesting conversation and hopefully, when you or others have other TAPUR-related trial results, perhaps they will again choose JCO PO as a destination for that work.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Bio: Dr. Apar Kishor Ganti, MD, MS, is professor of medicine and Associate Director of Clinical Research, Fred & Pamela Buffett Cancer Center at the University of Nebraska Medical Center and Staff Physician at VA Nebraska Western Iowa Health Care System.
Guest COIs:
Apar Kishor Ganti, MD, MS
Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Flagship Biosciences, Cardinal Health, Sanofi Genzyme, Regeneron, Eisai
Research Funding: Apexigen (Inst), NEKTAR Pharmaceuticals (Inst), TopAlliance BioSciences Inc (Inst), Novartis (Inst), Iovance (Inst), Mirati Therapeutics (Inst), Chimeric Therapeutics (Inst)
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JCO PO author Dr. Alicia Latham shares insights into her JCO PO article, “Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome.” Host Dr. Rafeh Naqash and Dr. Latham discuss microsatellite instability-high status as well as familial risk and testing. Click here to read the article!
TRANSCRIPT
Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center.
Today we are excited to be joined by Dr. Alicia Latham, Medical Director at the Memorial Sloan Kettering-CATCH, and the Assistant Attending Physician, General Internal Medicine and Clinical Genetics. Dr. Latham is also the author for our JCO Precision article titled "Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome."
At the time of this recording, our guest on this podcast had no disclosures.
Dr. Latham, thank you so much for joining us today, and welcome to our podcast.
Dr. Alicia Latham: Very happy to be here today. Thank you for inviting me.
Dr. Rafeh Naqash: For the sake of this podcast, we'll refer to each other using our first names if that's okay with you.
Dr. Alicia Latham: Sure.
Dr. Rafeh Naqash: So this is a very interesting, broad topic that I wanted to discuss with you, and hopefully, our listeners find it very interesting. It touches on a broad range of currently relevant precision medicine-related topics, which is mismatch repair deficiencies, colorectal cancers, and Lynch syndrome. Could you try to give us an understanding of what we know so far about colorectal cancers that are mismatched repair deficient as well as Lynch syndrome, which would be, hopefully, an interesting segue into your article?
Dr. Alicia Latham: Sure. In general, I think when speaking of mismatch repair deficiency in the setting of colorectal cancer, we know that the vast majority of the time it's somatically driven, not necessarily that there was an inherent genetic predisposition that drove it, and we've known that for quite some time. But the issue is that there's still about 15% of the time or so when you're looking at colon cancers, that a germline component is probably driving that mismatch repair deficiency, i.e. Lynch syndrome. And that became exceptionally relevant whenever universal screening for said tumors was occurring as a way to screen for Lynch syndrome. And even perhaps more importantly, with the usage and increasing usage of immune checkpoint blockade because we know that those cancers respond exquisitely well because of that driver. And in terms of our understanding, typically because patients with Lynch syndrome inherently have a defect in mismatch repair, their tumors, pan-cancer, which we published on previously in JCO, demonstrate mismatch repair deficiency or MSI high status, if that was contributed.
So really the point of looking at this was to take that initial work and kind of turn it on the flip side. And rather than assessing all tumors for MMRD status or MSI high status, to look at colorectal cancer tumors at our institution, find the underlying prevalence of Lynch syndrome, and then see how many presented with a mismatch repair proficient tumor and what that may or may not imply or mean for the patient clinically. That was really the whole point.
Dr. Rafeh Naqash: Excellent, thank you so much for the explanation. Now, I do remember when I was a fellow in my first-year fellowship, I would often get confused, and I think NGS was just becoming the thing of the day a couple of years back, especially for metastatic tumors. I would often get confused between MMR deficiency and MSI high. And for trainees who are going to start in a week or so into their fellowships, who hopefully will be listening to this, could you give us a simpler version of how you would explain to a new trainee what MMR deficiency versus MSI high is?
Dr. Alicia Latham: Sure. So we'll start with MMR deficiency. So IHC or immunohistochemical analysis has been around for a while. That's kind of your classic way of assessing for this. And really what that means is that when the tumor is stained for the mismatch repair proteins, they're found to be deficient, meaning that one or more of said proteins is not expressed in the tumor. So that's mismatch repair deficiency. Usually, the staining patterns have a very unique pattern to them, meaning that you'll typically see MLH1 and PMS2 absence go together, or MSH6 and MSH2 absence go together. They go hand in hand. I call it the “buddy system.”
Microsatellite instability - before defining what that means, I think it's important to explain what microsatellites themselves are. And so when I talk to trainees, I say microsatellites are just little repeat sequences throughout our genome that are kind of little “bookmarks.” And our mismatch repair system finds those little repeat sequences to try to look for errors, spelling errors. That's the spell checker of the mismatch repair. And so it scans, finds a bookmark, reads to see if there's a mismatch. If there is, it corrects it and then goes to the next one, and so on and so forth.
Over time, if those mismatches aren't repaired, then you may see a discrepancy in the now cancerous tissue versus the normal. And that is what's called microsatellite instability, meaning that the tumor, the variance in those repeat sequences is different in the tumor versus the normal tissue. They typically have a concordance rate of greater than 90%.
Dr. Rafeh Naqash: So basically, in your practice, do you often do, and I know you've touched upon some of the overlapping incidences in your paper, but do you, in your practice, do MSI testing using NGS and IHC testing on all patients that need to be tested?
Dr. Alicia Latham: So it depends on how they get to us. By the time patients have gotten to genetics, usually at MSK because we have this institutional protocol, MSK-IMPACT, these patients are offered paired NGS sequencing, so tumor-normal sequencing, and they can either consent to just somatic profiling, or somatic and germline. And so by the time we see them, our NGS profile uses MSIsensor for categorization of the MSI status. So they usually have that.
But if there's any discordance or surprising feature, say the patient comes in, their tumor is MSS but the patient has a known MLH1 germline mutation and the family history looks striking for Lynch syndrome, that's suspicious. So we'll do an orthogonal method to look at the tumor, usually starting with IHC to see if it's mismatch repair deficient because that's very easy to do. And then we can also have an additional analysis that's in the process of going through clinical validation called MiMSI, which is essentially an algorithm that has been trained as a machine learning tool on the original impact data and MSIsensor that has a higher clinical validity in tumors that have low tumor content. So MSIsensor is known to have a bit of a flaw in that in tumors with less than 10% of tumor content in the sample, that it may be artificially low. So that's why we also look at that too. So we typically do, if we're suspicious, we'll do an additional method.
Dr. Rafeh Naqash: Interesting. Now, going to this interesting work that you published in JCO PO, it seems the premise is more or less around understanding what percentage of patients with Lynch syndrome have mismatch repair proficient colorectal cancers that could be driven by other sporadic changes, genomic changes, or whatever factors that could be, perhaps, leading to tumorigenesis. So was that how you started this project? Or were you trying to answer a different question but understood that this could be a very clinically relevant or meaningful question also?
Dr. Alicia Latham: Honestly, how this came about was we had our first patient come in with- had known Lynch Syndrome and had a proficient tumor. And what brought up the question about it as to why it was clinically relevant is one, they were considering immunotherapy, and the oncologist was like, “Do I or do I not do this?” And then the second question is: well, what does this necessarily mean for the family? If this tumor is truly mismatch repair proficient, does that mean that the Lynch syndrome caused it, and so, therefore, someone that tests negative, or deficient, someone who tested negative for the Lynch syndrome, may be off the hook for screening? Or if it's truly proficient, does that family member now have a familial risk for colon cancer and should perhaps consider increased screening? So those were the clinical questions that came up in that case.
And because of that case, that was like, well, how many times does this really happen? Has anybody published on this yet? And we didn't see anything at the time, and we had this large impact data cohort. So we decided to dive a little bit deeper and see what we can find. It is rare, but it happens.
Dr. Rafeh Naqash: You bring this very interesting point that some of the very clinically relevant projects or research, it stems from a unique clinical patient scenario where you saw an individual, you tried to understand why, and you took it to the next step. In fact, I do drug development, Phase 1 clinical trials, and I have an individual with a history of Lynch syndrome and germline positive with osteosarcoma but mismatch repair proficient. And before reading this paper, I've come across some other data. In the Phase I setting when you don't have a target, your next best option is to go for immunotherapy--novel immunotherapy-based approaches. And in this individual, I was debating whether an immunotherapy approach would be reasonable or not. But based on the data and then looking at your paper, I am less convinced that with a mismatch repair proficient tumor, because in the standard care setting, obviously, immune checkpoint inhibitors have an indication for tumor MSI high, not germline. So these are rare, but when they happen, it does bring into question, like you said, implications for the family, whether or not immunotherapy is a relevant option in those individuals. So, very, very important to understand this.
So could you tell me, and the listeners also, walk us through the data set that you looked at? What was the denominator and how did you end up with the sample size that helped you understand this topic?
Dr. Alicia Latham: Sure. So we first started with just looking at our overall MSK IMPACT cohort at the time that had undergone germline or analysis of their DNA. And so that was over, at the time, 17,000 cases. Then looking at those, we wanted to understand and assess the underlying Lynch syndrome prevalence of all of those cases. So overall, it was 17,617 pan-cancer patients. And we found, of those, about a 1.5% prevalence of Lynch syndrome pan-cancer. And then of those we assessed, of those patients with known Lynch syndrome, how many had at least one colorectal tumor that underwent that NGS profiling, and that came out to about 36% or 86 cases.
Of course, because Lynch syndrome is known to have synchronous and metachronous tumors, there were a few patients that had more than one colorectal cancer assessed, so it actually ended up being 99 pooled tumors. So then you're looking at 99 pooled tumors there of those Lynch syndrome cohorts, of which about roughly 10% were found to be mismatch repair proficient, and they were also MSS or microsatellite stable by MSIsensor. So that was how we broke it down.
Dr. Rafeh Naqash: Interesting. Now, looking through your manuscript, I understood that you identified some unique differences between the mismatch repair proficient Lynch syndrome-positive individuals and mismatch repair deficient individuals in the cohort. What were some of the highlights of the different clinical characteristics that could be clinically meaningful?
Dr. Alicia Latham: Sure. So I think one of the most important things, at least from a genetics perspective, was we did find an enrichment among the mismatch repair proficient group of those having either an MSH6 or PMS2 germline variant. And that's notable because those are known to be kind of our lower-risk genes. And in fact, oftentimes patients and families don't meet typical clinical criteria for genetic testing in those families. So PMS2 is probably the most obvious case of that where the families don't really look suggestive of classic Lynch syndrome. That was significant even in a small cohort, so it was 89% of patients with mismatch repair proficient tumors had MSH6 or PMS2 mutations.
The other, while it didn't quite achieve statistical significance simply because it was a small cohort, the age of onset was different. So mismatch repair proficient, they were a little bit older. Our median age of onset was 58 in that group and then the mismatch repair deficient group median age was 43%. So I think if we had a larger sample size that would achieve statistical significance there.
The other important caveat was just kind of when they presented, what stage did they present at. So, unfortunately, we did see a higher prevalence of patients presenting with metastatic disease in our mismatch repair proficient group. And that makes sense because if these are patients that are typically with Lynch syndrome, that is perhaps a milder phenotype if you will, maybe they weren't identified early enough because the family histories weren't suggestive. So they weren't undergoing high-intensity surveillance compared to those that were in the mismatch repair deficient group that had the higher risk genes. And likely their family histories met clinical criteria for Lynch syndrome.
Dr. Rafeh Naqash: Thank you so much. Now, the number that stands out in your manuscript is 10%--with individuals that had Lynch Syndrome and having mismatch repair proficient colorectal cancers. In your tumor boards that you perhaps participate in with GI, medical oncology, or other multidisciplinary tumor boards, do you try to discuss some of this early on so that implementation and uptake of whether it's NGS or germline testing is high right from the get-go? Do you try in your tumor boards to suggest to the treatment team that they should have perhaps germline testing also before they see you or at least have ordered it by the time they see you and also a full NGS panel? Or is that something that's just routinely done at your cancer center?
Dr. Alicia Latham: It's routinely done at MSK. We are fortunate because of the MSK IMPACT protocol that they are routinely done. Having said that, if there is any sort of question, like I said before, oftentimes we'll talk to the oncologist about doing an orthogonal method just to verify. We also have patients that come from outside and maybe they've already had some sort of initial screening and so they wouldn't necessarily be candidates with insurance criteria, etc., for additional assessment. So we have to get a little bit creative in terms of our workup and how we can help those patients as well. But yes, we typically do. If you're suspicious, yes, we do recommend it.
Dr. Rafeh Naqash: Excellent. And I know, I think, with more and more precision oncology coming up, I was speaking with a few other clinical geneticist experts at ASCO, I think incorporating individuals with clinical genomics and genetics expertise like yourself, incorporating those individuals into tumor boards, not just molecular tumor boards, but the multidisciplinary tumor boards early on, I think, could make an impact as far as testing is concerned and as far as identifying some of these things early on is concerned.
Now I would like to ask you an interesting, provocative question that you necessarily haven't addressed in the paper, but it is nevertheless interesting. So when you found or you mentioned that some of these genes have different penetrants or some are higher risk in the MSI group, the mismatch repair deficient genes, or when you think about DNA damage response, you think about neoantigens, which goes into the context of immune checkpoint inhibitors. Has there been any data or what would you think from a perspective of whether a certain gene has a higher neo antigen burden associated with it, meaning a higher number of antigens that are necessarily something that the immune system thinks that they're foreign, which helps immune checkpoint inhibitors to work? So do you think there is a difference from a neoantigen perspective in these genes suggesting that a certain tumor with a PMS deficiency versus another tumor with an MSH6 deficiency have different responses or outcomes to immune checkpoint therapy?
Dr. Alicia Latham: My gut tells me perhaps. We know that when you're looking at different tumors for their MSI status or their MMR status, that MSH6, for example, mutation carriers, seem to have lower levels of that. So even just looking at our MSIsensor scores in general, they tend to be lower for MSH6 mutation carriers. So to me that signal, if it's not as pronounced, you would think that perhaps that's also there. And I think other groups have looked at that, that you're seeing that. As far as clinical response, I don't know if you're, in terms of comparing tumor to tumor, if they have the same profile, I would suspect that the response would be similar. Of course, if there's something varied, then I think that whichever profile has that higher tumor mutation burden or those neoantigens would respond better.
But I think at least as a non-oncologist, as a geneticist, and someone who's very interested in prevention, I think it's something that is incredibly important for the vaccine trials that are going on to understand and making sure that patients that we are recruiting to these trials have PMS2 and MSH6 associated Lynch syndrome, that we're not just focusing on those that we know have higher tumor mutation burden or MSI status because those are the patients we want to make sure that we're including in designing those and targeting the appropriate antigens for those trials because that is very important work that I know colleagues at other institutions are working on diligently.
Dr. Rafeh Naqash: I think those are very interesting thoughts and perhaps somebody in the near future will address some of these interesting concepts.
One of the things that I didn't see in the paper that we are discussing today is what were the potential somatic, tumor somatic, events in the mismatch repair proficient colorectal cancers in the 10% that you identified that could have led to their tumor genesis. Did you look into that? Is there any subsequent work that is going on in that space?
Dr. Alicia Latham: Yeah, we are looking at it subsequently, we didn’t for the content of this paper. We were really focused on the MSI and mismatch repair proficiency. But yes, there was actually a study that is assessing this - really more of a pan-cancer study. We started here and one of my colleagues at MSK is working on looking at this pan-cancer and trying to understand these orthogonal methods, the tumor somatic drivers. They actually presented this abstract at ASCO this year. So trying to understand what actually did drive this. And is that something in terms of treatment that we need to be very much aware of? And I think the answer is ‘yes.’ So more to come on.
Dr. Rafeh Naqash: That's excellent. So hopefully, we'll see something in that space from your group in the coming months.
Another question you touched upon earlier is the implications for familial testing. So if an individual, for the sake of our listeners, if an individual comes to my clinic tomorrow with a mismatch repair proficient tumor but with a Lynch syndrome history, something similar to that I described earlier for my patient with sarcoma, what would the counseling be from a geneticist standpoint for the family? How would you explain the risk? How would you explain the tumor in that individual and then testing for the family members?
Dr. Alicia Latham: So regardless of what the tumor demonstrated, I think it would be important, if this is a known Lynch syndrome patient, explaining to close family members that they have a risk of having this, a first-degree family member’s 50% chance of sharing the mutation. And that's important regardless of what the tumor shows. Where I think it's more of the nuance is explaining to particularly those patient family members that test negative for Lynch syndrome. For example, in colon cancer, we say that if you have a first-degree relative with colon cancer, that, regardless of the looks like familial colon cancer without a genetic explanation, that you start colonoscopies a little sooner and you do them more frequently. So rather than 45, you start at around age 40, rather than every ten years, you repeat every five. Of course, if polyps appear, that's altered.
And so because we don't quite know if a mismatch repair colon cancer was really driven by that germline, say PMS2 mutation, could this in fact be a sporadic colon cancer that's incidental to the PMS2 mutation? Therefore, that family member that tests negative may be at an elevated risk of colon cancer and may want to consider doing colonoscopies a little sooner and a little more frequently. Having said that, I think that it's a very important conversation to have with the family members to make sure that they are very clear on that. But I think that there's a lot of work that needs to be done to understand - is it truly the case? Is there any role at all? What can we use as far as understanding kind of a different pathway for certain mutation carriers like MSH6 and PMS2? Is there something else that we're missing? So for now, I counsel my patients that I would recommend, even if you test negative, to screen a little bit earlier and a little more frequently until we understand this a little better.
Dr. Rafeh Naqash: Thank you so much for that explanation. And this was a very interesting opportunity for me to help take a deeper dive into this paper, hopefully for our listeners as well. Now, a few questions about yourself, Alicia. So we like to know a little bit about the individual or individuals behind the work. So tell us a little bit about your training and your current interests and also what advice you have for early pre-investigators in the space of precision medicine, the way it's developing right now.
Dr. Alicia Latham: Sure. My training is a little bit unique, so I'm not a medical oncologist by training. I knew that I wanted to be on the prevention side, not necessarily the treatment side because when I was in medical school what was available was chemotherapy. And that wasn't for me. I didn't want to do that. And so I trained in family medicine and then completed a fellowship in medical genetics with a focus on cancer. And my clinical focus is really taking care of patients with a genetic predisposition, so at-risk patients. In that regard, I serve as Medical Director for our program at MSK called MSK CATCH, which is really for patients that have a germline susceptibility of cancer, but they want to be followed and managed at Sloan. So that's my clinical focus.
And then my research is really looking at germline predisposition, primarily Lynch syndrome, to try to understand what do we know and more importantly, what don't we know about this pan-cancer syndrome and how can we help these patients and families. Many of my studies have looked at that from understanding descriptively Lynch syndrome among different types of cancer, like small bowel cancer or the MSI status pan-cancer paper. But importantly, where we're going in the future and where I am going in the future is looking at where can we go to early detection in these patients and really increase screening because right now, the only proven effective screening for Lynch syndrome is colonoscopy, and yet it's a pan-cancer syndrome. So we have a lot of work to do.
Dr. Rafeh Naqash: Thank you so much. It was really awesome to talk to you today. And thanks for explaining some of the interesting concepts around MSI-high colorectal cancers and Lynch syndromes. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Biography: Dr. Alicia Latham is Medical Director at Memorial Sloan Kettering-CATCH and Assistant Attending Physician, General Internal Medicine and Clinical Genetics
COIs: none
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JCO PO authors Dr. Michael J. Kelley and Dr. Katherine I. Zhou share insights into their JCO PO article, “Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion–positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.” Host Dr. Rafeh Naqash, Dr. Kelley, and Dr. Zhou discuss the robust Veterans Affairs (VA) National Precision Oncology Program (NPOP), accurate identification of gene fusions, and toxicities landscape of TRK inhibitors. Click here to read the article!
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and assistant professor at the OU Stephenson Cancer Center in the Division of Medical Oncology.
Today, I'm thrilled to be joined by Dr. Michael J. Kelley. Dr. Kelley is the executive director of Oncology for the Department of Veterans Affairs. He's also the chief of Hematology-Oncology at the Durham VA Medical Center, and also a Professor of Medicine at the Duke University School of Medicine. And he's also a member of the Duke Cancer Institute. We are also joined by Dr. Katherine I. Zhou who is a Hematology-Oncology fellow at the Duke University. Dr. Zhou also spent time at the Duke Medical Center as part of her fellowship training, which I believe is how this project that was led by her came to fruition.
So thank you both for joining today. This is going to be, hopefully, of very high interest to our listeners and I look forward to chatting with you both.
Dr. Michael Kelley: Great, thanks for having us.
Dr. Katherine Zhou: Thank you for having us.
Dr. Rafeh Naqash: Thank you so much for joining. So I was very intrigued with this paper, and this paper follows a recent podcast that we had with Dr. Alexander Drilon, who's led some of the NTRK tropomyosin receptor kinase inhibitor studies that have been published in the last several years. And we had a very interesting discussion a couple of weeks back and I felt this was going to be a very interesting subsequent discussion into what was also an interesting discussion with Dr. Drilon. So what caught my attention is obviously the fact that you guys in this report, which is a real-world report, did not exactly see what we generally expect from clinical trials as far as response to target therapies in NTRK fusions.
So before I ask you questions related to this project, one of the very interesting things at least I found was the fact is that the Veterans Health Administration is the largest integrated health system. Studies, whether conducted in the UK, for that matter European countries, or in Canada, they have integrated health systems which we do not. But we do have this advantage of the VA trying to do things in a very unique, centralized manner. So I wanted to ask Dr. Kelley first, how is it that you have implemented this National Precision Oncology Program, the NPOP as you call it, into the VA precision medicine workflow and how does it help in conducting research studies like the one that you published in the JCO Precision Oncology?
Dr. Michael Kelley: Yeah, thanks for that question, Dr. Naqash. The NPOP started in 2016 as a national program and right from the beginning it grew out of an effort that was a joint collaboration between both clinical operations in the VA and the Research Office or the Office of Research and Development. It was designed from the very beginning to support discovery, new knowledge generation, and identifying patients for clinical trials in addition to bringing them best-in-class molecular testing and a consultation service.
So it was initially funded out of the Cancer Moonshot 1 in 2016 when President Biden was then Vice President. The VA endorsed the model going forward in 2019 and now it's continued on and grown even bigger, it's expanded both in terms of scope and the complexity of the testing that's been done. So it was offered as services to facilities. They didn't have to do this, but I think they all saw the value of using NPOP to provide this group of services and that's what led to the generation of the robust underlying dataset that Dr. Zhou has used for this paper.
Dr. Rafeh Naqash: Definitely. Thank you so much for that explanation. I did not know, and was not well aware, of how robust this program is. So I think it's a great learning opportunity for our listeners to know that a program like this exists. As we all know, there are different platforms, sequencing platforms, that each institution uses, whether it's commercial or whether it's in-house based. But the fact is, until and unless we have big pool datasets like the ones that you have generated or have access to, it's not easy to answer real-world questions.
So first of all, I'd like to congratulate you and the rest of the VA administration to set up a program like this that hopefully is helping in matching the right patients to the right therapies and in clinical trial approvals. Now, before we take a deeper dive into the study that Dr. Zhou led, I did want to ask you, you have access to this amazing centralized platform, what are the kind of sequencing strategies or platforms that you use as part of this program? And is there an incorporation of molecular tumor boards to help understand some of these sequencing results that sometimes can be a little complicated to understand even for oncologists who look at these reports on a daily basis? So could you tell us a little bit more about that, Dr. Kelley?
Dr. Michael Kelley: Yeah, certainly. So the VA contracts for the sequencing service, currently we're contracting with Foundation Medicine and Tempus for the comprehensive genomic profiling. There are some other services, and before we started using Foundation, there were two other companies that we used. There is a molecular tumor board. Our molecular oncology tumor board is designed primarily for case-based education. But there's also an asynchronous on-demand consultation service that occurs electronically because we have a unified electronic health record system. So any oncology provider in the country can enter a request through what's called an interfacility consult. It comes to a team, that team vets that, discusses it with the appropriate experts; that includes molecular oncologists, molecular pathologists. A lot of oncology pharmacists have been trained at a course that’s at the University of Kentucky.
And we have a lot of experience in doing this since that service was set up in 2016 as well, right from the beginning, because we understood the complexity of the data and the need for every oncologist across our enterprise to have access to the very best interpretation of that.
We also have educational sessions that are integrated into the molecular tumor board time slot we call primers in terms of the underlying science of why you do the interpretations the way you do. And then there's also some additional education that we'll be endeavoring to offer to our staff and our oncologists coming up this year.
Dr. Rafeh Naqash: Excellent. It sounds like you definitely have taken this into a very multidisciplinary approach where you're incorporating oncologists, pharmacists, and perhaps even genetic counselors and then, obviously, keeping the patient at the center and trying to find the best possible therapies that are most relevant for that individual.
Now, going to Dr. Zhou's study here. Dr. Zhou, first of all, it's great to see a fellow lead a study and then especially, I think you're our first fellow on the podcast. We've had a lot of different individuals, but we have not had a fellow before. So thanks for coming.
Could you tell us, for our listeners, what drove your interest into NTRK fusions? As we know, they are rare, something that is not commonly seen, and we do have clinical trial data in this space. So what was the idea behind looking at a real-world data set? Did you start out with a hypothesis or were you just interested to see how targeting these fusions in the real-world setting, actually, what kind of results does it lead to?
Dr. Katherine Zhou: Yeah, well, first of all, thanks for the question. And I do just want to mention that although I did sort of bring this project to the finish line, it was started by another fellow, Vishal Vashistha. So just wanted to mention that. And I think the interest was really just that NTRK is such a rare fusion and just a difficult one to be able to study, like you said, in the real-world setting. And we have the advantage of having so much data through the VA and through NPOP, specifically. And so having seen such great results with the TRK inhibitors and clinical trials, I think there's this big question of how that translates into the real-world setting. We have the ability to do that with our large patient population.
Dr. Rafeh Naqash: Excellent. And again, it's nice to acknowledge the support that you had from the other individual who co-led this study. Now, since you would have, I’m guessing, done most of the analysis here and looked into the whole idea of the kind of results that you saw—and from my understanding, you looked at the entire VA data set and tried to understand first the incidence or frequency of NTRK fusions and also responses to treatment, which I think is the main message—but could you tell us a little bit more about the data set? How did you acquire the data set, and what it took to analyze? Because obviously every project has a very unique story, and I'm guessing there's one very unique story here, since as a fellow you have limited time to do all this interesting work. So how did you navigate that and analyze and work with some of the things that you had to look at to get to the results?
Dr. Katherine Zhou: Yeah, so again, this was work that was done with multiple people involved, of course. And we used what we had, the resources we had available, some tools we had available through the VA. So first, looking at NPOP and looking at patients who are sequenced through NPOP, we could just find all the ones who had an NTRK rearrangement of some kind. The second way we went about finding patients was through the CDW or the Corporate Data Warehouse where we could see which patients were prescribed larotrectinib or entrectinib and kind of go backwards from there and see which of those patients had NTRK alterations or specifically NTRK rearrangements. And so we combined the patients from both of those different methods to come up with our cohort at the end of 33 patients with NTRK rearrangements and 12 patients who are treated with TRK inhibitors.
Dr. Rafeh Naqash: Excellent. Could you walk us through what was the subsequent analysis as far as how many NTRK fusions? I know you mentioned in the paper about DNA versus RNA-based testing. So how many were DNA-based, how many were RNA-based? I think there's some element of ctDNA-based testing also, or what tumor types those people had so that we get an understanding of what's the landscape of the findings that you had.
Dr. Katherine Zhou: Sure. Since this is a real-world setting, as you may expect, the vast majority of the sequencing was done through tissue DNA sequencing, and that was the case. So for the 25 patients who were sequenced through NPOP that we found who had NTRK rearrangements, 23 of them had tissue DNA sequencing. And then one was tissue DNA RNA, and one was cell-free DNA sequencing. And so using that and being able to go back and look at how many patients have been sequenced in NPOP in total, we could kind of come up with a yield, although the numbers are very small. But we do see that there does seem to be probably a lower yield, for example, with cell-free DNA sequencing, as one might expect.
And then looking at our total group of 33 patients, if we look at what types of cancers they had, we did have quite a few patients just based on prevalent tumors at the VA, I think, and in the population, prostate cancer was common, lung cancer, and then we had smaller numbers of colon and bladder, and I think there's a pancreatic cancer patient. We did have some of these rarer tumor types that more commonly have NTRK fusions as well, so like papillary thyroid carcinoma, and salivary gland cancers as well as soft tissue sarcomas.
Dr. Rafeh Naqash: Question for you, Dr. Kelley, related to this data set: do you think that given that the denominator that you have is a unique population, the VA population, that's often males, they're usually above the age of 18, could the frequency have been influenced by that denominator where you may not have been able to capture, let's say, some of the rarer tumors that happen in the younger patient population, for that matter? Could that be a little bit of a bias here?
Dr. Michael Kelley: Definitely. The population of veterans that have cancer that is treated in the Veterans Health Administration do represent generally adult males in the United States, but there is some skewing in certain regards. One of them is towards a higher frequency of smoking status. So not current smoking, which is actually about the same as the national average of about 11%, but the former smoking rate is about twice as high as it is in the rest of the United States. So we may have a lower frequency of some actionable variants in cancers in general because there's a higher etiological role for tobacco smoke in our population. But overall, looking at adult men if we look at like EGFR mutations, our incidence of EGFR mutations in adenocarcinoma is similar to what is reported in other real-world evidence bases from the United States, which is significantly lower than that which is found in academic medical centers.
Dr. Rafeh Naqash: Thank you. I'm a big fan personally of real-world data sets. I do a lot of this with some other collaborators and generally, I do phase I trials, which is why I’m interested in precision medicine. And two weeks back, actually, I had a patient with prostate cancer, who ended up having NTRK fusion on a liquid biopsy. Now, you do talk about some of this related to in-frame or out-of-frame fusions and how that can have interesting aspects related to the kinase domain functionality and RNA expression. Dr. Zhou, for the sake of our listeners, could you briefly describe why understanding some of that is important and what implications it has?
Dr. Katherine Zhou: Yeah, so I think the oncogenic NTRK fusion that we think of and that's being targeted by the TRK inhibitors is a fusion 5-prime of a protein that forms a dimer and on the 3-prime end is the kinase domain of the tropomyosin receptor kinase. And so you have to have some kind of a gene fusion that results in not only the transcription of that RNA fusion, RNA transcript, but then the translation of that fusion protein. So that needs to be, like you mentioned, that has to be in frame so that the entire protein is translated and expressed and it needs to include the kinase domain. It can't be the other end of the NTRK gene. And both of the genes need to be in the same orientation, of course. And then also the partner gene probably matters in that the ones that we know that actually cause activation of this oncogene are the ones that sort of spontaneously dimerize. And so that's a lot of requirements that we don't necessarily see when we just get, for example, a DNA sequencing result that says there's an NTRK rearrangement.
Dr. Rafeh Naqash: Excellent way to describe the importance of understanding the functionality of the activated oncogenic fusion. Now, I know here in most of the patients that you have is DNA sequencing and I'm sure you'll talk about some of the results. And when you connect the results to the kind of data that you have, do you think not having the RNA assessment played a role in not knowing perhaps whether those fusions were functionally active?
Dr. Katherine Zhou: Yes, I think we can't know for sure without having the RNA sequencing data. But certainly, that is a pattern in our small number of patients that we saw and something that makes sense just in terms of the mechanism of this oncogenic fusion protein. So I think that is a question of when should we be doing RNA sequencing to confirm that a fusion that we see on DNA sequencing is actually transcribed into RNA and how do we use RNA sequencing in a cost-effective and useful way to be able to detect more of these NTRK fusions that are actually clinically relevant.
Dr. Rafeh Naqash: I absolutely agree with you and this is an ongoing debate. I know some platforms, commercial platforms that is, have incorporated RNA sequencing both bulk or whole transcriptome as part of their platform assessments, but it's still not made inroads into some other sequencing platforms that are commercially used. So it's an ongoing debate, but at the same time helping people understand that certain fusions need some level of RNA assessments to understand whether they're functionally active or not. Which again has implications, as you pointed out in terms of therapies are extremely relevant.
Now, going to the results, which again was very interesting, could you tell us about the findings from the therapeutic standpoint that you observed and what your thoughts are about why you saw those results which were very different from what one would have expected?
Dr. Katherine Zhou: Right. So in the clinical trials of larotrectinib and entrectinib, there were quite high objective response rates on the order of 60%, 70%, even almost 80%. In our very small real-world group of 12 patients who were treated with TRK inhibitors, nobody had an objective response and five patients had stable disease and everybody else, the other seven patients, progressed.
And so the question is why did we see such a big difference compared to the trials? I sort of think of this as two big buckets. One is the population that we were looking at. So this is a real-world population. For example, in the clinical trials, there were almost no Black or African American patients, whereas here we had about 30%-40% Black or African American patients. Because it’s a VA population, it was very heavily male, of course, the age groups are also different in that we didn't have children in the VA population whereas children were included in the trials. And the tumor types also differed because I think in the trials, which makes sense, there's a bias towards tumor types that have more NTRK fusions, and some of the tumor types we were looking at are just common tumor types like prostate and lung cancer where NTRK fusions are not common. But just because there are so many patients with these cancers, we did see them. And so certain of these groups, particularly certain racial and ethnic groups as well as certain tumor types, were not really represented in the trial to the extent that we can make conclusions about whether TRK inhibitors are effective in this population. So that's one.
The second part, I think we've already talked about some, is just the method of detecting these NTRK fusions and how many of these NTRK fusions were actually truly producing oncogenic fusion proteins. And I tried to sort of categorize some of these fusions as being canonical in that they've been more studied. We know the partner gene, they are known to produce an oncogenic protein and to respond to TRK inhibitors. But actually of the four patients who had what we called canonical fusions, all four of them had stable disease at least, whereas the ones that were noncanonical mostly did not have a response or have even stable disease and mostly just progressed. And so then you wonder whether they even had the actual target protein we thought we were targeting. So this is where the real-world setting we're not doing the RNA sequencing or this additional testing to confirm that it's an oncogenic fusion protein.
Dr. Rafeh Naqash: And I do see in your results there's a patient especially—you pointed out canonical and noncanonical fusions—you have a patient with a papillary thyroid cancer that I believe had a stable disease for close to two years plus. Is there anything interesting apart from an NTRK fusion in that specific patient where certain co-mutation could have played a role or certain other factors that do you think played into the fact that this patient had stable disease but didn't respond on the TRK inhibitor?
Dr. Katherine Zhou: I don't have a great answer for that. I think this is one of the cancers that was well represented in the trials and that commonly has NTRK, or more likely has NTRK fusions. And this was a well-studied canonical NTRK fusion. So I think those are all reasons. The question of co-mutations I think is really interesting. We didn't have the data for every single patient, but for the ones we looked at a lot of the time, NTRK fusions are mutually exclusive with other driver mutations. So we didn't see a whole lot of commutations that we could sort of differentiate between responders or stable disease and progression.
Dr. Rafeh Naqash: Thank you. Going to the toxicities, as a phase I trialist myself toxicity is the bane of my existence where we have to label toxicities, attribute toxicities, understand toxicities. The trial, obviously, as you very well know, that in the trials, they didn't have a lot of toxicities that caused patients to come off or required significant dose reductions, which is not the case compared to what you saw. Could you tell us a little bit about the landscape of toxicities for TRK inhibitors and what you saw in your cohort? That, again, I feel was interesting.
Dr. Katherine Zhou: Of the 12 patients, I think two-thirds of them had either dose reduction or interruption or discontinuation, or some combination of the above. The toxicities we saw were more common than, or at least led to discontinuation and interruption and dose reduction more commonly than in the trials. But the toxicities we saw were also seen in the clinical trials. So LFT elevations, creatinine elevations, neurotoxicity, some cytopenias. We didn't actually see a whole lot of that, but those were present as well, and then some sort of nonspecific things like fatigue. And so, as much as we could tell from retrospective trial review, at least these were severe enough to lead to holding the drug.
Dr. Rafeh Naqash: Thank you so much, Dr. Zhou. Question for you, Dr. Kelley. Putting this into perspective, the analysis that you did, how would you connect it to other real-world questions that one could answer using these kinds of data sets? So basically, what are the lessons learned from this amazing program that you guys have run successfully and are, I'm guessing, expanding in different directions? And how can you use a program like this to look at some of these unique questions using real-world data sets?
Dr. Michael Kelley: There are a couple of, I guess, next steps for us that are based off this study and other information that we've gotten in other analyses from our NPOP data set. So, first of all, access to an RNA-Seq test. So that has been resolved to some extent, in that we now have two options for comprehensive genomic profiling, one of which does have RNA-Seq.
And then the other approach that we're doing is to do more robust data generation. So we're going to be launching a study to collect prospective data on patients who are treated with off-label drugs. And as part of that, we will also have an on-label cohort for rare populations or any investigator in the VA who's interested in a particular drug or a particular genetic variant. They'll be able to tie into this protocol, and we will then collect data from across the system prospectively, which we think will improve the quality to some degree.
And then thirdly, I think there's an opportunity to merge the initial generation of data in rare genetic types or other populations, which are highly selected by doing a distributed type of clinical trial where patients can be enrolled in prospective treatment trials. So we're not just generating data based on their real-world exposure to FDA-approved drugs, but we're generating data as we're developing the new drugs, we can have a much more heterogeneous and representative population of patients enrolled in clinical trials. So this is called the decentralized clinical trial model. We're starting to launch some trials with industry partners in this area to test out the model. If it works, I think we'll be able to help contribute to the knowledge that we all can use in terms of the patient types, the patient characteristics, but also some of the different tumor characteristics, and also to bring clinical trial opportunities to a more representative group. A lot of the initial clinical trials are done in urban areas, rural populations in VA are about a third of our patients live in rural areas, compared to only 14% of the country. So we think this is a very important diversity issue that should be addressed. Those are some of the ways that we're taking a lesson from this trial and other data that we have to sort of bring it forward.
Dr. Rafeh Naqash: Those are excellent next steps and I think the kind of work that the VA is doing and this specific program, Precision Oncology Program, the NPOP program is doing, it's definitely setting up a unique standard in the United States where we have been limited by not having a centralized database. So setting something up of this sort hopefully will help answer a lot of these unique, interesting questions as you have access to data. And then the fact that you mentioned decentralized clinical trials and trying to cater to this access issue for patients in the VA system, I think that would be huge.
And again, I congratulate you and your team on these efforts, and once again, thank you for joining us today and making JCO Precision Oncology a destination for your interesting work. We hope to see more of this work subsequently and hopefully, I get a chance to talk to you more about all the exciting stuff that you guys are leading within the VA health system.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.
The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Bios:
Michael J. Kelley, MD, is Executive Director of Oncology for the Department of Veterans Affairs, Chief of Hematology-Oncology, Durham VA Medical Center, Professor of Medicine at Duke University School of Medicine and Member of the Duke Cancer Institute.
Katherine I. Zhou, MD, PhD is a hematology-oncology fellow at Duke University. She also spends time at the Durham VA Medical Center as part of her fellowship training.
COIs:
Michael J. Kelley, MD
Research Funding: Novartis (Inst), Bristol-Myers Squibb (Inst), Regeneron (Inst), Genentech (Inst), EQRx (Inst)
Katherine I. Zhou, MD, PhD: No disclosures
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JCO PO author Alexander E. Drilon, MD, shares insights into his article, “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers” and the article’s findings of the activity of larotrectinib in patients with advanced lung cancer harboring NTRK gene fusions. Host Dr. Rafeh Naqash and Dr. Drilon discuss drug development, testing for fusions, resistance mechanisms, and cancer metastases. Click here to read the article!
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center.
Today we are excited to be joined by Dr. Alexander Drilon, Chief of the Early Drug Development Service and Medical Oncologist on the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center and lead author of the JCO Precision Oncology article “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers.” Our guests' disclosures will be linked in the transcript.
Dr. Drilon, welcome to the podcast and thank you for joining us today. We're really excited to be discussing this topic with you.
Dr. Alexander Drilon: It's my pleasure and thank you for the invitation.
Dr. Rafeh Naqash: For the sake of this podcast, we will refer to each other using our first names. So, Alex, you've led the development for some of these agents targeting NTRK. So it's really timely that you're coming onto this podcast to not just discuss this very interesting paper that you published in JCO Precision Oncology, but also the general landscape of NTRK. So could you briefly tell us about the history of the drug development process behind NTRK fusions, when it started, how you got involved, and where it stands currently?
Dr. Alexander Drilon: Sure. So, as you mentioned, my background is in lung cancer, where when I came on as a fellow, there was a lot of excitement around EGFR and ALK, but then subsequently other oncogene drivers were also discovered and many of them were fusion. So, as we know, ALK in the fuse state is a driver of many tumors, as is ROS1 and RET. And interestingly, NTRK fusions share many similarities with ALK, RET, and ROS1 in that you have an intact kinase domain that's in the three prime position, it's fused to a different gene in the five prime position and basically describes oncogenesis.
And the beautiful thing about NTRK fusions is that they are widely found across many different cancers. And I like to think of these cancers in two major buckets. So there is a bucket for cancers that are rare where we see these NTRK fusions with a very high frequency. And examples here are your secretory carcinomas of the salivary gland and the breast, for example, more congenital fibrosarcoma, where the frequency exceeds 90% in some series, and then there are much more common tumors where the frequency is much lower. So lung cancer is an example where you find it in less than 1% of cases. There are some other tumors like GI cancers also where the frequency is low. And beyond these two major groups, we also see these NTRK fusion-positive cancers occur not just in the adult population, but the pediatric population. All of that thrown together means that it was a really great setup for exploring the activity and safety of targeted therapy in what we call a ‘basket trial’ paradigm, where you design a trial and instead of selecting patients based on cancer type, you ignore cancer type and, of course, you accrue by an enrolling alteration, which in this case is the NTRK fusion.
Dr. Rafeh Naqash: Excellent. Thank you for that summary. It's interesting that just yesterday in my phase I clinic, I had an individual who was supposed to go on a certain study, and liquid biopsy came back and showed an NTRK fusion for a very odd presentation of a prostate cancer, which, again, got me thinking about the paper that you published trying to read about NTRK and then this happened and I got thinking about a bunch of other questions. But, for starters, though, from a receptor standpoint and I know you published on this in different journals, could you briefly tell, for the sake of the audience, describe the pathway and the tyrosine kinase signaling and associated resistance pathways that are concurrently acting in a different direction, perhaps, and also discuss briefly from neural development? I know the pathway, the NTRK gene or TRK gene as such is involved in different neuronal signaling aspects. Could you briefly touch on that?
Dr. Alexander Drilon: Sure. And thankfully there are a lot of parallels with other things that perhaps some of the listeners are more familiar with. We'll start with the fact that it is a receptor tyrosine kinase, NTRK. It's a gene that encodes a receptor tyrosine kinase just like other receptor tyrosine kinases that may be fused such as ALK, RET, and ROS1. But remember also that other RTKs are EGFR, FGFR, which are also well known. The important thing to remember for NTRK is that you have three different genes, NTRK 1, 2, and 3 that encode three different proteins which are called TRK A, B, and C. And as you intimated, in the non-oncogenic state, these are very important for the development and the maintenance of the nervous system. And in the fused state, of course, similar to other fusions that we spoke about, the chimeric oncoprotein will drive downstream signaling and tumor growth and metastases. And in general, these cancers can be very reliant on downstream signaling in the MAP Kinase pathway but may also on occasion activate other downstream pathways like the PI3 Kinase pathway.
Dr. Rafeh Naqash: And I know some of that could potentially play into resistance mechanisms for some of these first or second-generation NTRK inhibitors. From a fusion partner standpoint, the data that I came across that you're very well aware of is different fusion partners, and maybe some have a slightly better prognosis than some other fusions. But, in your practice and in your experience, does it matter what the other fusion partner is if the kinase domain is intact, meaning the signaling for the NTRK gene is intact? Have you seen any differences there from the other fusion partner standpoint?
Dr. Alexander Drilon: From a patient-matching perspective, as long as you think the fusion is real, and by that I mean that you look at the report and you're sure the kinase domain is there and you're sure it's in frame, meaning connected well to the five prime partner so that the DNA strand is read through, the five prime partner does not play a major role in my deciding to give a TRK inhibitor or not. I would give anyone with a functional NTRK 1, 2, or 3 fusion a TRK inhibitor. Now, the data on whether or not select fusions do better than others is, I would say, still a little immature and perhaps conditioned by a few things. There are some of the cancers in the first bucket that we talked about, like the secretory carcinomas that harbor a recurrent event such as ETV6 NTRK3. And those cancers, in my experience in clinic, patients with those tumors can be on a TRK inhibitor for a very long time. And it's unclear if that's because of the exact fusion event or if it's because of the cancer type that might be more, say, genomically naïve compared to a gastrointestinal tumor, like a colorectal cancer with an NTRK fusion. So I hesitate to say that there are very strong and convincing data that if you have a particular five prime partner, you'll absolutely do better or worse. So, in the interim, I think the most important piece is just making sure that the event is real and actionable, and if it is, then you can give a TRK inhibitor.
Dr. Rafeh Naqash: Thank you so much. I totally agree. And I think, for the sake of our listeners, as we see more and more sequencing being done on patients with cancer in the advanced stage setting especially, it's important to keep in mind when you have something that you can act on that has an actionable target that is FDA approved, then it's important to give the patient that option, especially in rare fusion events such as NTRK or TRK.
Now, you've touched upon this in your paper, but before we go into the details of the paper, specifically, I wanted you to briefly talk about the testing mechanisms which are important for some of these fusions and play into, for example, ROS1 ALK fusions also. Could you tell us what are the most appropriate ways to test for these fusions in patients harboring cancers, both from a tissue standpoint and from a blood-based assay standpoint?
Dr. Alexander Drilon: This is a great question because if you don’t have a test that’s optimally poised to pick up an NTRK fusion, then you can’t act on it. And a patient who would have benefited very durably from a TRK inhibitor won’t get access to it. So there are different ways of testing for NTRK fusions, and I like to think of the central dogma here where you have DNA becomes RNA becomes protein because that really helps anchor the different types of assays that you might use. We commonly use next-generation sequencing of DNA, but even if you have a very good next-generation sequencing assay, that does have its limitations because there are some fusions that are structurally just difficult to pick up even with a great DNA-based NGS assay.
And for that reason, we and others have found that in tumors that have an equivocal NTRK fusion, or perhaps where you didn’t find something but you really suspect that you missed something, particularly in cases where, historically, like congenital fibrosarcoma where you know there’s a very good likelihood of finding NTRK fusion, we then reach for an RNA-based assay because at the RNA level, you’ve removed things like the intra-DNA based capture challenging. And so I think that from a nucleic acid standpoint, leveraging a test that looks both at DNA and RNA, maximizes the likelihood of finding this fusion. And just remember that there are different NGS assays in terms of the approach to design and some might be more Amplicon-based and that’s less optimal, but the hybrid-capture-based ones tend to be better. The DNA and RNA tests can be done on tumors, and in blood, you could do a liquid biopsy. It’s very hard to fish out RNA in blood given the current technology so we’re still limited to circulating tumor DNA which shares the liabilities of doing DNA testing on a tumor sample. But if you find it and it looks real, then it’s certainly actionable even if you detect an NTRK fusion with a liquid biopsy.
Now going back to the central dogma there, the third piece which we haven’t touched on is protein. And there have been many papers published now on the utility of immunohistochemistry, and this helps you confirm that the TRK A, B, and C proteins are actually expressed. And what tends to happen is in many fusions, the chimeric oncoproteins strongly express as TRK A, B, and C that helps provide a complementary test or assay that confirms that you’re dealing with something that is actionable.
So that is a very contemporary approach and a very thorough approach to looking for these NTRK fusions where you do DNA and RNA if possible. And if you still have questions, ask your pathologist to see if they can do Pan-TRK IHC. But depending on the resource environment that you’re in, there are older tests like FISH which we use for ALK that can also find these fusions. RT-PCR which only finds particular events, these can detect NTRK fusions but really don’t have the breadth and comprehensiveness as the other assays that we discussed like NGS.
Dr. Rafeh Naqash: Thank you so much, Alex, for that amazing summary of all the methods that potentially could help detect this rare but important event. From a therapeutic standpoint, now, taking a deeper dive into your very interesting JCO Precision Oncology paper that looked at larotrectinib data from a pooled analysis of two trials, a phase II and a phase I. Could you tell us a little background about these two trials, the patient population and what kind of data were you trying to evaluate? And then we can discuss some of the interesting results that you showcase in the paper.
Dr. Alexander Drilon: It really helps as a background to realize that the initial approach to this was really on a basket trial where the programs for larotrectinib, which is a selective TRK A, B, and C inhibitor, and the other drug entrectinib, which inhibits ROS1 in addition to TRK, really accrued pediatric and adult cancers with NTRK fusions. And this paper pulls out the lung cancer subset and we'll discuss that in detail. But before getting into that, it's important to know that in the tumor agnostic data set of all patients with an NTRK fusion of any type, larotrectinib achieved a response rate of approximately 80%, entrectinib of approaching 60%, and disease control was durable with a median PFS for larotrectinib of approximately 28 months, and with entrectinib numerically, the number was lower at 11 months.
So with that background, this paper in JCO PO, in the interest of featuring the activity for lung cancers with NTRK fusions, pulled out 20 patients with NTRK fusion-positive lung cancers. And the punchline is that the activity was pretty comparable to that seen with a bigger data set. So the objective response rate was 73% and many patients had a partial response, 67% of the cases, 7% had a complete response, and really only a minority had primary progressive disease, 1 patient out of the 15 evaluable patients. These responses and clinical benefit overall were durable and the median duration of response was almost 34 months, with a median progression-free survival of almost 35 and a half months and an overall survival median of 40.7 months.
And just to talk about how that stacks up compared to other targeted therapies, this certainly is in the ballpark of some of the best ALK inhibitors that we have for ALK fusion-positive lung cancer. It's also comparable to osimertinib for EGFR mutant lung cancer. So we can confidently view TRK inhibition in lung cancers with NTRK fusions as a highly-active therapy.
Dr. Rafeh Naqash: Absolutely. I think you touched upon this earlier where in your cohort at least 50% of patients had central nervous system involvement, and it looks like larotrectinib does have CNS activity and benefit. Could you speak to the differences between potential entrectinib and larotrectinib from a CNS efficacy standpoint? And the second part of that question was going to be when you identify this fusion in patients, for example, with lung cancer, now, since TRK does have a role in neuronal development, do you think there is a role for closer CNS monitoring in these patients if they have not had brain metastasis identified because of the fact that they have an NTRK fusion? Is there some predilection for CNS involvement from a metastasis standpoint? It's just something that I've been thinking of over the last couple of days after I saw my patient who does have CNS involvement but with prostate cancer, which I have not seen in the phase I setting in all the prostate patients that I've come across. So what are your thoughts on that?
Dr. Alexander Drilon: These are great questions. In lung cancers with NTRK fusions, there is a proclivity for metastasis to the CNS. And thankfully, both of these TKIs, larotrectinib and entrectinib, do have coverage of the CNS. Now, from a design perspective, the initial thought was perhaps entrechtinib was more CNS-penetrant. But if you look at the overall response rates in patients with brain metastases and the intracranial response rates where you have patients with target lesions in the brain that you're able to measure; if you look across the aisle, entrectinib and larotrectinib have comparable results, with the objective response rate being in the order of 50% to 60% and the intracranial response rate being also in the order of about 50% to 60%. So at the end of the day, it appears as if, despite the previous hypothesis that maybe one drug would work better in the CNS than the other, we're seeing equally good effects with both drugs.
For the second question you asked, it's also a very interesting question because, like you mentioned, the TRK receptors play a role in nervous system development. But we have not observed a much higher frequency of CNS metastases in NTRK fusion-positive lung cancers or cancers in general that I know of, compared to cancers that are wild type for an oncogene or have other oncogenes. So what's more important really to think about when you sort of chew on the fact that these TRK inhibitors are involved in nervous system development are the potential side effects that you may see in patients that you treat with these TRK inhibitors.
Dr. Rafeh Naqash: Absolutely. Now, from the therapy standpoint that you discuss here, duration of responses, objective responses that you saw in your analysis were very impressive for these patients with lung cancer. In your clinical practice if you see a lung cancer patient with this fusion and you treat them with larotrectinib or entrectinib, and they have, let's say, de novo CNS metastases that are asymptomatic, do you generally try the targeted therapy first and hold off, perhaps, brain directed therapy in that setting? Similar to what one would do with osimertinib perhaps or alectinib?
Dr. Alexander Drilon: Absolutely. It's the same paradigm because we know that we are seeing in a larger population of patients, just generally good activity, both extracranially and intracranially. The goal is to try to spare patients the extra side effects of doing radiation by only giving the TKI. And in practice, even outside of the trial, in patients that I've treated with CNS metastases, the activity has been very good.
Dr. Rafeh Naqash: Thank you so much. Now, all TKI therapies have, unfortunately, resistance mechanisms that come up eventually, in my experience at least. What is your experience as far as understanding resistance mechanisms on TRK-based therapies and potential second options after that, whether it's second-generation TRK inhibitors or subsequent targeted therapies in this space?
Dr. Alexander Drilon: Thankfully, this has been looked at extensively and I like to categorize resistance into two major groups. So there's a type of resistance which we call on-target resistance and another type which we call off-target resistance. In simple terms, cancers that acquire on-target resistance are still dependent on the NTRK or TRK pathway. And often what happens is, like with other oncogene-targeted therapy pairs, you see the acquisition of a resistance mutation in the kinase domain of NTRK 1, 2, 3 that either changes the dynamics of the kinase or sort of kicks the drug off of the binding site due to steric hindrance.
And for those patients, companies have designed next-generation TRK inhibitors that abrogate resistance, meaning they were designed so that they would work despite the presence of these resistance mutations. And a few of them include repotrectinib, talatrectinib, and selitrectinib that are thought to have activity, but there are many other newer ones that are currently being explored. I will say that there's proof of concept that has been published as well showing that patients who progress on a first-generation TRK inhibitor like larotrectinib or entrectinib who develop acquired resistance that's on-target can respond very well to a next-generation NTRK inhibitor. And while these aren't approved just yet, these are of course available in clinical trials.
Now, the second major group is more problematic. This is off-target resistance. And when I describe this to patients, what I usually say is that the cancer sort of ‘phones a friend’ and activates a second gene perhaps that isn't NTRK. And examples of that include KRAS or MET or BRAF, very well-known oncogenes in other contexts, but it leads to a reliance outside of the NTRK or TRK pathway per se, which still effectively reactivates the MAP kinase pathway. What to do in that situation? Well, there are select cases and there have been case reports published of patients who get a combination. Say if it's acquired MET amplification, you give a MET inhibitor with a TRK inhibitor and that combination can work. But in many other cases where you don't have access to a combination on a clinical trial or on compassionate use, then you really default to the standard of care for that cancer type. So if it's lung cancer and they've never had chemotherapy before, then it would be platinum-based chemotherapy, say with pemetrexed and a third drug, perhaps if they have lung adenocarcinoma.
Dr. Rafeh Naqash: Thank you so much. This is definitely an exciting field and exciting time to be in this space of drug development, and especially when we have so many interesting tumor-agnostic approvals that have come along in the last few years and more to come. And you've led a lot of this development with several other leaders in this field. So it was very nice discussing this with you, and hopefully, our listeners find it equally interesting and educationally relevant to what we see day in and day out as we perform more and more sequencing for patients with cancer and try to identify some of these rare or not so rare events that are targetable and can definitely change the course of a patient's therapy and outcomes. So thank you once again, Alex, for the discussion on this paper.
But before we end, we'd like to spend a couple of minutes trying to know about the investigator. So could you tell us a little bit about your career trajectory, how you started your fellowship perhaps, how you ended up in drug development, and how you've successfully contributed so much in this field to date?
Dr. Alexander Drilon: Sure. So I'm originally from the Philippines, was born there, finished med school, and really wanted to come to the United States to sort of broaden my education and my residency program in internal medicine, then called St. Luke's Roosevelt under Columbia, had a program that sent people to rotate through Memorial Sloan Kettering Cancer where I currently work. So that was my first exposure with oncology. I fell in love with it and eventually became a fellow, fortunately, at Memorial Sloan Kettering. And I mentioned earlier that during that time I had subspecialized in lung cancer and there was a lot of excitement around targeted therapy for oncogene-driven lung cancer. And that was my point of entry. I saw these drugs work very well and I said that if I were in a position to develop newer agents, perhaps for other oncogenes where there wasn't anything developed just yet, that would be really cool. And that was my entry into the phase I world where things later on expanded really the tumor agnostic interrogation using the same principles that were familiar to me in the lung cancer world. And I think I've been very fortunate with the environment and the ability, especially with good in-house sequencing, to match many patients to these trials. And it's been wonderful to see several of these drugs approved. Larotrectinib was the sort of seminal tumor-agnostic approval of a targeted therapy for the first time by any regulatory body. And like you said, the hope is that we see several more of these.
Dr. Rafeh Naqash: Awesome. That sounds like a very interesting, phenomenal journey that you've had, and a lot of it is also probably related to the kind of people that you met, mentors, and other people who helped you along the way. And then, of course, you've done a lot for other fellows and trainees in this space of drug development. So thank you again, Alex, for joining us, and thank you for choosing JCO Precision Oncology as a destination for your work. I look forward to interacting with you further subsequently and hopefully seeing more development in this space of novel therapies for fusions and other interesting targets in the lung cancer space.
So thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Bio: Alexander E. Drilon, MD, is a medical oncologist specializing in the treatment of lung cancer. He is chief of early drug development service at Memorial Sloan Kettering Cancer Center. He has clinical expertise in lung cancer and early-phase clinical trials.
COIs
Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView
Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare Therapeutics
Research Funding: Foundation Medicine
Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)
Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology
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JCO PO author Dr. Brandon Huffman shares insights into his JCO PO article, “Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients With Esophageal and Gastric Cancers” and discusses the article’s findings of ctDNA levels in the preoperative, postoperative, and surveillance settings in patients with EGC. Host Dr. Rafeh Naqash and Dr. Huffman discuss ctDNA assessments, treatment paradigms and interventions, and tumor-informed assays.
TRANSCRIPT
Dr. Abdul Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, social media editor for JCO Precision Oncology, and I'm also an Assistant Professor in Medical Oncology at the OU Stephenson Cancer Center. Today, I am excited to be joined by Dr. Brandon Huffman. Dr. Huffman is a gastrointestinal medical oncologist, and he's also an instructor in medicine at the Dana-Farber Cancer Institute at the Harvard Medical School. He's the lead author on today's JCO Precision article, "Analysis of Circulating Tumor DNA to Predict Risk of Recurrence in Patients with Esophageal and Gastric Cancers."
Our guest’s disclosures will be linked in the transcript.
Dr. Huffman, welcome to our podcast and thanks for joining us today.
Dr. Brandon Huffman: Of course. Thanks for having me.
Dr. Abdul Rafeh Naqash: For the sake of this discussion, we'll refer to each other using our first names. So, Brandon, exciting to have you today. We're going to talk about this very interesting topic on circulating tumor DNA and how your team used the ctDNA assessment in patients with esophageal and gastric cancers. For the sake of the listeners, could we start by asking you what are the current treatment paradigms for early-stage esophagogastric cancers? Since you practice this on a daily basis, what is the current approach, briefly, which will play into how this study looked at ctDNA in the context of early-stage esophagogastric cancers?
Dr. Brandon Huffman: Yes, definitely. Thanks first for having me. Thanks for highlighting our work, and I'm really excited to talk with you about our manuscript and research today. To answer your question about how to treat localized esophagogastric cancer, it's a little bit more specific depending on where in the esophagus, GE junction or stomach where the tumors arise. For instance, we treat esophageal and upper gastroesophageal junction cancers with, often, chemoradiation, neoadjuvantly, and that is followed by surgery. And if there's a pathologic incomplete response, then many patients will get Adjuvant Nivolumab, a PD-one inhibitor, whereas the lower the tumor is in the upper GI tract, most often, perioperative chemotherapy is used for the lower GEJ and gastric cancers.
Dr. Abdul Rafeh Naqash: Thank you so much. And I know, I think to some extent, if I remember correctly, immunotherapy has been incorporated into this paradigm. Is that a fair assessment?
Dr. Brandon Huffman: That's exactly right. So, excitingly, we treat patients with neoadjuvant chemo or chemoradiation, and surgery is really the crux of the treatment paradigm for esophagogastric cancers in general. However, recently the CheckMate 577 clinical trial for the use of adjuvant Navolumab showed an improvement in disease-free survival in patients who had an incomplete path response. They used one year of Nivolumab compared to placebo. So it has recently become a standard of care where I practice, and I feel like a common practice around the country.
Dr. Abdul Rafeh Naqash: Thank you so much. Now, going to the premise of this paper where you and your team basically looked at circulating tumor DNA as a prognostic marker in these patients that had early-stage esophagogastric cancers, was there a specific reason why you wanted to look at the early stage? What was the rationale for evaluating this biomarker in this patient population?
Dr. Brandon Huffman: So, esophageal and gastric cancers affect a large number of patients every year. And unfortunately, despite our best efforts with curative intent therapy, over 50% recur within three years. So we know that there are pre surgical risk factors such as a larger bulky primary tumor or lymph node-positive disease that increase the risk for progression or recurrence after surgery. And we know, in addition, in other GI malignancies and other malignancies such as colorectal cancer, for instance, that the presence of circulating tumor DNA after surgical resection of localized tumors is associated with an increased risk of recurrence. So this has actually led to clinical trials investigating whether or not ctDNA can be integrated into the decision-making for adjuvant colorectal cancer treatment, such as ongoing trials such as the BESPOKE trial, COBRA, DYNAMIC trials that have recently been reported.
The use of ctDNA is being used in other malignancies. And to give you a little bit of background, this project started when I was seeing patients with Dr. Sam Klempner at Mass General during my fellowship, where I was in the combined Dana-Farber/Mass General program. And he and others had begun collecting serial plasma samples on every patient we saw with esophagus, gastroesophageal junction and gastric cancers to assess for the presence or absence of ctDNA. And we used the tumor-informed ctDNA assay from Signatera, which, for those who aren't familiar, this is a ctDNA platform where a panel is built from the results of whole exome sequencing on the patient's FFPE tumor. The panel includes 16 patient-specific somatic single nucleotide variants for each patient, and it's new for each patient. Once that panel is built, the cell free DNA is tested from a plasma sample. And if there are two or more of the tumor-specific variants present, then they're considered ctDNA positive. So some of those colorectal cancer trials that I mentioned before are using this assay, and we wanted to investigate whether or not this high-risk population could be further assessed for risk of recurrence.
Dr. Abdul Rafeh Naqash: Excellent. Thank you so much. And I know that a lot of these ctDNA based assessments have made inroads into the GI malignancy space, lesser in the other tumor types. I think we are all trying to catch up to what you guys are doing in the early-stage colon cancer space or the early-stage esophagogastric cancer space. So it's definitely very a interesting avenue to assess minimal residual or molecular residual disease.
Now, going back to the methodology, I found it very interesting, and I think it's very important for listeners especially to understand the context of ctDNA assessments because I think a majority of oncologists are used to the liquid biopsy aspect. But this is not necessarily the liquid biopsy. It's somewhat different. So what I've understood, and I'd like to ask you to explain in the context of tumor-informed and tumor uninformed assays, what are the assays that are available, and how do they differ in terms of serial monitoring? And why is this ctDNA-based assessment somewhat different or more patient-customizable than our regular liquid biopsy assays, which are also blood based but not tumor-informed?
Dr. Brandon Huffman: That is the question of the hour. And many different research projects are ongoing to try and identify which one is better, if one is better. I know that there are some commercial assays, for instance, that are not tumor-informed. They take a blood sample and then test for cell free DNA. The risk behind that is it's testing for common genetic mutations from a next-generation sequencing panel platform. And it may also detect CHIP variants or clonal hematopoiesis of indeterminate potential variants that aren't related to the underlying solid tumor malignancy.
So a tumor-informed assay, for instance, such as the one that we used in this study, uses the patient's tumor and sequences it with whole exome sequencing and identifies very specific variants within the tumor that are only present within the tumor because they compare it also with a normal blood sample from the patient at the same time. And so they pick tumor-informed specific variants that then they test for on their assay. And that increases the sensitivity of the ctDNA assay so that you can really try to understand, is this cell free DNA that we are detecting related to the tumor or can we ignore it potentially? I don't know if we can necessarily ignore it in all honesty because it could affect- there's a lot of ongoing work that is looking at the risk of CHIP. But overall, this is specific for the primary tumor that we were investigating.
Dr. Abdul Rafeh Naqash: I definitely agree with you there. I think the important point, as you mentioned, is that using the whole exome approach, in the blood and the tumor, you're able to eliminate the CHIP variants or the germline variants that may not be contributing. And that way you're able to specifically look at certain genetic alterations that eventually, I think using PCR-based approaches, you identify the same and quantify the same in the blood serially. And that's how this tumor-informed assay is somewhat unique and different.
Now, going to the crux of this study, could you tell us a little about the patient population? I think you stratified patients. You had a pre-operative cohort, you had an MRD cohort, you had a surveillance cohort, and you had a cohort where you assessed ctDNA positivity at any time point. So, several different cohorts, and you assess recurrence-free survival in those cohorts. Could you tell us a little bit more about how you evaluated these cohorts? What were the selection criteria, and how many patient samples did you have for these different cohorts?
Dr. Brandon Huffman: Absolutely. So, we aimed to determine the feasibility of testing ctDNA in patients with gastroesophageal cancer. And so, there were several clinicians from over 70 institutions across the United States who began prospectively collecting serial plasma samples for the presence or absence of the tumor-informed ctDNA. And they included patients from stages one through stage four, gastroesophageal cancer specifically, they included patients who were stages one through four with gastroesophageal cancer. They were collected at the discretion of the ordering clinicians and then incorporated into their routine clinical care as they saw fit. Within this dataset, we have a subset, a large number of patients that is unique to this dataset, specifically in that we have clinical outcomes, treatment, and follow-up data for the patients that were reported on the main findings in the paper. So, overall, we collected and analyzed over 900 plasma samples in almost 300 patients with gastroesophageal cancer, esophageal, gastroesophageal junction and gastric cancers. And in many of the analyses, we lumped them all together. But then we also wanted to separate it out because, as I mentioned before, the treatment paradigm does differ amongst a more proximal esophageal tumor compared to a distal gastric cancer.
So, we focused a majority of our analyses on the detection of ctDNA and localized disease, which included 212 patients with stages one through three gastroesophageal cancer. And I would say we had three major findings. Most of the patients who were tested beforehand, which was a small subset, as I mentioned, this was pragmatic at the discretion of the ordering clinician, but most of the patients who were tested beforehand had positive preoperative ctDNA present. Of the patients who were tested for postoperative ctDNA at any time point, and then specifically within the different subsets of populations that we talked about, postoperative ctDNA was associated with at least a tenfold increased risk of recurrence in all subsets. And ctDNA detection postoperatively was independently associated with recurrence when controlling for age, sex, tumor location, and microsatellite status.
So, a few of the populations that we wanted to test for, one in particular was the molecular residual disease, or MRD window. We labeled this MRD window as the time from surgical resection until 16 weeks. So, if patients were ctDNA positive within that window, we counted that in the primary outcome. And the reason that we chose the MRD window, in addition to this time point of 16 weeks - I should say that the 16 weeks is without any therapy postoperatively, so they have not been treated with any chemo or immunotherapy in this window. We thought that this MRD window was an interesting research topic because the CheckMate 577 Adjuvant Nivolumab clinical trial identified that 16 weeks was the window in which patients could be enrolled up until that timepoint to receive adjuvant nivolumab. So, we're thinking from a future project standpoint, a future clinical trial, perhaps, that if we have identified that patients who are ctDNA positive within this timepoint window, is there an increased risk for recurrence? Because if there is, then perhaps nivolumab intervention will decrease that risk or something that is escalated further. And that's a question that we don't have the answer for, a question that our data can't answer adequately. But it's an interesting one that I see the future questions that can be answered from these data.
Dr. Abdul Rafeh Naqash: Thank you so much. And I agree with you there that this is a very intriguing approach of finding out whether treatment escalation has to be done based on ctDNA positivity, but also, conversely, treatment de-escalation, which there is a lot of emphasis being laid on, especially in the early phase trial in lung cancer, especially in the early setting when targeted therapies or immunotherapies are approved for one to three years, depending on what kind of therapy you're looking at. In those individuals that perhaps have negative ctDNA after one year, maybe therapy de-escalation would be a reasonable approach. So, definitely more interesting clinical trial ideas in this space focusing on ctDNA assessments.
Now, one of the questions that comes to my mind is, when you use ctDNA-based assessments, initially, the patient gets biopsied, and it usually takes four to six weeks for ctDNA-based assessments to come back--I'm talking about tumor-informed assay results to come back, in my personal experience. So, could that potentially, or in your practice, how do you mitigate those delays? If you're trying to schedule a patient for surgery, for example, does that cause any delays in any care because you're trying to get the assessment done, or does your workflow proceed as planned and then you get the results and then subsequently you perhaps make a decision based on their ctDNA assessment?
Dr. Brandon Huffman: At the present time, we are trying to gather more data to understand what we should do with the results that we're receiving. And I think the starting point of collecting serially to just understand the process is helpful. One of the questions we wanted to know that we weren't able to answer with this dataset was: is there lead time? In many cases, ctDNA detection can occur even a year prior to radiographic recurrence. In our case, because this was a pragmatic, clinically at the discretion of the investigators when they decided to test patients for ctDNA, there is heterogeneity among those who are ctDNA positive, and when they get their radiographic imaging, maybe they were moved up. I know in our practice with Dr. Klempner, when I was seeing these patients with him, it was a flag for us to order scans earlier in a patient that we might not have historically ordered so that we could then see, is there something intervenable? Maybe there was a positive lymph node on PET imaging that we could radiate or that wasn't included in the neoadjuvant radiation, for instance. So, we could not predict the lead time from positivity to radiographic recurrence, but I think that that's the hope is that we detected micrometastatic disease, my hope is that we can intervene in the future. But these data aren't able to quite answer that question perfectly.
Dr. Abdul Rafeh Naqash: Sure. And there's definitely caveats to doing this in a pragmatic manner based on investigator assessments.
Now, another question I was thinking of is, when you do do these ctDNA based assessments, and since these are tumor-informed, meaning you biopsy the tumor initially, you identify certain single nucleotide variants and those are the ones that you basically barcode and do PCR assessments using blood. We've learned time and again that tumors can change based on the kind of therapy that you give the patient. So, if your tumor is seeing FOLFOX nivolumab, or all the other novel therapies that you guys give in the setting, is there a chance that the tumor changes over time and you may not be able to capture those newer single-nucleotide variants that are coming up? It's just a provocative question, but I wanted to see what your thoughts are on that.
Dr. Brandon Huffman: It's a great question. I don't entirely know the answer. I'll just be forthright about that. I do think that when designing these assays, they try to choose the more clonal rather than subclonal variants. And so the hope is that, despite the heterogeneity that we know occurs in esophagogastric cancers, we can eliminate that possibility. But you're right, there's no perfect way of knowing that.
Dr. Abdul Rafeh Naqash: I really appreciate you using that word subclonal versus clonal. I think that perhaps makes a difference there. But again, more to do in this field to understand how the tumor evolves and whether it's the clonal mutation, subclonal mutation that needs to be followed. But definitely a lot of interesting work in this space that's ongoing, and, like you mentioned, there are ongoing trials, and both in the neoadjuvant adjuvant space, this field is definitely moving fast in the right direction.
I briefly want you to highlight that one patient case study example that you had. And this was a patient with oligometastatic disease recurrence where you used the ctDNA assessment. And I do some of this in my daily practice, and I really found it useful to have this sort of a patient case example that elaborates in the bigger picture of how this kind of assessment works in a real-life scenario. So it's not just data, it's a patient's trajectory over the course of time where the treating physician was able to use this assay. Could you tell us a little bit more about this individual example here?
Dr. Brandon Huffman: Yeah, absolutely. So this was a 56-year-old man that we saw in clinic with stage three esophageal adenocarcinoma, and was treated with the standard neoadjuvant cross chemoradiation, had an R0 resection with residual disease with a significant treatment effect. And there were lymph nodes that were positive on surgical resection with 39 lymph nodes removed. The patient recovered well and was followed with the standard of care radiographic and clinical surveillance. We also were looking for ctDNA, and what we noted was that there were, often you find these undulating pulmonary nodules that come and go, and they may or may not be infectious, and maybe there's one that's sub-centimeter that slowly grows, and what we found was that at about five months post-surgery, there was a positive ctDNA MRD, and we repeated it at short interval and noted a rising value, which this assay will give you a quantitative value. Once we did that, we ordered imaging and saw a nine-millimeter pulmonary nodule and ultimately biopsied it. It was there in the right upper lobe, and it was positive for metastatic adenocarcinoma. So we treated the patient with the standard FOLFOX plus Nivolumab and actually did SBRT, stereotactic body radiotherapy, to the lung metastasis. And his ctDNA became undetectable.
So because FOLFOX is toxic, we transitioned to a maintenance of Nivolumab and he was on maintenance therapy for several months and had no radiographic evidence of disease and remained ctDNA negative for twelve months. So we biopsied the right upper lobe lung lesion. It was positive for metastatic adenocarcinoma, and then after a multidisciplinary discussion, we treated him with SBRT and then FOLFOX and Nivolumab and then dropped down to Nivolumab maintenance once his ctDNA was undetectable. That highlights the fact that this was an isolated recurrence, which we continued to monitor, and then he had another site of disease a few months later, and we did SBRT to that area while he maintained on just Nivolumab, and the ctDNA came down as well.
So I think, although it doesn't prove anything necessarily, other than demonstrating there is a correlation with the newly diagnosed metastatic disease, it does note that you can use this in dynamic ways, and if it really helps patients live longer, although this is anecdotal--who knows? If we hadn't done SBRT to that area, it was 9 mm. We could have waited until it grew, but then maybe some subclonal, more aggressive metastasis could have really put this patient in a much tougher situation. So it's an interesting case example, and there are several others that we could have put in here that are pretty similar.
Dr. Abdul Rafeh Naqash: Thank you so much for highlighting that case. I couldn't agree more that there is a certain aspect to the ctDNA assessment, where in individuals like the example that you've highlighted here, this can provide lead time potentially and help with earlier management of perhaps more like oligometastatic disease rather than diffuse disease burden.
And in that context, one of the questions that I was going to ask you, based on your data, was there any correlation of tumor burden preoperatively and ctDNA positivity after surgery that you guys were able to identify or thinking of identifying?
Dr. Brandon Huffman: Unfortunately, with our data set, we weren't able to look at that assessment of comparing the overall tumor burden to the quantitative value. But it's an interesting one because we know that in other malignancies, for instance, if there is a correlation of overall disease burden, it also depends on the tumor type, but we also know that perhaps patients will respond differently to chemo or immunotherapy if they have a lower tumor burden, if they have a lower ctDNA value, potentially. I think that's an interesting question for a future project.
Dr. Abdul Rafeh Naqash: Thank you so much, Brandon.
We do like to talk a little bit about the person behind the work. So tell us a little bit more about yourself, your training, your interests, and some little advice for other early-career investigators who might be looking into a similar space and hopefully get inspired by the kind of work that you've done or are planning to do.
Dr. Brandon Huffman: Sure. So, as I mentioned, when I started this project, I was in fellowship. I was seeing patients with Dr. Sam Klempner at Mass General, where I saw patients with him for a year, and as part of my clinical training in the Dana-Farber/Mass General HemOnc Fellowship. Since that time, I have graduated fellowship. I'm a GI Medical Oncologist at Dana-Farber Cancer Institute, and in the GI division, I see patients with all GI malignancies, and I focus on the development of clinical trials in upper GI malignancies, along with investigating the use of circulating tumor DNA as a biomarker, hopefully, we can understand whether it's a predictive biomarker that we can intervene upon in the future.
I think the greatest advice that I received and that I will give to all future trainees; I'm not sure that I'm qualified to tell this to all the junior investigators, but here it is: Find yourself a mentor who really cares and invests in you and your ideas. I have that with Sam, and this project was an incredible part of my development as a junior investigator. I've asked really interesting questions. There are more questions that can be answered from this data set, and I'm excited for the opportunity.
Dr. Abdul Rafeh Naqash: Thank you so much, Brandon. Thanks for taking the time to speak with us today and thank you for choosing JCO Precision Oncology as a destination for your work. Hopefully, we'll see more of this subsequently in the years to come.
Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating, a review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Bio
Dr. Brandon Huffman, MD, is a gastrointestinal medical oncologist and Instructor in Medicine at Dana-Farber Cancer Institute and Harvard Medical School.
Guest Disclosures
Brandon M. Huffman
Stock and Other Ownership Interests: Doximity
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JCO PO author Dr. Mohamed Salem shares insights into his JCO PO article, “Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers” and the article’s findings of a large-scale, pan-cancer genomic characterization of KRASG12C. Host Dr. Rafeh Naqash and Dr. Salem discuss KRASG12C mutation, KRASG12C -mutated tumors and comutation with STK11 and KEAP1. Click here to read the article!
TRANSCRIPTDr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology and assistant professor of Medical Oncology at the OU Stephenson Cancer Center.
Today I'm thrilled to be joined by Dr. Mohamed Salem, Gastrointestinal Medical Oncologist, and Research Director at the Levine Cancer Institute in Charlotte, North Carolina. Dr. Salem is the lead author of the JCO Precision Oncology article ‘Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers’.
Our guest’s disclosures will be linked in the transcript.
Dr. Salem, welcome to our podcast, and thank you for joining us today.
Dr. Mohamed Salem: Thank you for having me. A pleasure and honor.
Dr. Abdul Rafeh Naqash: For the sake of this podcast, we'll be referring to each other using our first names. So thank you for coming on to our podcast and discussing this very interesting paper. And one of the reasons why we decided to incorporate this is because, as you very well know, KRAS is one of the most common altered genes in cancer, and I'm pretty confident and sure that oncologists, whether it's academic oncologists or community oncologists, have treated patients in different settings having tumors that harbor KRAS alterations. So give us a little bit of a background on where KRAS alterations stand currently and where is drug development in the space of KRAS to give our listeners some idea of why we're interested in this gene.
Dr. Mohamed Salem: Sure, thanks again for having me. And as you mentioned, KRAS mutation happens to be, I think, by far the most common oncogenic mutation we see in oncology and solid tumors. The problem with KRAS is that, for a long, long time, there was very much nothing we could do about it; it was, in fact, called an undruggable target. Until recently, we started to realize this might not be true, and, in fact, we start to see successful efforts trying to target KRAS mutation. Currently, there are several KRAS inhibitors. I think it started with G12C. I personally don't think there was anything specific about G12C, but it just happened to be one of the first targets that we were able to approach. And the initial result from using anti-G12C therapy that was published in the New England Journal of Medicine, I think, a year ago now, showed this is feasible and perhaps effective.
Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Salem, for that explanation. And being a Phase I trialist, I personally have seen a lot of exciting combination-based approaches in the setting of KRAS-altered tumors, especially KRASG12C.
Now, specifically delving into your paper, given the extensive length and breadth of data that you've covered here, could you tell us a little bit about why you decided to use KRAS as an interesting topic for your study and the kind of data set that you chose to explore this question?
Dr. Mohamed Salem: What happened once we started to realize how important it is to figure out which KRAS mutation we're dealing with because, at least in colorectal cancer, it's a very common mutation, almost like 40-50% of patients with colorectal cancer tumors carry KRAS mutation. Until very recently, we really didn't pay close attention to which variant it is. Is it KRAS G12D, 13, or G12C? And so on and so forth. And the reason we didn't really pay much attention to that is because there was nothing to do about it; whether the patient has this or that variant was really nothing therapeutically wise it really didn't have an impact. But once we started to realize now there is a therapeutic option and, in fact, now there is a change in the way we think about KRAS mutation, there is a proof of concept that we actually can target KRAS mutation, we started to pay closer attention to this.
And I think this was a paradigm shift in our thinking. So for patients who have KRAS mutation, now we have data showing that KRASG12C is something we can target, whether with single agent or with combination therapy. But it was a new era for us because most of us realized it's not going to stop there. It’s not going to be just G12C; I think G12C is the tip of the iceberg, and likely the science is going to go forward, try to target the other variants. So one of the obvious questions was what are the other variants and how commonly those exist, and which tumor types also carry those variants. Because as we were talking before the recording for Phase I, now it is not like one approach fits all; it started to kind of like focus on either molecularly driven or disease-type approaches. And it was very important for us to try to figure out, okay, which tumor type carries the most KRAS variants and, within that tumor, which variants are the most common. And this is what we're trying to answer in this paper.
Dr. Abdul Rafeh Naqash: Thank you so much, Mohamed. I looked at your data set that you had access to, very large data set of around 79,000 tumor samples and close to 14,000 KRAS mutated tumors. Could you tell us a little more about this data set and how you started with looking at the distribution of KRAS across different tumors, and what were the kind of interesting results that you came across as far as KRAS distribution is concerned?
Dr. Mohamed Salem: It's very obvious to all of us now that the field is moving from one size fits all to a targeted approach or treatment target approach. And this is very important and very interesting because usually, when we do that, we achieve better outcomes and lesser toxicity. But the problem that comes with this is that none of us, as a single, even two centers, will have enough data to ask and answer questions. And when you are talking about something like MSI-high or BRAF or KRAS, usually it becomes very challenging for one single institution, doesn't matter how big they are, to try to answer either prevalent or therapeutic approaches. Because of that, most of us now start to understand that cooperation is very important across centers and also across nations.
So, like as you see here in this paper, there was a global cooperation between investigators in the U.S. and in Europe and Austria, and other countries. And what we did as a group we worked with one of the third-party profiling companies. Our group tried to answer what is the prevalence, just a very simple question, what is the prevalence of KRAS mutation, and what is the prevalence of each variant type in each tumor? And none of us could have answered that question on their own. Because of that, we actually collaborated with one of the third-party companies that do next-generation sequencing for tumors, and we were able to collaborate with them to have access to that database and answer some of those questions.
Dr. Abdul Rafeh Naqash: Excellent. As everybody knows, NGS is a standard of care testing that oncologists do, especially for advanced settings, to identify driver alterations or therapeutic interventions that may be relevant for patients. So in this data set, it seems you had access to NGS data, tumor mutational burden, and PD-L1 data for these tumor types. Could you tell us about the differences in the distribution for KRAS and the KRAS subtypes that you identified in this data set?
Dr. Mohamed Salem: Sure. So, as you mentioned, we looked actually at almost 79,000 tumor samples that underwent next-generation sequencing by our collaborator. And it appears that about 17% of the tumors or so had some kind of KRAS mutation. And then, after that, we start to see G12C when we start looking at each variant. G12C were about 11%, 12%, and about 88% of the remaining KRAS mutant tumors harbored some different kind of KRAS mutation.
The next question was, in general, in all tumors, what was the most common KRAS variant seen? I think it mimicked what was already out there. It appears that G12D happened to be perhaps the most frequent mutation seen in KRAS mutation tumors, followed by G12V, followed by G12C, and then G12/13, and then others. What was very interesting, actually, an observation we saw, is that we were able to realize the distribution of KRAS variants varies according to the tumor subtype. So, for example, in pancreatic cancer, we could see patients who had G12R KRAS mutation variants. This was not seen commonly in other tumors. And the reason that's important is because maybe that will be something in pancreatic cancer tumors that will be worth looking at and do therapeutic approach there. But also, I'm sure you're already dealing with this in your clinic quite often. It was interesting, obviously, that non-small cell lung cancer was the most common organ that actually carries G12C, followed by colorectal cancer; followed by a very interesting actual observation that was very interesting for us to see was in appendiceal cancer. As you know, appendiceal cancer is not a common disease; it's a relatively rare disease. And we were surprised to see some of them actually have G12C mutation. And again, the reason that's important is that it just opens the door for possible therapeutic options and in context of clinical trials.
Dr. Abdul Rafeh Naqash: Excellent. Definitely, the advantage of having such a rich data set like you did enabled you to look into some of these unique distributions across rare tumors, which makes it very interesting.
Now, one thing that I realized in the paper is that these tumors of unknown origin, where you identified or your group identified that they had a certain percentage of KRAS alterations, suggesting maybe their tumor of origin is perhaps lung or upper diaphragm, which could have therapeutic implications. Could you tell us a little more about this?
Dr. Mohamed Salem: Yeah, this was another very interesting observation we saw because it is not uncommon for us in the clinic, we get like a cancer biopsy, but we cannot tell where it's coming from. And there are multiple ongoing efforts to try to identify that for the obvious reasons. But it was very interesting when we looked at those groups that when you had cancer adenocarcinoma but of no identified origin, it was the fourth common tumor that we see G12C. I think if you can just make the assumption - I don't think we have proved that - but since lung cancer was the most common tumor that exhibited G12C mutation, and now we have tumors of unknown origin also, many of them exhibit G12C mutation, we thought this could be a lung primary. As you know, there are also now a few platforms trying to identify the tumor origin based on the agent sequencing, but we didn't try to associate it with that.
Dr. Abdul Rafeh Naqash: Thank you for that explanation. Now, one of the other things I observed is you tried to delve into smoking status, very interestingly, and how that correlated with KRAS alterations. And as we know, lung cancer, obviously there is a strong predilection in patients who are smokers, but irrespective of smoking, there can be other alterations that drive lung cancer. But interestingly, in your paper, you identified a unique correlation between smoking and G12C and also found out something on those lines in colorectal cancer, which, to my understanding, has not been described before. What is your understanding of why that happens? What could be the mutational events that lead to something like that, and how could that be potentially therapeutically exploited?
Dr. Mohamed Salem: I think this was one of the very interesting findings we observed. And you are right; just because the nature of lung cancer, we know many of patients are either active smokers or former smokers. So it was not a surprise for us to see that there is some kind of association with smoking status and lung cancer. But to your point, what was really surprising and, in a way, interesting for us to see, actually, that association for patients with colorectal cancer. Smoking actually happens to be one of the risk factors, like in colon cancer, but obviously not as high as lung cancer. But when we looked at the data, demographic, and clinical features, it was obvious actually that current smoking status, whether a current smoker or prior smoker, had an association with G12C. And also, with gender as well, females tend to have more G12C, or G12C mutation was more likely to be seen in females than males. So the fact that we were able to identify the smoking status and gender as more likely to harbor G12C mutation was interesting.
I have to tell you, the reviewer, when we submitted the paper for review, the reviewer came back and asked us, did this happen just because you had too many lung cancer, and most lung cancer patients smoke, that's why you're seeing that association? And we went back and looked at the data again and spoke with our biostat team in the study, and we were able to actually run the analysis and show that, no, it is not just because of the enrichment; it's actually a real association between the smoking status and G12C. It's very interesting to see, at least in colorectal cancer, it's following the same trend in lung cancer.
Dr. Abdul Rafeh Naqash: Right. And one of the other things I remember when I was reading through your paper and smoking status, I remembered this paper that was published in Science Magazine 2016, looking at how mutational burden changes in patients that have a history of smoking. But when you connect the dots here, interestingly, it seems like, especially in lung cancer, from what you guys have described here, is that the smoking status impacts what kind of KRAS alteration is present. But at the same time, you didn't see a tumor mutational burden that was significantly higher in G12C, mutated non-small cell lung cancer, where you would expect a lot of these G12Cs to be related to smoking. But on the other hand, the tumor mutational burden was not necessarily increased. And I understand you may not have an explanation for that through the data that you've published on, but that was kind of an interesting observation that I had. I don't know if you have any specific comments on that.
Dr. Mohamed Salem: No, it's absolutely correct. What we thought is that we should see that because the obvious rationale is just cited, but it wasn't. And until today, we're actually trying to figure out why the disconnect because you have people who smoke usually you expect like PD-L1 is positive, you expect higher tumor burden, but it didn't show at least a statistically significant correlation.
Dr. Abdul Rafeh Naqash: Thank you. And I guess it's notable to mention that you did have some interesting correlations for tumor mutational burden overall, and with PD-L1. Could you tell us about that for different KRAS genetic alterations?
Dr. Mohamed Salem: There were few papers published before by our colleagues trying also to understand the correlation between G12C mutation and immunostatus or immune microenvironment and some biomarkers. And I think, at least to my understanding, there was not one consensus. I think it was different findings to some degree. So, in general, when we actually looked at the entire cohort, regardless of the tumor type, it appears that tumors that carry G12C mutation also happened to have higher PD-L1 expression. What was very interesting was that once we started to look at different tumor types, this was not seen across all tumors. So some tumors did actually carry that, and some other tumor types didn't show that correlation. And to be honest with you, I'm still, until today, I'm not sure why. Is this just a function of number, or actually there is more tumor biology that reflects that? I have to say my own feeling, and that's something we need to study further, is that I think it is tumor biology. One thing was also very interesting to us from the clinical side. You have G12C mutation in lung, and you have G12C mutation in colorectal, and in the New England Phase I study, you could see very clearly that targeted G12C is more effective in the lung compared to colorectal. It's the same target, the same drug, yet the response is different once you start to have two different tumor types. So that just got me to think there must be something with the tumor type and microenvironment of the tumor and also associated co-mutations and other factors that impact that.
Dr. Abdul Rafeh Naqash: I couldn't agree with you more, and I totally have seen that in some of the work that has been published or data that I've been part of where different tumor biology, the tumor microenvironments, even sites of metastasis make a difference in how a certain mutation behaves. So definitely something that needs further validation with perhaps proteomic and transcriptomic data to understand functional characterization of the downstream consequences for some of these mutations. And you pointed out co-mutation status. That's an ever-emerging question for some of the potentially druggable alterations, whether combination approaches targeting some other co-occurring common co-mutation would have more benefit. Could you tell us about some of the unique, interesting commutations that you identified in your cohort that were more common in certain KRAS subtypes?
Dr. Mohamed Salem: Sure. I think that's also something we try to look at for the reason I just mentioned. We know that tumor origin and tumor type influence response and sensitivity to therapy. I think the best example we have, at least in colorectal cancer, is the BRAF mutation. When we saw the BRAF inhibitor having very nice response rate and control of BRAF mutant melanoma in colorectal cancer, we saw that it’s going to be the same thing, the same drug, the same target, same thing’s going to happen. And obviously, it was not the case. And this was a lesson for all of us to understand. Even if it is the same target, even if it's the same drug, tumor origin matters, and that’s likely because of the associated co-mutations that will influence the pathway of the tumor and perhaps either the sensitivity to the drug or maybe resistance to the drug.
So it was very important for us to look also at the associated co-mutations. And I think one of the KEAP1, and perhaps you will comment on this more than me, but the KEAP1 gene was likely to be mutated in those tumors who have G12C mutation than others. Another one was STK11. And there were a few other ones, it depends on which tumor type, but KEAP1 was a very interesting finding for us too. Because as you're aware, it's important, at least in lung cancer, and maybe will impact therapeutic approach too.
Dr. Abdul Rafeh Naqash: You're definitely right. It is important in lung cancer, and there's data that has shown both the STK11 and KEAP1 tumors have inferior outcomes to checkpoint inhibitors and are partly involved in metabolic reprogramming of the tumors. So there's definitely emerging targets that are trying to see if combination approaches in STK11 mutant lung cancer will demonstrate some level of benefit. But I think the co-mutation status would potentially have some sort of impact. But again, functional studies that help us understand what are the downstream consequences of one mutation versus another need to be further performed to get a better understanding of this space.
But I think this is definitely interesting work and very interesting results. Hopefully, our listeners will feel the same and maybe even try to go through the paper to understand some of the other additional results that you have published as part of this extensive paper.
We thank you on behalf of JCO Precision Oncology for submitting your work to JCO Precision Oncology, and hopefully, you'll consider us for further subsequent work in this space. Thank you so much for being with us today.
Dr. Mohamed Salem: No, thank you for having me, and actually, on behalf of my co-authors, I also wanted to thank JCO Precision Oncology for their interest in our paper. And, of course, for the reviewers, because there was no doubt they actually made our paper a much better one. So thank you for having me today, thank you for the entire team.
Dr. Abdul Rafeh Naqash: Reviewers definitely remain the people hidden behind the scenes who help in getting work refined and eventually published. So thank you again.
And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or a review, and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcasts
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Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Bio
Mohamed E. Salem, MD, is Research Director, Associate Professor of Medicine, and Gastrointestinal Medical Oncologist in the Department of Solid Tumor Oncology at the Levine Cancer Institute.
Guest Disclosures (See also: Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers)
Mohamed Salem:
Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca, Merck
Speakers' Bureau: Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck, Pfizer
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JCO PO authors Dr. Edward Esplin and Professor Heather Hampel share insights into their JCO PO commentary, “Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer” and discuss practical implications of testing for patients, geneticists, and clinicians. Host Dr. Rafeh Naqash, Dr. Esplin, and Professor Hampel discuss standard of care guidelines, insurance coverage, and benefits of testing. Click here to read the article!
TRANSCRIPT
Dr. Abdul Rafeh Naqash: Welcome to ASCO's JCO Precision Oncology Conversations, where we bring you the highlights and overview of Precision Oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant JCO PO articles. These articles can be accessed at ascopubs.org/journal/po.
Hello and welcome. My name is Dr. Abdul Rafeh Naqash. I'm a medical oncologist and assistant professor at the OU Health Stephenson Cancer Center. I'm also the social media editor for JCO Precision Oncology, and you're listening to JCO Precision Oncology Conversations podcast.
Today I am thrilled to be talking with Dr. Edward Esplin and Professor Heather Hampel about their recent paper, ‘Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers’. Heather Hampel is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Dr. Edward Esplin is a clinical geneticist and also the Head of Clinical Trials at Invitae in San Francisco, California.
For the purpose of this podcast, we'll be referring to each other using our first names. So welcome both Heather and Ed. Thank you for joining us today.
Dr. Edward Esplin: Thank you, Rafeh.
Professor Heather Hampel: Thanks for having us.
Dr. Abdul Rafeh Naqash: Well, first of all, I'd like to start by discussing some of the context behind this very interesting commentary. For the sake of our listeners, this is one of our first commentaries that we're doing a podcast on because this is very clinically relevant, especially for patients with cancer and without cancer, as I was reading through this commentary. So could you tell us, Ed, what prompted you to start this commentary, and what was the context of and the importance behind why something like this would make a difference in the clinical care of patients with cancer?
Dr. Edward Esplin: Yes, I'd be glad to. I think that we have seen over the past couple of years an ever-growing application and opportunity for application of precision therapies in patients with cancer of various kinds. And there has been with that a growing amount of evidence connecting germline genetic variants of a pathogenic nature with various types of cancer, breast cancer being one of the ones that is the most prominent. And as we've seen this evidence accrue in cancer types such as breast, which has probably got the longest history of a connection to germline genetics, but also accruing in other cancer types such as pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, it became clearer and clearer that there is evidence to support a broader application of germline genetic testing than is currently the standard of practice. In part driven by the desire for access to these precision therapies that are driven in part by patients' germline genetic makeup and for the opportunity that germline genetic testing results have for affording patients potential access to clinical treatment trials - so the cutting edge of what is driving some of these treatment opportunities - and reviewing the amazing amount of work that has been done by a number of people across the country and across the world to support these opportunities and support this becoming more and more the standard of care really motivated us to do this project together, and we've been fortunate to have been involved in a number of the studies that we review in this commentary.
Dr. Abdul Rafeh Naqash: Thank you so much for that explanation, Ed. So, Heather, you, and both Ed, have obviously led and been part of a lot of work in this space and have developed guidelines in this space. For the sake of our listeners, whether they are clinicians or patient advocates, what are the current guidelines behind germline testing for patients with cancer and patients without cancer?
Professor Heather Hampel: That's a really good question, and that's a lot of what's driving it for me, just from a clinical perspective.
So currently, we mainly use the NCCN guidelines in the US for deciding when a patient is appropriate for germline genetic testing. And they only recommend or suggest considering germline genetic testing for all cases of three particular cancers: all cases of ovarian, pancreatic, and, most recently, this summer, all cases of colorectal cancer, they've said you could consider offering germline testing to. The other one that has a recommendation is prostate cancer, but that's restricted to patients with metastatic or advanced prostate cancer, so it's not all prostate cancers. When you look at the guidelines, you ask yourself, how did they decide that? Was it based on the prevalence of finding a germline mutation? Because if it was, there are several other cancers where germline mutations are just as prevalent, but that recommendation has not been made.
And what is happening really on the front lines is that some patients are not having access to genetic testing because we have very complex criteria requiring ages of diagnosis, certain tumor markers, particular family history constellations that make the criteria difficult to use for frontline primary care physicians and patients deciding who needs referred, and do I need to see cancer genetics? And how much more straightforward would it be if we just said everybody with cancer needs gene testing? At this point, we pulled the data together for this commentary. We feel like the odds of testing positive are high enough in every single solid tumor to support a change in the recommendations like that.
Dr. Abdul Rafeh Naqash: Thank you. And from the data that you highlight in this commentary, apart from the tumors that you mentioned, Heather, that have recommendations for germline testing, what other tumors would you try to incorporate this in subsequently as a first, second, third approach, maybe if you can't get to all tumors at the same time?
Dr. Edward Esplin: I would say that one of the ones that we would highlight, I think, also, is breast cancer, right? That's one that there's a clear link. And as Heather appropriately noted, while a universal guideline per se has not been established by the NCCN for breast cancer, about three years ago now, based on a publication in Journal of Clinical Oncology, there was the observation that the guidelines that existed at that time did not find a significantly increased number of pathogenic germline findings in patients who met the criteria as they existed at that time compared to those patients who did not meet the criteria. And based in part upon that data, the American Society of Breast Surgeons came out with guidelines that recommended, indeed, the time is now for universal germline genetic testing for all patients who have been diagnosed with breast cancer. So I think that one's another one that there's a great deal of opportunity for that to be implemented, consistent with what Heather has already noted.
And I think there is also data that's been presented at ASCO here very recently, suggesting that similar evidence supports testing not just for metastatic prostate cancer but possibly for a broader collection of prostate cancer patients as well, perhaps all of them with a similar finding where in a prospective observational cohort of unselected patients with prostate cancer. Again, when you applied the current guidelines for testing, there was no statistically significant difference in the number of actionable pathogenic germline findings in patients who met the current criteria compared to those who do not. Which unfortunately suggests that all those patients who are being excluded when we adhere to these guidelines are not able to access the genetic information that could be crucial to their treatment. And it's just because they're not being considered, even though there is a significant fraction of those individuals who do have germline genetic information that could impact their care and possibly the preventive care of their at-risk family members as well.
Professor Heather Hampel: And, Ed, let me add a study I did with you and your team on endometrial cancer. So the truth is, Rafeh, we don't want to pick. We want all solid tumor patients to get germline genetic testing through a multigene panel. But I think if we did have to pick, I would also add endometrial. We did a study of nearly 1000 unselected endometrial cancer patients in the state of Ohio and found just over 10% had a pathogenic variant in a cancer susceptibility gene. And you really could not predict, based on personal or family history factors, who was going to test positive.
Dr. Abdul Rafeh Naqash: And that was definitely something interesting that I caught in this commentary as I was going through it. One of the sentences that was definitely interesting for me was where you mentioned that these guidelines should include risk factors beyond family history and just testing for genes beyond BRCA1 and BRCA2, which are commonly identified entities associated with germline testing, that prompt germline testing.
But one of the other things is the financial aspect of it, which you have highlighted in your commentary. So, I wanted to briefly touch on that and understand what are the policies. It seems like different coverage policies cover different aspects of germline testing, so that's number one. Could you comment on that? And number two, a few years back, there has been an effort you might have heard of related to TMB or Tumor Mutational Burden Harmonization. Could there be some sort of harmonization to identify what are the most important testing genes that are or should be covered by some of these insurance policies? And could you highlight some of the aspects around that?
Dr. Edward Esplin: That's an excellent point. And what we have found has been the course this usually proceeds through is when the guidelines have established what the criteria should be for testing, then, over a certain period of time, naturally, the various insurance payers will then incorporate this into their medical policies. And, for better or for worse, this takes time. I think, in the opinion of most, the time that it takes is unfortunately prolonged for reasons that I don't personally understand.
But noting a bright spot, I'll highlight that UnitedHealthcare has actually taken the step of instituting a very patient-first medical policy. They did this back in 2020, where they recommend and consider medically necessary standard of care germline genetic testing for any patient who has a diagnosis of any cancer that is associated with Lynch syndrome. So meaning that any patient covered by their policy who has a personal diagnosis of colon cancer, endometrial cancer, the long list of cancers associated with Lynch syndrome, qualifies for germline genetic testing. And that's covered as part of the standard of care, which is a great move in the right direction for this, the largest private commercial insurance provider in the United States.
Now, do we need to see more of that? We absolutely do, because, as Heather’s already noted, there is an access issue, and there is a disparity issue for those individuals that don't meet the criteria of their own insurance policies, medical policy, they don't have access. And that requires them, if they choose, to get germline genetic testing, to pay an out-of-pocket cost of $250 or more, depending. And that may be something that is simply not accessible to individuals. And so there's a tremendous amount of effort that needs to be done to incorporate the guidelines as they currently exist into medical policy.
And I think, to your point as well, the discrepancies between various medical policies is certainly a challenge, and I don't have a good answer for how to address that. But it is frustrating, to say the least, that any clinician has to guess what their own particular patient that's sitting in front of them right now has in terms of medical policy coverage for germline genetic testing. And then that should in any way cause them to have to second guess ‘How am I going to get the standard of care to this patient?’ One of the other challenges that that potentially raises is, as we noted in our commentary as well, unfortunately, even for those cancer types where there is an established recommendation for universal germline testing, there is nowhere near the implementation of that that there ought to be.
For ovarian cancer, I think it's in the neighborhood of 30% of patients with ovarian cancer are getting this testing. For breast cancer, I think it's 25%. I can't remember if this was cited in this paper or not, but in a recent publication that we did with collaborators from Optum Health, we found that 5% or less of colorectal cancer patients who fell under this very progressive UnitedHealthcare policy were getting testing where everyone qualified for it under the medical policy. And so it really raises concerns about these missed opportunities in the setting of not effectively implementing germline genetic testing even when it is already recommended as the standard of care for the guidelines as they currently exist and not to be available to many more patients with various cancer types, as we've already noted.
Dr. Abdul Rafeh Naqash: Thanks for highlighting some of those very extremely important points. And, to your point, it's not implemented as much as it should.
Heather, have you, or others in this field, tried to understand what are those exact barriers that maybe me, as a clinician who sees at least patients with cancer, should know, or any other community-based oncology practice physician, should know that these are patients where testing is important and will have clinical implications. But what would be the barriers that potentially do not result in as much of a higher implementation of this testing than one would expect?
Professor Heather Hampel: Well, you may be surprised to hear this coming from a genetic counselor, but I've become convinced over the years that requiring pretest genetic counseling is one of the biggest barriers that actually keeps patients from getting genetic testing when it's appropriate. And not that we're trying to be, but just that we have long wait times. Patients may have a lot of appointments because of a new cancer diagnosis, and they’re overwhelmed. It just adds one more thing that's a little difficult.
And so, I really am interested in flipping the paradigm, and this is what we're doing at City of Hope now, currently, which is offering a precision medicine or a mainstreaming approach, where every single patient at the institution is offered germline genetic testing regardless of age, regardless of family history, regardless of tumor type. And then, believe it or not, this actually supports hiring more genetic counselors because you're dealing then with thousands of results that need to be hand-reviewed, and all positives, of course, get invited in for full post-test genetic counseling. And that saves that resource, that scarce resource of genetic counseling for the people who need it the most, the people who tested positive, whose family members need testing, who need to implement all the management that comes with testing positive.
I find those sessions much more rewarding because I can be much more helpful for the patient and the family, and our negative patients, or patients with variants of uncertain significance, get templated letters. We've got a team of genetic counseling assistants that are helping get those out because, of course, that's the majority of patients. But if they have questions or concerns or a strong family history, they can, of course, come in for post-test genetic counseling, too. But I think we're on the cusp of switching the paradigm of how cancer genetics is delivered, and that's really the only way to get it at scale to the large number of patients who actually need it.
Dr. Abdul Rafeh Naqash: Thank you. And, to that point, I wanted to say that, as cancer care becomes more and more multidisciplinary, it's right there in front of us that, I think, genetic counselors or clinical geneticists need to be part of these multidisciplinary teams, whether it's through molecular tumor boards or outside of molecular tumor boards. But I think that's where the gap is, at least from what I see on my end. And that's where communication gaps create issues. I recently had at least two patients in their 30s and 40s, one with a PALB2 and another with the CHEK2 alteration and initially identified on liquid biopsy, actually, and that prompted me to check for germline testing. And lo and behold, both were positive. And that resulted, as Ed, you mentioned, cascade testing and eligibility for trials, both ended up on different DNA damage-based trials. So, definitely a lot of clinical implications.
In your practice, when you were on the academic side, Ed, did you have instances where you definitely could see a lot of difference with respect to clinical management of a patient when such an event was identified when a pathogenic germline alteration was identified? And could you give us a few examples so that listeners maybe could try to understand better how some of these things can have significant clinical implications?
Dr. Edward Esplin: Well, I practiced when I was at Stanford in perhaps a little bit of a skewed environment, skewed to the better, where much of my interaction with patients with cancer and with molecular tumor board as well was in the setting of the Stanford Cancer Genetics Clinic. And so that's certainly highly enriched for well-informed individuals, very genetic-savvy medical oncologists. Obviously, the genetic counselors were the foundation there, and me, as a clinical geneticist, was actively involved in such a way that, yes, I think it made a lot of difference from the standpoint of patients with cancer, knowing what all of their options were. And in a number of cases also, the first thing, I think that at least from my standpoint, thinking about genetics a lot that many patients want to know is: why do I have this cancer? Did I do something to cause this? What's the underlying reason for this? And being able to either provide them reassurance that this was not something that was genetic, that this was not something that anyone in their family needed to be particularly concerned about, or that there was anything further that needed to be done about that. Versus the alternative, each of those answers was incredibly valuable to the patient and the patient's family for the reasons I think that you already alluded to.
If there is a genetic cause, then there are known actions that can be taken, whether it's an approved precision therapy or a clinical treatment trial. But then I think equally important, especially in those families where there was a known history of various cancers, and this is the first person who had any genetics done, then being able to share with that patient and with the patient's family that they're going through an excruciating disease course, but there is an opportunity for some of that to be mitigated, some of that risk to be mitigated in their family members; I think brought a certain amount of, I don't know if reassurance is the right word, but it was valuable and was greatly appreciated by those individuals.
One situation that I recall actually was a patient that– I can't remember what her age was, she was probably in her 40s or 50s, but she had developed a colorectal cancer. She had had appropriate germline genetic testing performed and had had a variant identified; I believe it was one of the Lynch syndrome genes, I’m not recalling exactly right now. But while she was undergoing her treatment, I mean, to her credit, she went right away to her family in particular, to, it happened to be her son who was one that got tested, and he was, I think, late teens, maybe early 20s, he had tested positive for the same thing. She made sure that he went in, he got his colonoscopy right away, and lo and behold, right, they find an advanced polyp in this 20-year-old kid that, had that not been done, that would have been identified in just a very tragic way. And yet, as a result of her taking charge and having the information that she needed to take charge for herself and for her family members, a cancer was literally prevented. And that individual's life was prolonged, if not saved, because of that action being taken on behalf of that individual who had the information they needed to do that.
Professor Heather Hampel: Yeah, I would just add I was talking to some of the docs at one of our network sites recently and talking about all of these benefits, which are 100% clear and really also hitting on the targeted therapy benefit quite a bit. And they reminded me of another benefit which we all often forget, and that is even surgical decision-making. So if we got this done early enough, there are certainly patients who have BRCA mutations who might elect to have bilateral mastectomies instead of a unilateral mastectomy or a lumpectomy and patients with Lynch syndrome who might elect to have a subtotal colectomy instead of a segmental resection. And again, this is where not only do we need to be offering this to everybody, but we need to be offering it early at the time of biopsy-proven cancer in some cases, where it could actually affect even their surgery.
Dr. Abdul Rafeh Naqash: Absolutely. And thanks, Ed, for highlighting some of those interesting and important examples.
Now, Heather, when we talk about 80%-85% of the places in the country, at least in the US, they may or may not likely have access to experts like yourself or elaborate, broad, experienced teams that you guys have been part of. So on the oncology side, in a clinic, we get a patient who gets next-generation sequencing done, a 500-600 gene panel where we may or may not have a geneticist, or the wait times are longer. What is your suggestion for individuals, both clinicians and for patients, in that setup? What are the things that one should think of to mitigate some of those delays in that setup where you may not get a geneticist to see that patient or a counselor to see that patient immediately? Looking at that sequencing panel, what couple of things would you think of should prompt a physician to refer a patient to a genetic counselor if it's on a need basis and not available for everybody?
Professor Heather Hampel: And you're talking about a tumor panel that's coming back.
Dr. Abdul Rafeh Naqash: Correct. I'm talking about NGS 600 gene panel because that's what gets done clinically every day, all day, when you're talking about patients with cancer. What are the few things that one should look out for?
Professor Heather Hampel: So there's some nice ESMO guidelines around this, and that's what we were using. Where I used to work, I would actually hand-review the tumor test that came in and kind of send an email to the docs when I said, "Hey, this may be germline. I think this patient needs a referral." Some of the labs are now calling those out themselves, which is nice. So if they're calling it out themselves, definitely pay attention to those boxes that say "Potential germline finding," and make sure you refer any patients with anything there. If you're using a lab that's not calling it out, certainly some of the rules—there's already guidelines - anyone with a BRCA1 or BRCA2 mutation found in their tumor should be referred, regardless of what kind of tumor they have. So that one's easy.
Some of the things I like to look at is what was the variant allele fraction. If it's around 50% or anything over 35%, you start thinking maybe that's germline, that's a nice red flag. Cautionary tales - every colon tumor has an APC mutation in it, so we don't want those referred to genetics. Most of them don't have familial adenomatous polyposis. So only send a patient with an APC mutation in their colon tumor if they– in the setting of polyposis. Same goes for TP53. You're going to find that in almost every tumor, and very few of them are going to have Li-Fraumeni Syndrome.
So in the ESMO guidelines, I believe in addition to having a TP53 and an APC around a VAF of over 35%, they want to see it in a young age tumor so that you have an indication that you might be dealing actually with Li-Fraumeni syndrome. The Lynch syndrome genes, I think the common genes, if you see a mutation in them, go ahead and refer. Consider the variant allele fraction and then beware of genes that are commonly mutated in all cancers because most of those won't be hereditary, and genetics can't handle seeing every single patient who has a TP53 mutation in their tumor. So we need to see an early age or some strong family history in those cases.
The other thing just to point out, because there are long waits and not everybody has a genetic counselor or geneticist on staff is COVID turned out to have a little silver lining for the genetics community, and that is cancer genetics transition very well to televideo medicine. And there are now multiple companies providing televideo medicine. And you can usually get your patient in within a day or two for a televideo genetic counseling appointment. And so, just be aware if you can't get them to an in-person clinic in a timely manner, there are many, many televideo companies now providing genetic counseling services remotely from the comfort of their own home within two days' notice, evening appointments, weekend appointments to make it convenient for the patient. I don't work for any of those companies, but I would say just that people should be aware that those options exist so that their patients don't have to have a long wait time.
Dr. Edward Esplin: Just one quick thought along those lines. And in the context of the commentary that we talked about, I think there is a good rationale that if the patient that we're talking about with respect to receiving the tumor profiling NGS they're having any of those solid tumor types that we're discussing, it does make a lot of sense now to order that Germline genetic test at the same time that they're getting that tumor test. And doing that via what I've heard described in the literature is a mainstream approach where the clinical oncologist can be the person who is initiating both the tumor test and that germline genetic test. Get both those things cooking at the same time, such that when you're getting those results back, and in many cases, you'll probably get the germline results back sooner, then you don't have to ask those questions. And the referral to genetics can take place at the same time as well, potentially, where those results can then be discussed in detail. And I say that in part because testing all these patients with these tumor types that we've described and taking a more universal approach can make a lot of difference, for example, in patients having the information they need to actually prevent or mitigate the risk for a second primary cancer.
We did a retrospective here a little while ago where we looked at patients who had received germline testing as a reflex to the tumor testing they’d received already. And appropriately so, I think, these savvy clinicians doing exactly what Heather described and referring them for germline testing. The unfortunate thing we found is in about 10% of the individuals that had a positive finding in their germline genetic test that was done as a downstream effect from their tumor profiling test, they had had this done on the second cancer that they had developed. And the genetic result that they received in their germline test was consistent with their first cancer that they had developed. In fact, if they had the germline testing done with the first cancer that they had developed, they would have the opportunity to have had that second cancer either downstaged by screening or completely avoided in its entirety with that information being at hand. And of course, it’s practically unconscionable that a patient who has successfully defeated cancer, beat it back into remission, would need to be at unknown increased risk of a second primary tumor simply for lack of getting germline genetic testing at the time when they were first diagnosed with cancer.
Professor Heather Hampel: And not to pile on, but I'm a big fan of paired tumor and germline testing as well. And I'll just mention a Memorial Sloan Kettering paper which showed that about 10% of the mutations found on germline testing had been missed on the tumor testing because they were large rearrangements or some other type of mutation that tumor testing is really not designed to detect. So you also can't feel reassured by a normal tumor test that there isn't a germline mutation because that's not the purpose of the test, and it doesn't find every type of mutation. And so I am also a big fan of paired testing when you can get it. I also think it gives you some potential for sorting out variants of uncertain significance because you can look for second hits, et cetera. So again, I think that's the future of cancer genetics.
Dr. Abdul Rafeh Naqash: Absolutely. And I learned a lot from all the stuff that you guys mentioned. And one of the things that you just mentioned that was on my mind was VUSs or Variants of Undetermined Significance. And briefly, I wanted to touch on VUSs. If I have a BRCA1, BRCA2 VUS, what should I do?
Dr. Edward Esplin: Nothing. Absolutely nothing.
Dr. Abdul Rafeh Naqash: Should I refer to genetics or just wait and watch?
Dr. Edward Esplin: Well, I'll speak with my Invitae hat on. The waiting and watching, like you describe, I think, is very relevant because Invitae and other labs are actively involved in interrogating these VUSs on a routine basis. We see thousands of patients every day, and we see these VUSs popping up, and we're combing the literature on an ongoing basis. We're depositing new variants into ClinVar all the time, and that is part of what we consider to be our responsibility to continuously review the evidence underlying these VUSs.
And in fact, in a paper published, I think it was in JCO Global Oncology here pretty recently, we noted that over the course of about, I think it was a five-year retrospective of patients who had undergone breast cancer testing, that we looked at how many of those individuals had a variant of uncertain significance, for example, in BRCA 1 and BRCA 2, and over that period of time how many of them got reclassified, and if so, what was the reclassification. There was some small fraction that over that time period got reclassified. I think I'm going to say it's in the order of like 10% or 20% and I'm saying that wrong. But more importantly, of all of the ones that got reclassified over that five-year period of time, 10% or less ended up being pathogenic or likely pathogenic. The vast majority of them ended up being benign or likely benign, which just underscores there's nothing that needs to be done for VUS when the evidence might ever accrue that would help to reclassify that. The vast majority of the time, it's going to end up downgrading it. That's not even the right term to use for a VUS. It's going to reclassify it as a benign or likely benign variant. And if it is something that should be actionable at some point in time, all of the reputable labs out there will notify clinicians of that change in status, and that is the time when action ought to be taken.
Professor Heather Hampel: Yeah, I think that's one of the biggest cons people will have against offering germline testing to every patient is the high variant of uncertain significance rate and a fear that those patients will be mismanaged as positives, particularly in settings where there aren't genetics professionals on staff. And so I think that's a really important point. I remember when Mary-Claire King was with her Lasker Award recommending germline genetic testing for all breast cancer, all women actually, unaffected, to try and prevent breast cancer. She had suggested that in that setting, they maybe should not report variants out at all because of the risk of them being mismanaged, and I think it's an interesting idea. Most of the academic centers like to have them; sometimes, they like to work on getting some of them reclassified. But I think it's something we need to consider if we start doing testing at this large of a scale or just being sure that everybody knows that a variant of uncertain significance should be treated like a negative until proven otherwise.
Dr. Edward Esplin: I'll pile on that just briefly to note that at ASHG American Society of Human Genetics just last year there was an entire session devoted to exactly that kind of topic, and it was broadly discussed, the potential opportunity to, for example, within a cancer gene multigene panel is that a panel where returning VUS is just not a useful thing to do, restricted to pathogenic, likely pathogenic. We do that on other panels already. We do that on panels for ostensibly healthy folks and other situations. So I think that is a very worthwhile approach to consider.
And at the same time, we've also seen in the literature, Heather brings up a concern that is broadly raised and repeatedly raised, we've seen evidence that clinicians are not acting inappropriately as much as they had done, perhaps in the past, that we're getting our house in order. Breast surgeons and other physicians are treating these things like the negative results that they, in reality, are, and so that in my opinion, the potential for increased VUS identification should not be an obstacle to folks getting clinically indicated testing because that's what's needed for them to have appropriate treatment and appropriate prevention.
Dr. Abdul Rafeh Naqash: Absolutely. Well, this has been very engaging and very interesting, and hopefully, our listeners will feel the same. Thank you, both Heather and Ed, for joining us today and especially choosing JCO PO as one of the destinations for your very interesting commentary.
Thank you for listening to JCO Precision Oncology Conversations. If you like today's episode, please leave a rating and review. You can find all our shows, including this one, at asco.org/podcasts and continue to stay updated by following JCO PO on Twitter with the handle @jcopo_asco. All JCO PO articles and series can be found at ascopubs.org/journal/po.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest bios
Prof. Heather Hampel, MS, is an Associate Editor of JCO Precision Oncology. She is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center.
Dr. Edward D. Esplin, MD, PhD, FACMG, CGAF, FACP is board-certified in clinical genetics and internal medicine and completed his clinical fellowship training in medical genetics at Stanford University. He now works at Invitae.
Guest disclosures (See also: Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers)
Heather Hampel
Stock and Other Ownership Interests: Genome Medical, GI OnDemand
Consulting or Advisory Role: InVitae, Genome Medical, Pomega, 23andMe, GI OnDemand, Natera
Edward D. Esplin
Employment: Invitae
Stock and Other Ownership Interests: Invitae
Consulting or Advisory Role: Taproot Health Inc
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JCO PO author Dr. Shilpa Gupta, MD, Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director, shares analysis on outcomes in real-world settings for metastatic urothelial carcinoma (mUC) patients. Host Dr. Rafeh Naqash and Dr. Gupta discuss the utility of tumor mutational burden (TMB) to determine treatment, and mUC patient response from immune checkpoint inhibitors (ICPI) as compared with carboplatin. Click here to read the article!
TRANSCRIPT
Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations. I am Dr. Rafeh Naqash, assistant professor of medicine at OU Stephenson Cancer Center. You're listening to the JCO Precision Oncology Conversations podcast.
Today I'll be talking with Dr. Shilpa Gupta, who is an associate professor of medicine at the Cleveland Clinic and also the GU Medical Oncology Director. And we'll be talking about their group's recent paper, ‘Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma’.
Full disclosures for our guest can be found on the article’s publication page.
Hello and welcome to the podcast, Dr. Gupta. It's nice to have you here. For the sake of this podcast, we'll be referring to each other using our first names. So welcome and thanks for joining us today.
Dr. Shilpa Gupta: It's my pleasure to be here, Rafeh, I’m really excited about chatting about this paper with you. Thank you for the opportunity.
Dr. Rafeh Naqash: Thank you so much. So today we'll be discussing this interesting publication of yours, talking about biomarkers. And I often refer to biomarkers as the Pandora's Box for immune checkpoint inhibitors because definitely one size does not fit all. And reading through your paper, I saw a lot of interesting findings that you have defined in this publication. But for starters, what was the premise and background of why you wanted to study this question of tumor mutational burden as a biomarker in this patient population?
Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. The treatment paradigm for urothelial cancer patients has really evolved over the last many years. For example, patients who are eligible to receive cisplatin-based chemotherapy, that's the treatment of choice. And for patients who are not eligible to receive cisplatin due to a variety of reasons like chronic kidney disease, heart failure, peripheral neuropathy, poor performance status, or hearing loss, in the past, we used to treat them with gemcitabine and carboplatin, but outcomes were quite dismal with median overall survival less than six months or so. And then in 2017, the approval of pembrolizumab and atezolizumab as single agents was welcome news because these patients had more durable responses and survival was longer than historically with gemcitabine-carboplatin. And this is what became the standard of care based on the FDA expedited approval.
However, in 2018, the FDA restricted the use of immunotherapy only to those patients whose tumors had high PD-L1 or who were not eligible to receive carboplatin, based on the interim analysis from the phase three trials IMvigor130, which compared atezolizumab to gemcitabine-carboplatin, one of the cohorts for cis-ineligible patients, and KEYNOTE-361, which compared pembrolizumab to gemcitabine-carboplatin in the cis-ineligible cohort. And furthermore, recently, the FDA actually further restricted the label for pembrolizumab, because in the phase 3 study, even in high PD-L1 subgroups, pembrolizumab did worse than gemcitabine-carboplatin, regardless of their PD-L1 status. There were early deaths, lower response rates, and in the IMvigor130 study, we recently saw that atezolizumab was actually withdrawn for this indication altogether.
So there has been this attraction for PD-L1 for a long time, but now multiple studies in urothelial cancer have shown that PD-L1 is not a durable biomarker. And we wanted to see if there's other biomarkers which can be accessible at the point of care. And we wanted to study how tumor mutational burden can or cannot pan out as a treatment selection or complementary to clinical criteria. Right now, there's no biomarkers to guide treatment for patients in urothelial cancer for carboplatin or immunotherapy use. And that was the premise for the study.
Dr. Rafeh Naqash: Excellent. Thank you so much for that detailed understanding of why you decided to pursue this.
Now, from the listener standpoint when you define cisplatin-ineligible patients, in your practice, what is the percentage of patients that you see who are technically cisplatin-ineligible? Does comorbidity play an important role in determining which patients, or does it depend on your discussion with the patient? What are those factors that you would describe to define what cisplatin-ineligibility would constitute?
Dr. Shilpa Gupta: So historically, Matt Galsky and colleagues described cisplatin-ineligibility as patients with a creatinine clearance less than 60 mLs per minute, hearing loss greater than grade two, poor ECOG performance status two or higher, peripheral neuropathy, which is significant or significant heart failure. Now, those all make patients ineligible for cisplatin.
Now, more recently, we know that we can safely give cisplatin as long as creatinine clearance is above 50. So for the real world, 50 is a threshold where we can use split dose cisplatin. And I'll say, given that bladder cancer or urothelial cancer is a disease of the elderly, median age being 71 years, a lot of our patients have these comorbidities, chronic kidney disease, diabetes, and whatnot, which precludes us from using cisplatin. So in the real world, I would say that around 50% of patients are ineligible to receive cisplatin.
Dr. Rafeh Naqash: Interesting. And that goes back to the point where not everything that resulted from clinical trials, or the data that we get, may not be exactly applicable to the real world patient population, as you have pointed out in this interesting paper. So going back to the manuscript now from a methodology perspective, what kind of data did you include to get to the results that we'll talk about next? What was the inclusion and what was the patient population in this analysis?
Dr. Shilpa Gupta: So the patient population basically were patients who had a confirmed diagnosis of metastatic urothelial cancer. And the databases we used were the US-wide Flatiron Foundation Medicine Clinical Genomic Database, which has patients who were listed as metastatic urothelial cancer. But in addition, they also had genomic testing performed from their tumors, and results were available. And we accessed the database between 2011 until April 2021. And all these patients had had genomic testing using Foundation Medicine assay. And this de-identified data was basically US-wide across 280 cancer clinics and that's around 800 sites of care. And there's a whole range of retrospective longitudinal clinical data that was available, derived from the electronic health records comprising patient-level structured and unstructured data and also their genomic information from the tumors. And there was clinical data including demographics, lab values, performance status, timing of treatment, exposure, as well as time of progression and survival.
We decided to include patients if they received a frontline single agent immunotherapy, no matter what it was, whether pembrolizumab, atezolizumab, Nivolumab, durvalumab or avelumab, or a carboplatin-based chemotherapy. And just for the readers, this is a retrospective review. So we just used these selected patients who got in these therapies. We also required that these patients had tumor mutational burden information available through the tissue biopsy and patients who received chemotherapy and immunotherapy together were excluded and details are present in the manuscript, but this was pretty much the broad selection criteria.
Dr. Rafeh Naqash: Thank you so much. And definitely a very representative patient population from a real world setting with different therapy and different other clinical variables that are relevant in the real world setting.
So from an analysis standpoint, you, from what I read, define both a predictive and a prognostic aspect to tumor mutational burden. Could you tell us more about those results and highlight some of the interesting findings from that perspective?
Dr. Shilpa Gupta: Yes, absolutely. So as you know, tumor mutation burden cut off of ten mutations per megabase is currently utilized by the FDA, whereby approval of pembrolizumab for tumor agnostic condition was made. So that's what we considered high versus low. And we found that in this, after propensity weighing in, the tumor mutational burden less than ten group, basically those patients did not benefit from checkpoint inhibitor single agent as compared to tumor mutational burden of ten or greater. And so basically, we found that patients who had tumor mutational burden ten or higher overall had more favorable progression-free survival time to next treatment, as well as overall survival when they got a single agent immune checkpoint inhibitor, as opposed to those who got carboplatin, and also when compared to those who had tumor mutational burden less than ten. So we also looked at PD-L1 information available from the genomic database, but it was only available for around 35% of patients and still we were able to see that PD-L1 did not correlate with any of these outcomes as we show in the paper.
Dr. Rafeh Naqash: I see. And as you mentioned, you show both time to treatment failure PFS being better in TMB high patients defined as ten mutations per megabase. I didn't specifically see results related to TMB high versus low in a carboplatin specific cohort. Is that analysis something that was looked at and trying to understand whether neoantigens in a platinum-based setting specifically make a difference whether high TMB is predictive there in the carboplatin setting. Was that looked at?
Dr. Shilpa Gupta: So yes, we looked at, in the Figure 4, for the comparison of the TMB and which we were looking at the checkpoint inhibitor versus chemo. So for TMB low the chemotherapy cohort had more favorable results. Is this what you were getting at?
Dr. Rafeh Naqash: Yeah, I think what I was specifically trying to look at, like you have shown in the paper, is TMB is predictive of benefit with checkpoint inhibitors and is also prognostic in the checkpoint inhibitor setting. So my question was more whether it had a prognostic implication in a carboplatin specific cohort. So meaning high TMB, whether it correlated with better outcomes with carboplatin therapy versus low TMB. So if that was looked at.
Dr. Shilpa Gupta: We didn't look at that specifically, we only compared whether high TMB did better with the immunotherapy or chemotherapy.
Dr. Rafeh Naqash: And some of the correlation of this in my mind comes from some data that people have looked at in the lung cancer setting, whether high TMB makes a difference and for example, resected lung cancer patients, which usually gets platinum-based adjuvant therapies. So that's why I was wondering if there's any correlation there. But this is definitely interesting.
Now, my next question was going to be in your manuscript you mentioned around 30% of patients had tumor mutational burden more than or equal to ten. Did you identify any other unique characteristics from any other mutational standpoint or a PD-L1 standpoint in the high TMB cohort?
Dr. Shilpa Gupta: Yes. So PD-L1 didn't really stand out to be a very steady biomarker in our experience. And this is also what was reflected in the phase three trials like DANUBE where they looked at the durvalumab and tremelimumab, IMvigor130 or KEYNOTE-361. So that was pretty consistent that these studies also showed TMB to be more useful in exploratory analysis. Of course, these patients were not stratified based on that. And we also looked at other emerging biomarkers, for example, F-TBRS and angiogenesis gene expression signatures as well as tGE3. And we need to evaluate them in a separate study to see what pans out.
But for now, I think as far as in the real world, we are looking at a lot of genomic testing being done and right now we really don't know how to use that for making treatment decisions, right? PD-L1 has really phased out as of any utility whatsoever. And using TMB; I think in addition to the clinical characteristics, like when possible, we should be offering patients carboplatin. There's no doubt about that for cisplatin ineligible patients. But there's those patients who, if they're refusing chemotherapy and we really can't make a case for giving them single agent immunotherapy, I think TMB can come in handy to justify and make sure that we're not doing them a disservice by not giving carboplatin. And I think future trials need to use this biomarker in a prospective setting to further establish its utility.
Dr. Rafeh Naqash: Definitely, I agree it's a case-by-case situation from a patient standpoint to determine what therapy is appropriate for the patient and what is most realistic, what is the expectation that the patient has, from that treatment.
Now, from a TMB standpoint, one of the ongoing debates is if it is a binary cut off or whether it could be tertiles for a certain tumor type or quartiles. Was there any subanalysis or any subsequent study that your team would be looking at from a TMB cut off standpoint? Maybe a higher cut off would mean a better outcome and maybe lesser duration of therapy in those patients. Is that somewhat of a consideration?
Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. And I think the reason we stuck to it as a binary end point is because that's the FDA definition, so people don't try to extrapolate based on anything higher or lower. But yeah, that's a great question. And I know in lung cancer they're looking at different ranges. As far as urothelial cancer, we just stuck to the ten mutations per megabase for now.
Dr. Rafeh Naqash: Of course. And one of the other interesting things I really like to see in the paper is your figure specifically on the ECOG performance status and how clinical trials sometimes do not include patients on the higher ECOG performance status spectrum. And your study obviously had a good representation on that standpoint. What were some of the findings from the ECOG standpoint that were somewhat different in your cohort than what you would see in clinical trials in general?
Dr. Shilpa Gupta: Yes, as we've shown in Figure 5, the ECOG in real world, it was quite an eye opener to see that there was a considerable number of patients who were documented as ECOG performance status three. And if you see the ECOG performance status two bar was around 50% and ECOG performance status one was also lower than what has traditionally been included in the phase three trials. And in the phase three trials, there's hardly any patients with ECOG performance status two compared to what we saw in the real world. And very few patients, in fact, hardly any had ECOG performance status zero in our real world analysis. So clearly the trials need to be more inclusive, as has been the ASCO message all along. And it's always very surprising to see the big gap between the real world and the clinical trial patient population.
Dr. Rafeh Naqash: Definitely, I think more and more, especially cooperative group trials that you and many others are leading, are trying to be as inclusive as possible, which is important to get a better understanding of how these therapies do in different patient populations. And one of the questions I wanted to ask you, and I've seen this a few times in different checkpoint therapy treated tumors, is this initial rapid progression in some patients where the chemotherapy arm does better, but the immunotherapy arm kind of falls rapidly and then starts plateauing. In your clinical experience, have you seen that? And if yes, what are the features of some of those patients that have this rapid progression from a clinical and both from a biomarker standpoint?
Dr. Shilpa Gupta: That's a great question, Rafeh, and we do see that every now and then, and especially in my experience, we've seen that in women in particular who have bone metastases are really challenging to treat with immunotherapy. And sometimes we find that the disease just rapidly blows through immunotherapy and we really need to do more biomarker work to understand what determines these biomarkers of hyper-progression, so to speak. I know there's a lot of work going on in the field and we are also trying to understand these by serially collecting blood and circulating tumor DNA from our patients during their treatment journey.
Dr. Rafeh Naqash: Exactly. Definitely work in progress and another unique patient population where more needs to be done to understand what are the events that lead to these hyper-progression aspects, whether it's in the bone or brain or any other compartment in the body.
Well, this has been exciting and interesting, but before we end, we try to know a little bit more about the investigator, the author. So, Shilpa, can you tell us a little bit about your journey in oncology and your journey as a trainee, your journey as faculty, as a clinical trialist, as a successful clinical trialist? And any advice for junior investigators listening to this conversation?
Dr. Shilpa Gupta: Yeah, thank you for asking. I think oncology always struck me as a very exciting field back in my residency days, 2005, 2006. And at the time, so much was going on, like just drugs like bevasizumab were just coming around for colorectal cancer and in lung cancer drugs like EGFR inhibitors were coming around. And that kind of really excited me. And talking with my mentor at the time, who was a really well-renowned transplanter, he said to me that if he had to do it all over again, he would love to get into solid tumor oncology with all the excitement that's going on. I was drawn to oncology also because of, not only it's a learning experience every day, but it can be very gratifying to see amazing responses and patients living longer despite having advanced disease, and also provides a lot of challenges every day when every patient is not the same. So I think that was the reason why I was drawn to oncology and provides us an opportunity to really develop new therapies as opposed to some of the other specialties because of how challenging the patient population is.
And as far as my journey, you know, I've now been in the US for almost 18 years and have been in a variety of places, and I think it's been a very rewarding journey despite multiple bumps along the way. And I'm really glad to be doing what I'm doing and trying to advance the field, clinical trials, and learning from people around me.
Dr. Rafeh Naqash: Thank you so much for giving us a little glimpse into your journey and your experiences. And it's always inspiring to listen to successful investigators and also try to emulate in some ways what you have done and what you've achieved. And thank you again for coming on this podcast. And thank you for choosing JCO Precision Oncology as a destination for your manuscript, and hopefully we'll see more of the same from you and your group in the subsequent years to come and more in this field of biomarkers.
Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one, at ASCO.org/podcasts or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journal/PO.
The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.
Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Guest Bio
Shilpa Gupta, MD, is Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director.
Guest disclosures
Stock and Other Ownership Interests: Nektar, Moderna Therapeutics
Honoraria: Bristol Myers Squibb
Consulting or Advisory Role: Gilead Sciences, Guardant Health, AVEO, EMD Serono, Pfizer, Merck, Loxo/Lilly
Speakers' Bureau: Bristol Myers Squib
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