JCO Precision Oncology Conversations

In this JCO Precision Oncology Article Insights episode, Mitchell Elliot provides a summary on "Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer" by Shaw, et al published on May 1st, 2024. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Mitchell Elliott: Hello and welcome to the 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, “Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long Term Follow up in Patients with Breast Cancer,” by Dr. Jacqueline Shaw and colleagues.  Circulating tumor DNA is shed readily into the peripheral blood by tumors. ctDNA makes up a small fraction of the total cell free DNA in the peripheral blood and can be detected using highly sensitive assays. ctDNA assays can be tumor-informed where blood samples are tested for the presence of tumor specific mutations, which are selected by sequencing the primary tumor, so the panels are patient specific. Tumor agnostic assays also exist which are typically looking for the presence of cancer driver mutations or cancer derived methylation signals, which are not patient specific but rather cancer specific. Several retrospective analyses of clinical trials and cohorts have demonstrated that the identification of ctDNA in patients in follow-up can predict relapse in breast cancer, lung cancer, and colon cancer. Personalized tumor informed assays have demonstrated high technical specificity, but to date there is no gold standard assay identified and no direct comparison between all of the available assays. While the literature to date has demonstrated that identification of ctDNA prior to clinical relapse is possible, no study has demonstrated that it improves patient outcomes.  In this specific study, the authors evaluated the Signatera assay, a tumor informed assay based on whole exome sequencing, enabling the design of personalized panels for up to 16 tumor specific variants detected via multiplex PCR next generation sequencing. This was evaluated in the exploratory breast lead interval study or EBLIS, which is a study based out of the United Kingdom. EBLIS is a multicenter prospective cohort study funded by Cancer Research UK and the National Institute of Health Research that opened for recruitment in 2012. This was a retrospective analysis so no results were directly shared with patients or physicians. Patients were eligible if they were 18 years or older, had histologically confirmed breast cancer and must have completed all surgery and chemotherapy within three years of entry into the study. They had to have an adjuvant online risk relapse at greater than 65% or mortality of greater than 50% at 10 years, which defines a very high risk subgroup for study enrollment.  The results of this study and the baseline patient characteristics reflected the predefined clinical risk. The majority received neoadjuvant or adjuvant chemotherapy. Most patients were diagnosed with invasive ductal carcinoma and were staged 2b to 3c. There were 156 patients identified from this cohort after 28 had insufficient DNA and 3 had unsuccessful whole exome sequencing, which are required for the assay generation. Of the 156 patients, there were 1136 plasma time points evaluated. Of the 1136 plasma time points, ctDNA was identified in 46, which represents approximately 4% of the total time points in this high risk cohort. 34 patients have experienced disease relapse, including 22 with hormone receptor positive HER2 negative disease, three with hormone receptor positive HER2 positive disease, seven with triple negative breast cancer, and two with hormone receptor negative HER2 positive disease. ctDNA was detected in 30 of the 34 patients who had a subsequent relapse with a patient specific sensitivity of 88.2%. Relapse was predicted with a lead time interval of up to 38 months with a median of around 10.5 months ranging from 0 to 38 months. 100% of relapses were detected through ctDNA in patients with hormone receptor positive HER2 positive disease, triple negative breast cancer and hormone receptor negative HER2 positive disease.  Patients with a positive ctDNA test had a poor recurrence free survival with a hazard ratio of 52.98 with a 95% confidence interval of 18.32 to 153.2 with a statistically significant p value. Patients also had a significantly reduced overall survival if ctDNA was detected in the adjuvant setting. Multivariate models incorporating clinical pathologic variables and ctDNA status were analyzed. In this, ctDNA status remained the most significant factor associated with recurrence free survival and overall survival. Interestingly, concurrent ctDNA analyses and CA 15-3 measurements were available for 100 patients. CA 15-3 status was defined as positive and negative at the cutoff value of 30 units per milliliter. A Fisher's exact test showed a borderline statistically significant correlation between ctDNA status and CA 15-3, with a p value of 0.053. Again, multivariate analyses indicated that ctDNA was independent of CA 15-3 in predicting recurrence free survival and overall survival. Interestingly, ctDNA was not detected in 4 patients who experienced subsequent disease relapse, even with consistent and frequent sampling. Furthermore, ctDNA was detected in 5 out of 122 patients who did not have a subsequent recurrence, all being hormone receptor positive HER2 negative. These patients also had mature follow up. It is unknown if there was a change in the adjuvant treatment associated with subsequent negative tests, and follow up continues.   In summary, the study reaffirms that personalized ctDNA assays have high technical sensitivity and specificity for the identification of patients at risk for disease relapse. The test is highly predictive of recurrence in patients with breast cancer, especially with triple negative subtype where all patients had ctDNA detected prior to clinical relapse. However, for patients with hormone receptor positive breast cancer, these results suggest that this test needs to be used with caution, as a small proportion of patients experience disease relapse with negative tests and others whose tests are positive have not yet relapsed. It is unknown if these patients with ctDNA detected have radiographically overt metastatic disease in the absence of clinical symptoms, as concurrent radiographic surveillance was not performed in the standard of care follow up. Prospective clinical trials are required to define a role for ctDNA surveillance in clinical care.  Again, I'm Mitchell Elliot, a JCO Precision Oncology editorial fellow. Thank you for listening to the JCO Precision Oncology Article Insight, 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 www.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.      

JCO PO author Dr. Jun Gong shares insights into his JCO PO articles, “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K1" and “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2”. Host Dr. Rafeh Naqash and Dr. Gong discuss the limited activity of FGFR inhibition in solid tumors with FGFR amplifications and mutations or fusions in this NCI-MATCH phase II trial. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations 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 Stevenson Cancer Center at the University of Oklahoma.  Today, we are excited to be joined by Dr. Jun Gong, Associate Professor in the Division of Medical Oncology at Cedars-Sinai Medical Center and lead author of the JCO Precision Oncology article entitled "Phase II Study of Erdafitinib in Patients with Tumors Harboring FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K1" and "Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K2."   Our guest's disclosures will be linked in the transcript.   Dr. Gong, welcome to our podcast and thank you for joining us.  Dr. Jun Gong: Thank you, Dr. Naqash and JCO Precision Oncology for having me. Dr. Rafeh Naqash: We are excited to be discussing some interesting aspects that you have led and published on from the NCI-MATCH trial. We were trying to understand from a background perspective, since this master protocol has been going on for quite some time, could you give us a little bit of background for the sake of our listeners on what the NCI-MATCH is and what were the specific objectives for these two subprotocols?  Dr. Jun Gong: Yes, of course, Dr. Naqash. So, as you may all know, the importance of targeted therapies in the current era of precision oncology. And on that backdrop, the NCI-MATCH was a national multicenter study designed essentially to look for signals of efficacy across various solid tumor and hematologic malignancy types, with a focus on specific mutations. The master protocol is unique in that there are several arms to the trial, each targeting a specific potential targetable alteration using available agents in cancer today. Dr. Rafeh Naqash: Excellent. Thank you for that background. I know this master protocol has been going on for quite some time with different subprotocols. I believe some of them are immunotherapy-based. Also, you've led two important subprotocols, which are the FGFR amplification and the FGFR mutation or fusion. There are some differences, from what I gather, in responses for the fusions versus the amplifications or mutations versus the amplifications. Could you first delve into the first paper of the fusions, and describe what were the tumor types? As you mentioned in the paper, some tumors were excluded. What was the reason for the exclusion of some of those tumor types? Why did you want to study the fusions and mutations versus the amplifications separately? What was the background for that? Could you highlight some of those points for us? Dr. Jun Gong: Firstly, as a kind of a more background, FGFR has been a recognizable target for a couple of tumor types. And if you look at the broad landscape of FGFR alterations, they occur in about 5%-10% of cancers, with the majority being FGFR amplifications actually, and mutations and rearrangements following second and third respectively in most commonly identified alterations. With that being said, FGFR mutations and rearrangements have already been established in a couple of tumor types. Actually, the first FDA approval for an oral FGFR inhibitor was erdafitinib, which was the agent used in both of these back-to-back trials. However, erdafitinib was first approved in urothelial carcinoma, and since then, there has been an explosion in oral FGFR inhibitors targeting fusions and mutations in other cancer types, such as cholangiocarcinoma.   More recently, there was even an FDA approval in a myeloid malignancy as well. So, we used erdafitinib, being that it was the first FDA-approved, orally available agent to target this alteration. We conducted the two back-to-back studies in recognition that although rearrangements and mutations have already been established in certain tumor types, we were more interested in looking at the more common FGFR alteration, that being amplifications. However, the efficacy in that was a little unknown, and so these two separate subprotocols were developed: K2, which was to look at FGFR mutations and fusions in tumor types, excluding urothelial carcinoma, to look if there was a signal of efficacy beyond currently FDA-approved indications, and amplification as a separate cohort. Dr. Rafeh Naqash: That's a very good explanation of why you concentrated on the tumor types in these protocols.  Now, going back to subprotocol K1, could you tell us what were some of the tumor types that you did include, and what was the sample size, and what was the hypothesis for the sample size as a meaningful level of activity that you wanted to see and would have potentially led to a bigger, broader trial? Dr. Jun Gong: So, subprotocol K1 was the arm investigating erdafitinib in those with FGFR amplifications, and these were predefined on the NCI-MATCH protocol, looking at FGFR 1, 2, 3, and 4 amplifications essentially. These were allowed to have local testing through a local CLIA-certified assay, but then they needed to be confirmed on a central assay, which is the NCI-MATCH Oncomine assay. These statistics are uniform for the NCI-MATCH trials, and the goal was at least 31 patients, with the hypothesis that if the response rate was 16% or more, this was considered a signal of activity. However, there was an additional protocol specific requirement in that if the sample size was fewer than 31 patients, then the primary efficacy population would be assessed against a null hypothesis overall response rate of 5%. Meaning that if there were less than 31 subjects, an overall response rate of greater than 5% would be defined as positive. Again, the NCI-MATCH was uniform. Secondary objectives included progression-free survival, overall survival, and safety and toxicity. With that being said, K1 originally began accrual. The NCI-MATCH actually launched in 2015, but in the subprotocol K1, 35 patients were initially enrolled in the study. If you go down the eligibility criteria, however, a lot of these patients dropped out due to a lack of central tumor confirmation and various reasons. Ultimately, 18 patients were included in the pre-specified primary efficacy cohort. Dr. Rafeh Naqash: Thank you. I did see for subprotocol K1, you mostly had stable disease in a couple of patients, no responses, and I think one individual with breast cancer had a prolonged stable disease.   Now, from an FGFR amplification standpoint, did you or were you able to correlate - again, this is not objective responses, it's not a partial response or a complete response - was there any correlation from the level of amplification to the duration of stable disease?  Dr. Jun Gong: That's actually the core of our discussion about why K1, despite a variety basket of solid tumor types, somewhere, preclinical data had suggested FGFR amplifications could be targeted, that K1 was ultimately a negative trial with a 0% response rate. We dive in that although we included as an eligibility criteria a copy number variation of seven as the threshold for amplification, we realized that if you look at some of the literature out there, that even in the FGFR 1 and 2 amplification cohorts, where these are the more common cohorts of amplified tumor types that have been targeted, you really needed a high level of amplification, more than 99% of tumor cells being amplified in the previous studies, to actually generate a response.  The thought was that we assumed that FGFR amplification would lead to protein expression and dependence on FGFR signaling, providing sensitivity to FGFR inhibition. However, we realized that there is a certain degree where a high level of amplification needs to happen, and it may not be for all FGFR amplifications. We looked into the literature that FGFR 1 and 2 were the more commonly studied FGFR amplifications. FGFR 1, if you actually look at the amplicon structure, it tends to amplify a lot of other genes because it's such a huge amplicon structure. But FGFR 2 is shorter and centered on just FGFR 2 with a few other genes co-amplified. So, actually in the literature, they've already been seeing that maybe FGFR 2 amplification tumors are more readily targetable based on the robustness of evidence, rather than FGFR 1. But across all of these, the higher the level of amplification, seems the more targetable. Dr. Rafeh Naqash: Those are interesting discussions around protein expression on the tumor that could imply therapeutic vulnerability. So I've always thought about it, whether trials like NCI-MATCH trials or ASCO TAPUR, for example, would be perhaps more informative if, on a secondary analysis standpoint, proteomics is something that could be done on the tumor tissue, because similar to NCI-MATCH, ASCO TAPUR has other sub protocols where some of these mutations or amplifications don't necessarily result in antitumor responses. But I think from a biology standpoint, as you mentioned, a certain amplification might correspond to RNA expression and that might correspond to protein expression, which is downstream. So looking at that would be something interesting. Have you planned for something like that on these tumor specimens?

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.  

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 muta

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.      

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 a

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.    

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 try

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.  

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 o

 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, f

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

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 ex

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 canc

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,

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 l

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 w

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 b

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 7

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!   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 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