Palbociclib in Tumors with CDKN2A Loss or Mutation

In this JCO Precision Oncology Article Insights episode, host Dr. Harold Nathan Tan summarizes "Palbociclib in Patients With Head and Neck Cancer and Other Tumors With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study" by Worden et al.  TRANSCRIPT Harold Nathan Tan: Welcome to JCO Precision Oncology Article Insights, where we explore research that is reshaping our understanding of cancer therapeutics. I'm your host, Harold Nathan Tan, and today's episode centers on the TAPUR study, an analysis that confronts a long-standing assumption in molecular oncology: namely, whether CDKN2A alterations create a therapeutic vulnerability that can be exploited by CDK4/6 inhibition with palbociclib. CDKN2A is one of the most frequently altered tumor suppressors across solid tumors. Its importance lies in its production of two proteins, p16 and p14, which serve as guardians of cell cycle progression. p16 directly inhibits CDK4 and CDK6, preventing phosphorylation of the RB protein and therefore blocking entry into S phase, whereas p14 stabilizes p53 by counteracting MDM2, enabling cells to pause or die in response to oncogenic stress. When CDKN2A is lost or mutated, these dual checkpoints collapse. CDK4/6 activity becomes unchecked, RB remains phosphorylated and inactive, and p53-mediated surveillance is blunted from a mechanistic standpoint. This creates a possible dependency on CDK4/6 signaling that could, in principle, be therapeutically reversed by palbociclib. The TAPUR study is a prospective phase 2 basket study designed to evaluate whether FDA-approved targeted agents can meaningfully benefit patients with advanced treatment-refractory cancers harboring specific genomic alterations. In this analysis, patients were eligible for palbociclib if their tumors carried CDKN2A loss or mutation and retained RB activity. Two cohorts were examined: one consisting of head and neck cancers, and another composed of a broad spectrum of tumor types that collectively shared the CDK2 alteration. The results from the head and neck cancer cohort are particularly intriguing. Among the 28 available patients, the study observed a disease control rate of 40%, surpassing the predefined threshold for a positive signal. Although the objective response rate was low at only 4% with one partial response, the durability of disease stabilization was clinically meaningful. However, the most important insight comes from examining which head and neck tumors benefited. The strongest and most durable disease control occurred in non-squamous malignancies, particularly salivary gland tumors such as adenocarcinoma, adenoid cystic carcinoma, and poorly differentiated parotid tumors, as well as in esthesioneuroblastoma. In contrast, classic head and neck squamous cell carcinoma rarely demonstrated sustained benefit. When progression-free survival was analyzed, non-squamous tumors achieved a median PFS of approximately 20 weeks compared to just eight weeks in squamous tumors. This divergence reflects deep biological differences. Many non-squamous head and neck cancers preserve an intact RB axis and rely on CDK4/6-driven cell cycle control as a core proliferative mechanism. By contrast, squamous tumors tend to accumulate a dense array of co-alterations that weaken or circumvent CDK4/6 dependency. Many squamous tumors also harbor disruptive TP53 mutations, removing essential checkpoint control and allowing the cell to bypass the growth-arresting effects of palbociclib. In other words, even though CDKN2A loss is present, CDK4/6 is no longer the dominant node controlling proliferation in these cancers, and the tumor simply finds other ways to drive cell cycle entry. One of the most thought-provoking findings from the TAPUR study involves esthesioneuroblastoma. Three patients with this rare tumor achieved durable disease control despite the lack of standardized systemic treatment options for this malignancy. Genomic analyses have shown that while esthesioneuroblastoma often carries TP53 or IDH2 mutations, a meaningful subset exhibits alterations in CDKN2A or related cell cycle regulators. The consistency of this disease stabilization observed in TAPUR may reflect a lineage-specific reliance on CDK4/6 signaling, opening the door for future exploration of CDK4/6 inhibitors in this orphan disease. In the histology-pooled cohort, which included 40 available patients across 18 tumor types, palbociclib did not achieve the disease control threshold required to declare activity, with only a disease control rate of 13% and an ORR of 5%. While a few isolated responses occurred, for instance in thymic carcinoma and B-cell lymphoma, the overall disease control rate was 13%, which failed to rise above what might be expected from the natural history of advanced refractory cancers. This outcome reinforces the principle that CDKN2A loss is not a universal predictor of CDK4/6 dependency. Many of the tumors represented in this cohort, such as pancreatic cancer, melanoma, and gastrointestinal malignancies, are well known to evolve multiple compensatory mechanisms that circumvent CDK4/6 as a critical proliferative node. The safety profile of palbociclib was consistent with its known hematologic toxicities. High rates of neutropenia, leukopenia, and thrombocytopenia were observed, along with one treatment-related death due to respiratory failure. In a setting where activity is limited to specific subgroups, these toxicities underscore the importance of careful patient selection and raise the bar for demonstrating clinically meaningful benefit, particularly in heavily pretreated populations. So what do these findings tell us about the broader landscape of precision oncology? First, they remind us that a mutation's functional role is dependent on the cellular and lineage context in which it occurs. CDKN2A loss may accelerate proliferation in many tumors, but the mechanism of that acceleration varies widely, and the degree to which a tumor relies on CDK4/6 signaling is anything but uniform. Second, the findings suggest that palbociclib monotherapy may hold meaningful and durable benefit in the subset of non-squamous head and neck cancers, particularly salivary gland malignancies and esthesioneuroblastoma. Third and perhaps most importantly, the results reinforce a growing consensus that the future of CDK4/6 inhibition in solid tumors lies not in monotherapy, but in rational combination strategies. CDK4/6 inhibitors have been shown to synergize with EGFR inhibitors, PIK3CA, and mTOR inhibitors, MEK inhibition, and even immune checkpoint blockade. These combinations aim to dismantle the compensatory pathways that allow tumors to escape CDK4/6 blockade and may unlock therapeutic potential in tumors that show limited sensitivity to monotherapy. Ultimately, the TAPUR findings challenge the notion that CDKN2A is a straightforward predictive biomarker. Instead, the study reveals CDKN2A as a biomarker whose meaning is modulated by tumor lineage, co-mutation status, and the broader regulatory circuit governing proliferation. Precision oncology must therefore move beyond single-gene interpretation towards integrated frameworks that situate genomic alterations within their biologic ecosystems. In some head and neck cancer subtypes, particularly non-squamous malignancies, that ecosystem appears amenable to CDK4/6 inhibition, and that insight, not the simplistic gene-to-drug match, represents the true value of the TAPUR analysis. Thank you for joining me for this episode of JCO Precision Oncology Article Insights. I'm Harold Nathan Tan, and I look forward to exploring more research that continues to refine how we understand and strategically exploit the vulnerabilities of cancer. 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. Shilpa Gupta at Cleveland Clinic Children's Hospital shares insights into her article, "Fibroblast Growth Factor Receptor 3 (FGFR3) Alteration Status and Outcomes on Immune Checkpoint Inhibitors (ICPI) in Patients with Metastatic Urothelial Carcinoma". Host Dr. Rafeh Naqash and Dr. Gupta discuss how FGFR3 combined with TMB emerged as a biomarker that may be predictive for response to ICPI in mUC. 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, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center. Today I am excited to be joined by Dr. Shilpa Gupta, Director of Genitourinary Medical Oncology at the Cancer Institute and co-leader of the GU Oncology Program at the Cleveland Clinic, and also lead author of the JCO PO article titled "Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With Metastatic Urothelial Carcinoma." At the time of this recording, our guest's disclosures will be linked in the transcript. Shilpa, welcome again to the podcast. Thank you for joining us today. Dr. Shilpa Gupta: Thank you, Rafeh. Honor to be here with you again. Dr. Rafeh Naqash: It is nice to connect with you again after two years, approximately. I think we were in our infancy of our JCO PO podcast when we had you first time, and it has been an interesting journey since then. Dr. Shilpa Gupta: Absolutely. Dr. Rafeh Naqash: Well, excited to talk to you about this article that you published. Wanted to first understand what is the genomic landscape of urothelial cancer in general, and why should we be interested in FGFR3 alterations specifically? Dr. Shilpa Gupta: Bladder cancer or urothelial cancer is a very heterogeneous cancer. And while we find there is a lot of mutations can be there, you know, like BRCA1, 2, in HER2, in FGFR, we never really understood what is driving the cancer. Like a lot of old studies with targeted therapies did not really work. For example, we think VEGF can be upregulated, but VEGF inhibitors have not really shown definite promise so far. Now, FGFR3 receptor is the only therapeutic target so far that has an FDA approved therapy for treating metastatic urothelial cancer patients, and erdafitinib was approved in 2019 for patients whose tumors overexpressed FGFR3 mutations, alterations, or fusions. And in the landscape of bladder cancer, it is important because in patients with non-muscle invasive bladder cancer, about 70 to 80% patients can have this FGFR3. But as patients become metastatic, the alterations are seen in, you know, only about 10% of patients. So the clinical trials that got the erdafitinib approved actually used archival tumor from local cancer. So when in the real world, we don't see a lot of patients if we are trying to do metastatic lesion biopsies. And why it is important to know this is because that is the only targeted therapy available for our patients right now. Dr. Rafeh Naqash: Thank you for giving us that overview. Now, on the clinical side, there is obviously some interesting data for FGFR3 on the mutation side and the fusion side. In your clinical practice, do you tend to approach these patients differently when you have a mutation versus when you have a fusion? Dr. Shilpa Gupta: We can use the treatment regardless of that. Dr. Rafeh Naqash: I recently remember I had a patient with lung cancer, squamous lung cancer, who also had a synchronous bladder mass. And the first thought from multiple colleagues was that this is metastatic lung. And interestingly, the liquid biopsy ended up showing an FGFR3-TACC fusion, which we generally don't see in squamous lung cancers. And then eventually, I was able to convince our GU colleagues, urologists, to get a biopsy. They did a transurethral resection of this tumor, ended up being primary urothelial and synchronous lung, which again, going back to the FGFR3 story, I saw in your paper there is a mention of FGFR3-TACC fusions. Anything interesting that you find with these fusions as far as biology or tumor behavior is concerned? Dr. Shilpa Gupta: We found in our paper of all the patients that were sequenced that 20% had the pathognomonic FGFR3 alteration, and the most common were the S249C, and the FGFR3-TACC3 fusion was in 45 patients. And basically I will say that we didn't want to generate too much as to fusion or the differences in that. The key aspect of this paper was that historically there were these anecdotal reports saying that patients who have FGFR alterations or mutations, they may not respond well to checkpoint inhibitors because they have the luminal subtype. And these were backed by some preclinical data and small anecdotal reports. But since then, we have seen that, and that's why a lot of people would say that if somebody's tumor has FGFR3, don't give them immunotherapy, give them erdafitinib first, right? So then we had this Phase 3 trial called the THOR trial, which actually showed that giving erdafitinib before pembrolizumab was not better. That debunked that myth, and we are actually reiterating that because in our work we found that patients who had FGFR3 alterations or fusions, and if they also have TMB-high, they actually respond very well to single agent immunotherapy. And that is, I think, very important because it tells us that we are not really seeing that so-called potential of resistance to immunotherapy in these patients. So to answer your question, yeah, we did see those differences, but I wouldn't say that any one marker is more prominent. Dr. Rafeh Naqash: The analogy is kind of similar to what we see in lung cancer with these mutations called STK11/KEAP1, which are also present in some other tumors. And one of the questions that I don't think has been answered is when you have in lung cancer, if you extrapolate this, where doublet or single agent immunotherapy doesn't do as well in tumors that are STK11 mutated. But then if you have a high TMB, question is does that TMB supersede or trump the actual mutation? Could that be one reason why you see the TMB-high but FGFR3 altered tumors in your dataset responding or having better outcomes to immunotherapy where potentially there is just more neoantigens and that results in a more durable or perhaps better response to checkpoint therapy? Dr. Shilpa Gupta: It could be. But you know, the patients who have FGFR alterations are not that many, right? So we have already seen that just patients with TMB-high respond very well to immunotherapy. Our last podcast was actually on that, regardless of PD-L1 that was a better predictor of response to immunotherapy. So I think it's not clear if this is adding more chances of response or not, because either way they would respond. But what we didn't see, which was good, that if they had FGFR3, it's not really downplaying the fact that they have TMB-high and that patients are not responding to immunotherapy. So we saw that regardless, and that was very reassuring. Dr. Rafeh Naqash: So if tomorrow in your clinic you had an individual with an FGFR3 alteration but TMB-high, I guess one could be comfortable just going ahead with immunotherapy, which is what the THOR trial as you mentioned. Dr. Shilpa Gupta: Yes, absolutely. And you know, when you look at the toxicity profiles of pembrolizumab and erdafitinib, really patients really struggle with using the FGFR3 inhibitors. And of course, if they have to use it, we have to, and we reserve it for patients. But it's not an easy drug to tolerate. Currently the landscape is such that, you know, frontline therapy has now evolved with an ADC and immunotherapy combinations. So really if patients progress and have FGFR3 alterations, we are using erdafitinib. But let's say if there were a situation where a patient has had chemotherapy, no immunotherapy, and they have FGFR3 upregulation and TMB-high, yes, I would be comfortable with using only pembrolizumab. And that really ties well together what we saw in the THOR trial as well. Dr. Rafeh Naqash: Going to the clinical applications, you mentioned a little bit of this in the manuscript, is combination therapies. You alluded to it a second back. Everything tends to get combined with checkpoint therapy these days, as you've seen with the frontline urothelial, pembrolizumab with an ADC. What is the landscape like as far as some of these FGFR alterations are concerned? Is it reasonable to combine some of those drugs with immune checkpoint therapy? And what are some of the toxicity patterns that you've potentially seen in your experience? Dr. Shilpa Gupta: So there was indeed a trial called the NORSE trial. It was a randomized trial but not a comparative cohort, where they looked at FGFR altered patients. And when they combined erdafitinib plus cetrelimab, that did numerically the response rates were much higher than those who got just erdafitinib. So yeah, the combination is definitely doable. There is no overlapping toxicities. But unfortunately that combination has not really moved forward to a Phase 3 trial because it's so challenging to enroll patients with such kind of rare mutations on large trials, especially to do registration trials. And since then the frontline therapy has evolved to enfortumab vedotin and pembrolizumab. I know there is an early phase trial looking at a next generation FGFR inhibitor. There is a triplet combination looking in Phase 1 setting with a next generation FGFR inhibitor with EV-pembro. However, it's not a randomized trial. So you know, I worry about such kinds of combinations where we don't have a path for registration. And in the four patients that have been treated, four or five patients in the early phase as a part of basket trial, the toxicities were a lot, you know, when you combine the EV-pembro and an FGFR3 inhibitor, we see more and more toxicity. So the big question is do we really need the "kitchen sink" approach when we have a very good doublet, or unless the bar is so high with the doublet, like what are we trying to add at the expense of patient toxicity and quality of life is the big question in my mind. Dr. Rafeh Naqash: Going back to your manuscript specifically, there could be a composite biomarker. You point out like FGFR in addition to FGFR TMB ends up being predictive prognostic there. So that could potentially be used as an approach to stratify patients as far as treatment, whether it's a single agent versus combination. Maybe the TMB-low/FGFR3 mutated require a combination, but the TMB-high/FGFR mutated don't require a combination, right? Dr. Shilpa Gupta: No, that's a great point, yeah. Dr. Rafeh Naqash: But again, very interesting, intriguing concepts that you've alluded to and described in this manuscript. Now, a quick take on how things have changed in the bladder cancer space in the last two years. We did a podcast with you regarding some biomarkers as you mentioned two years back. So I really would like to spend the next minute to two to understand how have things changed in the bladder cancer space? What are some of the exciting things that were not there two years back that are in practice now? And how do you anticipate the next two years to be like? Maybe we'll have another podcast with you in another two years when the space will have changed even more. Dr. Shilpa Gupta: Certainly a lot has happened in the two years, you know. EV-pembro became the universal frontline standard, right? We have really moved away from cisplatin eligibility in metastatic setting because anybody would benefit from EV-pembro regardless of whether they are candidates for cisplatin or not, which historically was relevant. And just two days ago, we saw that EV-pembro has now been approved for localized bladder cancer for patients who are cisplatin ineligible or refusing. So, you know, this very effective regimen moving into earlier setting, we now have to really think of good treatment options in the metastatic setting, right? So I think that's where a lot of these novel combinations may come up. And what else we've seen is in a tumor agnostic trial called the DESTINY-PanTumor trial, patients who had HER2 3+ on immunohistochemistry, we saw the drug approval for T-DXd, and I think that has kind of reinvigorated the interest in HER2 in bladder cancer, because in the past targeting HER2 really didn't work. And we still don't know if HER2 is a driver or not. And at ESMO this year, we saw an excellent study coming out of China with DV which is targeting HER2, and toripalimab, which is a Chinese checkpoint inhibitor, showing pretty much similar results to what we saw with EV-pembro. Now, you know, not to do cross-trial comparisons, but that was really an amazing, amazing study. It was in the presidential session. And I think the big question is: does that really tell us that HER2-low patients will not benefit? Because that included 1+, 2+, 3+. So that part we really don't know, and I think we want to study from the EV-302 how the HER2 positive patients did with EV and pembro. So that's an additional option, at least in China, and hopefully if it gets approved here, there is a trial going on with DV and pembro. And lastly, we've seen a very promising biomarker, like ctDNA, for the first time in bladder cancer in the adjuvant setting guiding treatment with adjuvant atezolizumab. So patients who were ctDNA positive derived overall survival and recurrence-free survival benefit. So that could help us select moving forward with more studies. We can spare unnecessary checkpoint inhibitors in patients who are not going to benefit. So I think there is a lot happening in our field, and this will help do more studies because we already have the next generation FGFR inhibitors which don't have the toxicities that erdafitinib comes with. And combining those with these novel ADCs and checkpoint inhibitors, you know, using maybe TMB as a biomarker, because we really need to move away from PD-L1 in bladder cancer. It's shown no utility whatsoever, but TMB has. Dr. Rafeh Naqash: Well, thank you so much, Shilpa, for that tour de force of how things have changed in bladder cancer. There used to be a time when lung and melanoma used to lead this space in terms of the number of approvals, the biomarker development. It looks like bladder cancer is shifting the trend at this stage. So definitely exciting to see all the new changes that are coming up. I'd like to spend another minute and a half on your career. You've obviously been a leader and example for many people in the GU space and beyond. Could you, for the sake of our early career especially, the trainees and other listeners, describe how you focused on things that you're currently leading as a leader, and how you shaped your career trajectory over the last 10 years? Dr. Shilpa Gupta: That's a really important question, Rafeh, and you and I have had these discussions before, you know, being an IMG on visas like you, and being in different places. I think I try to make the most of it, you know, instead of focusing on the setbacks or the negative things. Like tried to grab the opportunities that came along. When I was at Moffitt, got to get involved with the Phase 1 trial of pembrolizumab in different tumor types. And just keeping my options open, you know, getting into the bladder cancer at that time when I wanted to really do only prostate, but it was a good idea for me to keep my options open and got all these opportunities that I made use of. I think an important thing is to, like you said, you know, have a focus. So I am trying to focus more on biomarkers that, you know, we know that 70% patients will respond to EV-pembro, right? But what about the remaining 30%? Like, so I'm really trying to understand what determines hyperprogressors with such effective regimens who we really struggle with in the clinic. They really don't do well with anything we give them after that. So we are doing some work with that and also trying to focus on PROs and kind of patient-reported outcomes. And a special interest that I've now developed and working on it is young-onset bladder cancer. You know, the colorectal cancer world has made a lot of progress and we are really far behind. And bladder cancer has historically been a disease of the elderly, which is not the case anymore. We are seeing patients in their 30s and 40s. So we launched this young-onset bladder cancer initiative at a Bladder Cancer Advocacy Network meeting and now looking at more deep dive and creating a working group around that. But yeah, you know, I would say that my philosophy has been to just take the best out of the situation I'm in, no matter where I am. And it has just helped shape my career where I am, despite everything. Dr. Rafeh Naqash: Well, thank you again. It is always a pleasure to learn from your experiences and things that you have helped lead. Appreciate all your insights, and thank you for publishing with JCO PO. Hopefully we will see more of your biomarker work being published and perhaps bring you for another podcast in a couple of years. Dr. Shilpa Gupta: Yeah, thank you, Rafeh, for the opportunity. And thanks to JCO PO for making these podcasts for our readers. So thanks a lot. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. 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. DISCLOSURES Dr. Shilpa Gupta Stock and Other Ownership Interests: Company: BioNTech SE,  Nektar Consulting or Advisory Role: Company: Gilead Sciences, Pfizer, Merck, Foundation Medicine, Bristol-Myers Squibb/Medarex, Natera, Astellas Pharma, AstraZeneca, Novartis, Johnson & Johnson/Janssen Research Funding: Recipient: Your Institution Company: Bristol Myers Squibb Foundation, Merck, Roche/Genentech, EMD Serono, Exelixis, Novartis, Tyra Biosciences, Pfizer, Convergent Therapeutics, Acrivon Therapeutics, Flare Therapeutics, Amgen Travel, Accommodations, Expenses: Company: Pfizer, Astellas Pharma, Merck    

In this JCO Precision Oncology Article Insights episode, Natalie DelRocco summarizes "Genomic Risk Classifiers in Localized Prostate Cancer: Precise but Not Standardized" by Góes et al. published on September 10, 2025. TRANSCRIPT Natalie DelRocco: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Natalie DelRocco, and today we will be discussing the editorial "Genomic Risk Classifiers in Localized Prostate Cancer: Precise but Not Standardized." This editorial by Góes, Li, and Chehrazi-Raffle, and Janopaul-Naylor et al. describes genomic risk classifiers, or GRCs, for patients with localized prostate cancer. Like any risk prediction model, GRCs are intended to help identify groups of patients that may benefit from less intense or more intense anticancer therapy. Risk prediction tools can be difficult to bring into clinical practice; they require a lot of validation. And as the authors describe, GRCs in localized prostate cancer are no exception. The authors of this editorial contextualize an article by Janopaul-Naylor et al., which attempts to retrospectively explore the clinical use of three available GRCs for localized prostate cancer: Decipher, Oncotype DX, and Prolaris. Each of these three GRCs is being used in clinical practice currently. In the original article, all three GRCs were associated with less intense therapy being prescribed in practice. However, the editorial authors note that this is likely selection bias due to the observational nature of the study design. It is conceivable that GRCs were more likely ordered to make decisions for patients who were already thought to be good candidates for less intensive therapy. Another weakness of the retrospective study design is that patient level covariates known to be associated with clinical prognosis in localized prostate cancer, such as staging, Gleason score, prostate specific antigen, were unavailable. The authors note that sampling bias may also be an issue. Uninsured patients are not included in the original article, and therefore may impede the ability to make conclusions about the association of GRC use with income level. The editorial authors highlight important study findings as well as these limitations, such as the heterogeneity of interventions following GRC result return. The Prolaris GRC was found to be associated with more surgical interventions, while the Decipher GRC was associated with more androgen deprivation therapy plus radiation. Additionally, patients with active surveillance were more likely to have a GRC in general ordered. While these conclusions are very interesting, the editorial authors note that further exploration and validation, given the retrospective study design and limitations outlined, are needed to fully understand the impact of GRCs in the practice of treating localized prostate cancer. Thank you for listening to JCO Precision Oncology Article Insights. Don't forget to give us a rating or a review and be sure to subscribe so that you never miss an episode. You can find all ASCO shows atasco.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.

Authors Drs. Jessica Ross and Alissa Cooper share insights into their JCO PO article, "Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in Neuroendocrine Carcinomas"  Host Dr. Rafeh Naqash and Drs. Ross and Cooper discuss the landscape of Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) across NECs from eight different primary sites. 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, podcast editor for JCO PO and an Associate Professor at the OU Health Stephenson Cancer Center. Today, I'm excited to be joined by Dr. Jessica Ross, third-year medical oncology fellow at the Memorial Sloan Kettering Cancer Center, as well as Dr. Alissa Cooper, thoracic medical oncologist at the Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School. Both are first and last authors of the JCO Precision Oncology article entitled "Clinical and Pathologic Landscapes of Delta-like Ligand 3 and Seizure-Related Homolog Protein 6 or SEZ6 Protein Expression in Neuroendocrine Carcinomas." At the time of this recording, our guest disclosures will be linked in the transcript. Jessica and Alissa, welcome to our podcast, and thank you for joining us today. Dr. Jessica Ross: Thanks very much for having us. Dr. Alissa Cooper: Thank you. Excited to be here. Dr. Rafeh Naqash: It's interesting, a couple of days before I decided to choose this article, one of my GI oncology colleagues actually asked me two questions. He said, "Rafeh, do you know how you define DLL3 positivity? And what is the status of DLL3 positivity in GI cancers, GI neuroendocrine carcinomas?" The first thing I looked up was this JCO article from Martin Wermke. You might have seen it as well, on obrixtamig, a phase 1 study, a DLL3 bi-specific T-cell engager. And they had some definitions there, and then this article came along, and I was really excited that it kind of fell right in place of trying to understand the IHC landscape of two very interesting targets. Since we have a very broad and diverse audience, especially community oncologists, trainees, and of course academic clinicians and some people who are very interested in genomics, we'll try to make things easy to understand. So my first question for you, Jessica, is: what is DLL3 and SEZ6 and why are they important in neuroendocrine carcinomas? Dr. Jessica Ross: Yeah, good question. So, DLL3, or delta-like ligand 3, is a protein that is expressed preferentially on the tumor cell surface of neuroendocrine carcinomas as opposed to normal tissue. It is a downstream target of ASCL1, and it's involved in neuroendocrine differentiation, and it's an appealing drug target because it is preferentially expressed on tumor cell surfaces. And so, it's a protein, and there are several drugs in development targeting this protein, and then Tarlatamab is an approved bi-specific T-cell engager for the treatment of extensive-stage small cell lung cancer in the second line. SEZ6, or seizure-like homolog protein 6, is a protein also expressed on neuroendocrine carcinoma cell surface. Interestingly, so it's expressed on neuronal cells, but its exact role in neuroendocrine carcinomas and oncogenesis is actually pretty poorly understood, but it was identified as an appealing drug target because, similarly to DLL3, it's preferentially expressed on the tumor cell surface. And so this has also emerged as an appealing drug target, and there are drugs in development, including antibody-drug conjugates, targeting this protein for that reason. Dr. Alissa Cooper: Over the last 10 to 15 years or so, there's been an increasing focus on precision oncology, finding specific targets that actually drive the cancer to grow, not just within lung cancer but in multiple other primary cancers. But specifically, at least speaking from a thoracic oncology perspective, the field of non-small cell lung cancer has completely exploded over the past 15 years with the discovery of driver oncogenes and then matched targeted therapies. Within the field of neuroendocrine carcinomas, including small cell lung cancer but also other high-grade neuroendocrine carcinomas, there has not been the same sort of progress in terms of identifying targets with matched therapies. And up until recently, we've sort of been treating these neuroendocrine malignancies kind of as a monolithic disease process. And so recently, there's been sort of an explosion of research across the country and multiple laboratories, multiple people converging on the same open questions about why might patients with specific tumor biologies have different kind of responses to different therapies. And so first this came from, you know, why some patients might have a good response to chemo and immunotherapy, which is the first-line approved therapy for small cell lung cancer, and we also sort of extrapolate that to other high-grade neuroendocrine carcinomas. What's the characteristic of that tumor biology? And at the same time, what are other targets that might be identifiable? Just as Jesse was saying, they're expressed on the cell surface, they're not necessarily expressed in normal tissue. Might this be a strategy to sort of move forward and create smarter therapies for our patients and therefore move really into a personalized era for treatment for each patient? And that's really driving, I think, a lot of the synthesis of this work of not only the development of multiple new therapies, but really understanding which tumor might be the best fit for which therapy. Dr. Rafeh Naqash: Thank you for that explanation, Alissa. And as you mentioned, these are emerging targets, some more further along in the process with approved drugs, especially Tarlatamab. And obviously, DLL3 was something identified several years back, but drug development does take time, and readout for clinical trials takes time. Could you, for the sake of our audience, try to talk briefly about the excitement around Tarlatamab in small cell lung cancer, especially data that has led to the FDA approval in the last year, year and a half? Dr. Alissa Cooper: Sure. Yeah, it's really been an explosion of excitement over, as you're saying, the last couple of years, and work really led by our mentor, Charlie Rudin, had identified DLL3 as an exciting target for small cell lung cancer specifically but also potentially other high-grade neuroendocrine malignancies. Tarlatamab is a DLL3-targeting bi-specific T-cell engager, which targets DLL3 on the small cell lung cancer cells as well as CD3 on T cells. And the idea is to sort of introduce the cancer to the immune system, circumventing the need for MHC class antigen presentation, which that machinery is typically not functional in small cell lung cancer, and so really allowing for an immunomodulatory response, which had not really been possible for most patients with small cell lung cancer prior to this. Tarlatamab was tested in a phase 2 registrational trial of about 100 patients and demonstrated a response rate of 40%, which was very exciting, especially compared with other standard therapies which were available for small cell lung cancer, which are typically cytotoxic therapies. But most excitingly, more than even the response rate, I think, in our minds was the durability of response. So patients whose disease did have a response to Tarlatamab could potentially have a durable response lasting a number of months or even over a year, which had previously not ever been seen in this in the relapsed/refractory setting for these patients. I think the challenge with small cell lung cancer and other high-grade neuroendocrine malignancies is that a response to therapy might be a bit easier to achieve, but it's that durability. The patient's tumors really come roaring back quite aggressively pretty quickly. And so this was sort of the most exciting prospect is that durability of response, that long potential overall survival tail of the curve really being lifted up. And then most recently at ASCO this year, Dr. Rudin presented the phase 3 randomized controlled trial which compared Tarlatamab to physician's choice of chemotherapy in a global study. And the choice of chemotherapy did vary depending on the part of the world that the patients were enrolled in, but in general, it was a really markedly positive study for response rate, for progression-free survival, and for overall survival. Really exciting results which really cemented Tarlatamab's place as the standard second-line therapy for patients with small cell lung cancer whose disease has progressed on first-line chemo-immunotherapy. So that has been very exciting. This drug was FDA approved in May of 2024, and so has been used extensively since then. I think the adoption has been pretty widespread, at least in the US, but now in this global trial that was just presented, and there was a corresponding New England Journal paper, I think really confirms that this is something we really hopefully can offer to most of our patients. And I think, as we all know, that this therapy or other therapies like it are also being tested potentially in the first-line setting. So there was data presented with Tarlatamab incorporated into the maintenance setting, which also showed exciting results, albeit in a phase 1 trial, but longer overall survival than we're used to seeing in this patient population. And we await results of the study that is incorporating Tarlatamab into the induction phase with chemotherapy as well. So all of this is extraordinarily exciting for our patients to sort of move the needle of how many patients we can keep alive, feeling functional, feeling well, for as long as possible. Dr. Rafeh Naqash: Very exciting session at ASCO. I was luckily one of the co-chairs for the session that Dr. Rudin presented it, and I remember somebody mentioning there was more progress seen in that session for small cell lung cancer than the last 30, 35 years for small cell, very exciting space and time to be in as far as small cell lung cancer. Now going to this project, Jessica, since you're the first author and Alissa's the last, I'm assuming there was a background conversation that you had with Alissa before you embarked on this project as an idea. So could you, again, for other trainees who are interested in doing research, and it's never easy to do research as a resident and a fellow when you have certain added responsibilities. Could you give us a little bit of a background on how this started and why you wanted to look at this question? Dr. Jessica Ross: Yeah, sure. So, as with many exciting research concepts, I think a lot of them are derived from the clinic. And so I think Alissa and I both see a good number of patients with small cell, large cell lung cancer, and then high-grade neuroendocrine carcinomas. And so I think this was really born out of a basic conversation of we have these drugs in development targeting these two proteins, DLL3 and SEZ6, but really what is the landscape of cancers that express these proteins and who are the patients that really might benefit from these exciting new therapies. And of course, there was some data out there, but sort of less than one would imagine in terms of, you know, neuroendocrine carcinomas can really come from anywhere in the body. And so when you're seeing a patient with small cell of the cervix, for example, like what are the chances that their cancer expresses DLL3 or expresses SEZ6? So it was really derived from this pragmatic, clinically oriented question that we had both found ourselves thinking about, and we were lucky enough at MSK, we had started systematically staining patients' tumors for DLL3, tumors that are high-grade neuroendocrine carcinomas, and then we had also more recently started staining for SEZ6 as well. And so we had this nice prospectively collected dataset with which to answer this question. Dr. Rafeh Naqash: Excellent. And Alissa, could you try to go into some of the details around which patients you chose, how many patients, what was the approach that you selected to collect the data for this project? Dr. Alissa Cooper: This is perhaps a strength but also maybe a limitation of this dataset is, as Jesse alluded to, our pathology colleagues are really the stars of this paper here because we were lucky enough at MSK that they were really forethinking. They are absolute experts in the field and really forward-thinking people in terms of what information might be needed in the future to drive treatment decision-making. And so, as Jesse had said, small cell lung cancer tumor samples reflexively are stained for DLL3 and SEZ6 at MSK if there's enough tumor tissue. The other high-grade neuroendocrine carcinomas, those stains are performed upon physician request. And so that is a bit of a mixed bag in terms of the tumor samples we were able to include in this dataset because, you know, upon physician request depends on a number of factors, but actually at MSK, a number of physicians were requesting these stains to be done on their patients with high-grade neuroendocrine cancers of of other histologies. So we looked at all tumor samples with a diagnosis of high-grade neuroendocrine carcinoma of any histology that were stained for these two stains of interest. You know, I can let Jesse talk a bit more about the methodology. She was really the driver of this project. Dr. Jessica Ross: Yeah, sure. So we had 124 tumor samples total. All of those were stained for DLL3, and then a little less than half, 53, were stained for SEZ6. As Alissa said, they were from any primary site. So about half of them were of lung origin, that was the most common primary site, but we included GI tract, head and neck, GU, GYN, even a few tumors of unknown origin. And again, that's because I think a lot of these trials are basket trials that are including different high-grade neuroendocrine carcinomas no matter the primary site. And so we really felt like it was important to be more comprehensive and inclusive in this study. And then, methodologically, we also defined positivity in terms of staining of these two proteins as anything greater than or equal to 1% staining. There's really not a defined consensus of positivity when it comes to these two novel targets and staining for these two proteins. But in the Tarlatamab trials, for some of the correlative work that's been done, they use that 1% cutoff, and we just felt like being consistent with that and also using a sort of more pragmatic yes/no cutoff would be more helpful for this analysis. Dr. Alissa Cooper: And that was a point of discussion, actually. We had contemplated multiple different schemas, actually, for how to define thresholds of positivity. And I know you brought up that question before, what does it mean to be DLL3 positive or DLL3 high? I think you were alluding to prior that there was a presentation of obrixtamig looking at extra-pulmonary neuroendocrine carcinomas, and they actually divvied up the results between DLL3 50% or greater versus DLL3 low under 50%. And they actually did demonstrate differential efficacy certainly, but also some differential safety as well, which is very provocative and that kind of analysis has not been presented for other novel therapies as far as I'm aware. I could be wrong, but as far as I'm aware, that was sort of the first time that we saw a systematic presentation of considering patients to be, quote unquote, "high" or "low" in these sort of novel targets. I think it is important because the label for Tarlatamab does not require any DLL3 expression at all, actually. So it's not hinging upon DLL3 expression. They depend on the fact that the vast majority of small cell lung cancer tumors do express DLL3, 85% to 90% is what's been demonstrated in a few studies. And so, there's not prerequisite testing needed in that regard, but maybe for these extra-pulmonary, other histology neuroendocrine carcinomas, maybe it does matter to some degree. Dr. Rafeh Naqash: Definitely agree that this evolving landscape of trying to understand whether an expression for something actually really does correlate with, whether it's an immune cell engager or an antibody-drug conjugate is a very evolving and dynamically moving space. And one of the questions that I was discussing with one of my friends was whether IHC positivity and the level of IHC positivity, as you've shown in one of those plots where you have double positive here on the right upper corner, you have the double negative towards the left lower, whether that somehow determines mRNA expression for DLL3. Obviously, that was not the question here that you were looking at, but it does kind of bring into question certain other aspects of correlations, expression versus IHC. Now going to the figures in this manuscript, very nicely done figures, very easy to understand because I've done the podcast for quite a bit now, and usually what I try to do first is go through the figures before I read the text, and and a lot of times it's hard to understand the figures without reading the text, but in your case, specifically the figures were very, very well done. Could you give us an overview, a quick overview of some of the important results, Jessica, as far as what you've highlighted in the manuscript? Dr. Jessica Ross: Sure. So I think the key takeaway is that, of the tumors in our cohort, the majority were positive for DLL3 and positive for SEZ6. So about 80% of them were positive for DLL3 and 80% were positive for SEZ6. About half of the tumors were stained for both proteins, and about 65% of those were positive as well. So I think if there's sort of one major takeaway, it's that when you're seeing a patient with a high-grade neuroendocrine carcinoma, the odds are that their tumor will express both of these proteins. And so that can sort of get your head thinking about what therapies they might be eligible for. And then we also did an analysis of some populations of interest. So for example, we know that non-neuroendocrine pathologies can transform into neuroendocrine tumors. And so we specifically looked at that subset of patients with transformed tumors, and those were also- the majority of them were positive, about three-quarters of them were positive for both of these two proteins. We looked at patients with brain met samples, again, about 70% were positive. And then I'd say the last sort of population of interest was we had a subset of 10 patients who had serial biopsies stained for either DLL3 or SEZ6 or both. In between the two samples, these patients were treated with chemotherapy. They were not treated with targeted therapy, but interestingly, in the majority of cases, the testing results were concordant, meaning if it was DLL3 positive to begin with, it tended to remain DLL3 positive after treatment. And so I think that's important as well as we think about, you know, a patient who maybe had DLL3 testing done before they received their induction chemo-IO, we can somewhat confidently say that they're probably still DLL3 positive after that treatment. And then finally, we did do a survival analysis among specifically the patients with lung neuroendocrine carcinomas. We looked at whether DLL3 expression affected progression-free survival on first-line platinum-etoposide, and then we looked at did it affect overall survival. And we found that it did not have an impact or the median progression-free survival was similar whether you were DLL3 positive or negative. But interestingly, with overall survival, we found that DLL3 positivity actually correlated with slightly improved overall survival. These were small numbers, and so, you know, I think we have to interpret this with caution, for sure, but it is interesting. I think there may be something to the fact that five of the patients who were DLL3 positive were treated with DLL3-targeting treatments. And so this made me think of, like in the breast cancer world, for example, if you have a patient with HER2-positive disease, it initially portended worse prognosis, more aggressive disease biology, but on the other hand, it opens the door for targeted treatments that actually now, at least with HER2-positive breast cancer, are associated with improved outcomes. And so I think that's one finding of interest as well. Dr. Rafeh Naqash: Definitely proof-of-concept findings here that you guys have in the manuscript. Alissa, if I may ask you, what is the next important step for a project like this in your mind? Dr. Alissa Cooper: Jesse has highlighted a couple of key findings that we hope to move forward with future investigative studies, not necessarily in a real-world setting, but maybe even in clinical trial settings or in collaboration with sponsors. Are these biomarkers predictive? Are they prognostic? You know, those are still- we have some nascent data, data has been brewing, but I think that we we still don't have the answers to those open questions, which I think are critically important for determining not only clinical treatment decision-making, but also our ability to understand sequencing of therapies, prioritization of therapies. I think a prospective, forward-looking project, piggybacking on that paired biopsy, you know, we had a very small subset of patients with paired biopsies, but a larger subset or cohort looking at paired biopsies where we can see is there evolution of these IHC expression, even mRNA expression, as you're saying, is there differential there? Are there selection pressures to targeted therapies? Is there upregulation or downregulation of targets in response not just to chemotherapy, but for example, for other sort of ADCs or bi-specific T-cell engagers? I think those are going to be critically important future studies which are going to be a bit challenging to do, but really important to figure out this key clinical question of sequencing, which we're all contemplating in our clinics day in and day out. If you have a patient, and these patients often can be sick quite quickly, they might have one shot of what's the next treatment that you're going to pick. We can't guarantee that every patient is going to get to see every therapy. How can you help to sort of answer the question of like what should you offer? So I think that's the key question sort of underlying any future work is how predictive or prognostic are these biomarkers? What translational or correlative studies can we do on the tissue to understand clinical treatment decision-making? I think those are the key things that will unfold in the next couple of years. Dr. Rafeh Naqash: The last question for you, Alissa, that I have is, you are fairly early in your career, and you've accomplished quite a lot. One of the most important things that comes out from this manuscript is your mentorship for somebody who is a fellow and who led this project. For other junior investigators, early-career investigators, how did you do this? How did you manage to do this, and how did you mentor Jessica on this project with some of the lessons that you learned along the way, the good and other things that would perhaps help other listeners as they try to mentor residents, trainees, which is one of the important things of what we do in our daily routine? Dr. Alissa Cooper: I appreciate you calling me accomplished. Um, I'm not sure how true that is, but I appreciate that. I didn't have to do a whole lot with this project because Jesse is an extraordinarily smart, driven, talented fellow who came up with a lot of the clinical questions and a lot of the research questions as well. And so this project was definitely a collaborative project on both of our ends. But I think what was helpful from both of our perspectives is from my perspective, I could kind of see that this was a gap in the literature that really, I think, from my work leading clinical trials and from treating patients with these kinds of cancers that I really hoped to answer. And so when I came to Jessica with this idea as sort of a project to complete, she was very eager to take it and run with it and also make it her own. You know, in terms of early mentorship, I have to admit this was the first project that I mentored, so it was a great learning experience for me as well because as an early-career clinician and researcher, you're used to having someone else looking over your shoulder to tell you, "Yes, this is a good journal target, here's what we can anticipate reviewers are going to say, here are other key collaborators we should include." Those kind of things about a project that don't always occur to you as you're sort of first starting out. And so all of that experience for me to be identifying those more upper-level management sort of questions was a really good learning experience for me. And of course, I was fantastically lucky to have a partner in Jesse, who is just a rising star. Dr. Jessica Ross: Thank you. Dr. Rafeh Naqash: Well, excellent. It sounds like the first of many other mentorship opportunities to come for you, Alissa. And Jessica, congratulations on your next step of joining and being faculty, hopefully, where you're training. Thank you again, both of you. This was very insightful. I definitely learned a lot after I reviewed the manuscript and read the manuscript. Hopefully, our listeners will feel the same. Perhaps we'll have more of your work being published in JCO PO subsequently. Dr. Alissa Cooper: Hope so. Thank you very much for the opportunity to chat today. Dr. Jessica Ross: Yes, thank you. This was great. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so as you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Disclosures: Dr. Alissa Jamie Cooper Honoraria Company: MJH Life Scienes, Ideology Health, Intellisphere LLC, MedStar Health, Physician's Education Resource, LLC,  Gilead Sciences, Regeneron, Daiichi Sankyo/Astra Zeneca, Novartis,  Research Funding: Merck, Roche, Monte Rosa Therapeutics, Abbvie, Amgen, Daiichi Sankyo/Astra Zeneca Travel, Accommodations, Expenses: Gilead Sciences

In this episode of JCO PO Article Insights, host Dr. Jiasen He summarizes the article, "Somatic Mutation Profiles of Colorectal Cancer by Birth Cohort" by Gilad, et al published October 11, 2025. TRANSCRIPT Jiasen He: Hello, and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today, we will be discussing the JCO Precision Oncology article, "Somatic Mutation Profiles of Colorectal Cancer by Birth Cohort," by Dr. Gilad and colleagues. Early-onset colorectal cancer is defined as colorectal cancer diagnosed before the age of 50. Several reports have suggested that early-onset colorectal cancer has unique characteristics. Compared with late-onset colorectal cancer, early-onset colorectal cancer cases are more commonly found in the distal colon or rectum, tend to be diagnosed at more advanced stages, and may display unfavorable histologic features. Although the overall incidence of colorectal cancer has declined in recent decades, the incidence of early-onset colorectal cancer continues to rise. This increase appears to be driven by birth cohort effects. The reasons behind this rise remain unclear but are likely multifactorial, involving changes in demographics, diet, lifestyle, environmental exposures, and genetic predisposition. At the same time, studies have shown conflicting results regarding whether there are differences in the mutation profiles between early-onset and late-onset colorectal cancer. Therefore, it is crucial to explore whether colorectal cancer somatic mutational landscape differs across birth cohorts, as this could provide important insight into generational shifts in colorectal cancer incidence. To address this question, the authors conducted a retrospective study to characterize the mutation spectrum of colorectal cancer across different birth cohorts. Consecutive colorectal cancer patients who underwent somatic next-generation sequencing at the University of Chicago pathology laboratory between 2015 and 2022 were retrospectively identified. Tumors were tested for 154 to 168 genes and categorized as either microsatellite stable or high according to established thresholds. Patients with hereditary cancer syndromes or inflammatory bowel disease were excluded. Participants were then grouped into birth cohorts by decades, as well as into two major groups: those born before 1960 and after 1960. Genes that were identified in at least 5% of the sample were selected and grouped into 10 canonical cancer signaling pathways. These genes and pathways were then included in the analysis to explore their association with colorectal cancer across different birth cohorts and age groups. A total of 369 patients were included in the study, with a median birth year of 1955 and a median age at colorectal cancer diagnosis of 62.9 years. 5.4% were identified as having microsatellite-high tumors. The median tumor mutational burden was 5 mutations per megabase for microsatellite-stable tumors and 57.7 mutations per megabase for microsatellite-high tumors. Patients with microsatellite-high tumors tended to have earlier birth years and were diagnosed at an older age. However, after adjusting for potential confounders, neither birth year nor age remained statistically significant. Similarly, after controlling for confounders, no significant associations were observed between birth year or age and mutation burden. In this cohort, APC, TP53, and KRAS were the most frequently mutated genes. No statistically significant differences in the prevalence of gene mutations were observed across birth cohorts. Correspondingly, the most affected signaling pathways were the Wnt, TP53, and (RTK)/RAS pathways. Similar to the gene-level finding, no significant differences in the prevalence of these pathways were identified among birth cohorts. When examining patients born before and after 1960, the authors found that the older birth cohorts were diagnosed at an older age and had higher tumor mutational burden. However, no significant differences were observed in any of the genes or pathways analyzed. Among microsatellite-stable tumors, 18.3% were classified as early-onset colorectal cancer, while 81.1% were late-onset colorectal cancer. Consistent with previous reports, early-onset colorectal cancers in this cohort were more likely to be left-sided and more common among more recent birth cohorts. However, no significant differences were identified in any of the examined genes or pathways when comparing early-onset to late-onset colorectal cancer. In this cohort, a higher prevalence of early-onset colorectal cancer was observed among more recent birth cohorts, consistent with previous reports. Still, no distinct mutational signature was identified between the early and late birth cohorts. The authors proposed that the lack of distinct mutational profile by age or birth cohort may be due to the limited number of key molecular pathways driving colorectal cancer. Although environmental exposures likely differ across generations, the downstream effects may have converged on similar biological mechanisms, leading to comparable somatic mutations across cohorts. Alternately, they proposed that the observed birth cohort differences in colorectal incidence may be driven by distinct mutation signatures, epigenetic alterations, or changes in the immune microenvironment rather than variations in canonical gene mutations. As the authors noted, given the retrospective nature of this study, its modest sample size, and the predominance of advanced-stage tumors, larger prospective studies are needed to validate these findings. In summary, this study found no significant differences in the mutational landscape of colorectal cancer across birth cohorts or age groups. The authors proposed that the generational shift in colorectal cancer incidence is unlikely to be driven by changes in the underlying tumor genomics. However, larger prospective studies are needed to validate these findings. Thank you for tuning in to JCO Precision Oncology Article Insights. Do not forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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. Bryson Katona at the University of Pennsylvania Perelman School of Medicine shares insights into his article, "Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection (PRECEDE) Consortium" Host Dr. Rafeh Naqash and Dr. Katona discuss how, given differing guidelines as well as lack of detail about how PC surveillance should be performed, approaches to PC surveillance across centers often differs. TRANSCRIPT 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, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I am thrilled to be joined by Dr. Bryson Katona, Director of the Gastrointestinal Cancer Genetics Program and Director of the Lynch Syndrome Program at the Penn Medicine's Abramson Cancer Center, and also lead author of the JCO PO article entitled "Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection or PRECEDE Consortium." Bryson, thanks for joining us again. Dr. Bryson Katona: Well, thank you so much for having me. I appreciate the opportunity. Dr. Rafeh Naqash: It is exciting to see that this work will be presented concurrently with the upcoming CGA meeting. Dr. Bryson Katona: Yes, it has been a fantastic partnership between JCO PO and the CGA-IGC and their annual meeting. And for those who may not be familiar, the CGA-IGC is the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. It is basically a professional organization dedicated to individuals who have hereditary GI cancer risk and focusing on providing education, promoting research, and really bringing together providers in this space from not just throughout the US but from across the globe as well. Dr. Rafeh Naqash: That is exciting to hear the kind of work you guys are doing. These are definitely interesting, exciting things. Now, going to what you have published, it is an area that is very evolving in the space of cancer screening, cancer surveillance, especially for a very aggressive cancer such as pancreatic cancer. Could you tell us currently, what are the general consensus? I know there are a lot of differences between different guidelines or societies, but what are the some of the commonalities if we were to start there first for pancreas cancer screening? If you are not a GI oncologist, you may not be aware that there is something with regards to pancreas cancer screening. Could you give us an overview and a background on that? Dr. Bryson Katona: Yeah, I think that pancreatic cancer screening really is one of the most controversial areas of all cancer screening. Part of that controversy is just because all the guidelines, the many different guidelines that are out there, do not always match up with one another, which I think leads to a lot of confusion, not just for providers but for patients who are trying to go through this, and then also the insurance companies in trying to get these screening tests covered. You know, when we think about who is eligible for pancreatic cancer screening, you know, it is important that these are not average-risk individuals. So really, we are only offering screening to high-risk individuals. And those can include people that have a strong family history of pancreatic cancer without a germline genetic susceptibility that has been identified. And those individuals we refer to as having familial pancreatic cancer. And the other big cohort is those individuals that carry hereditary pancreatic cancer predisposition. These are due to cancer risk mutations in many different genes, including many of the breast cancer risk genes like BRCA1 and BRCA2, as well as ATM and PALB2, but then other genes such as the Lynch syndrome genes, and then some of the higher risk genes such as those leading to Peutz-Jeghers syndrome as well as FAM, which is due to CDKN2A mutations. Dr. Rafeh Naqash: Thank you for that. Again, another practical question, and this may or may not be exactly related to your specific topic here, but perhaps to some extent there might be an overlap. If I get a patient from a colleague, and I see people in the early-phase clinical trial setting, so many different tumors for novel drugs, and I find an individual with, let us say, lung cancer who has a pathogenic BRCA2, which is somatic, should I be worried about pancreas cancer screening in that individual? Or have we not met that threshold yet in that circumstance? Dr. Bryson Katona: A lot of times these variants or these genes that are associated with pancreatic cancer risk get picked up on the somatic tumor profiles. Now, you know, whether or not those are truly germline variants typically requires the next step of referring the patient for germline genetic testing. So you know, I would not screen or make any kind of screening choices based on a somatic variant alone, but nowadays germline testing is so easy, so efficient, and relatively cheap that it is easy enough to confirm whether or not these somatic hits are in fact just somatic or may confer some germline risk in addition. Dr. Rafeh Naqash: So from what I understand from what you have said, there is debate about it, but it is something that should be done or is important enough that you need to figure out a path moving forward. Was that one of the reasons why you performed this project through this very interesting consortium called the PRECEDE Consortium? Dr. Bryson Katona: Yeah, that was one of our main reasons for doing this. And for those who do not know about the PRECEDE Consortium, this is a very large international, multi-institutional organization really focused on reducing death and improving survival from pancreatic cancer, primarily through increased and more effective use of screening and early detection strategies. This is an international consortium. There are over 50 sites now with nearly 10,000 patients who are enrolled in the consortium. So it really is at this point the largest prospective study of individuals who are at high risk for pancreatic cancer who are undergoing screening. And you know, I think amongst all of us in the consortium, just amongst discussions between colleagues and then, you know, often times when I see patients that are transferring their care to Penn who maybe had their screening done in another center before, what we were realizing is that, you know, although we all do a lot of screening, it seems that people are doing it slightly differently. And it does not seem that there is a real consensus approach across all centers about how pancreatic cancer screening should really be done. And it is one thing if you are thinking comparing, okay, well, maybe in the US we do it differently than, you know, in Europe or in other locations, but even among centers within the United States, we were still seeing very large differences in how pancreatic cancer screening in high-risk individuals were done. And so that led us to really pursue this survey of pancreatic cancer screening practices across the PRECEDE Consortium. So for this survey, we actually have 57 centers who the survey was sent out to. As you know, surveys are oftentimes very difficult to get good response rates back on, but we were fortunate to have 54 of the 57, or 95% of the centers, actually get back to us about their screening practices for this particular project. Dr. Rafeh Naqash: That is good to know. I hope you did not have to use any kind of gift cards for people to respond to the survey. But nevertheless, you got the information that you needed. Could you tell us what are some of the common denominators that you did identify and some of the differences that you identified? From your perspective, it sounds like there is no established consensus guidelines. There are different societies that have different perspectives on it. So I am sure some of what you found will probably have implications in maybe creating some guidelines. Is that a fair statement? Dr. Bryson Katona: Definitely a fair statement, and we found some very interesting results. I think one important result is really just the heterogeneity in the consortium. And so even before we got into pancreatic cancer screening practices, we also, we were asking consortium sites, "At your particular site, who is the individual that is leading these in-depth discussions about pancreatic cancer screening?" And while about 50% of the sites had a gastroenterologist leading it, about a quarter of the sites had a medical oncologist, a quarter had a surgeon leading these discussions as well. And we also found heterogeneity in who is the physician or the provider actually ordering these screening tests, again, with multiple different specialties across the different sites. But really one of the main areas that we wanted to hone in and focus on was how the different pancreatic cancer screening guidelines were actually utilized in each of the particular centers. The biggest controversial area in the field is for the gene mutation carriers, whether or not we should be requiring that a family history of pancreatic cancer be present in order for those individuals to qualify for pancreatic cancer screening. And the reason that is so controversial, let us take an example of BRCA1 and BRCA2 carriers. Currently, if you look through the guidelines, NCCN and the ASGE guidelines recommend that really all BRCA2 carriers undergo pancreatic cancer screening regardless of whether or not there is a family history, starting at age 50. However, other guidelines such as the AGA guidelines, or the AGA Clinical Practice Statement, as well as guidelines from the CAPS consortium, do recommend that a family history of pancreatic cancer be present in order to qualify for screening. But then we have different things for other genes. So for BRCA1 carriers, in fact, it is the ASGE guidelines that recommend all BRCA1 and 2 carriers undergo screening, whereas NCCN and the other guidelines that are out there do not recommend those individuals undergo screening. Again, this huge heterogeneity in guidelines is quite striking. And so when we assessed all the sites in the PRECEDE Consortium, we found some really interesting results with respect to these particular genes. For BRCA2 carriers specifically, we found that about half of the sites required a family history for recommending pancreatic cancer screening, but about half of the sites would offer it to all BRCA2 carriers regardless of if there was a family history of pancreatic cancer screening. Rates for BRCA1, PALB2, and ATM carriers were a little bit lower, where about a third of sites would offer screening really regardless of whether or not there is a family history of pancreatic cancer. And for Lynch syndrome, those rates were very, very low, with only about 13% of sites offering screening to Lynch patients in the absence of a family history. But I think, you know, we are all in the same consortium, but there is still just a lot of heterogeneity in how our own individual practices are run. Dr. Rafeh Naqash: Definitely different thoughts, different practices. But from what you saw, did it matter as far as outcomes are concerned whether it was a gastroenterologist doing the screening, or it was a medical oncologist, or a geneticist? Or is it a combination of all of these that actually makes the most difference? Dr. Bryson Katona: So I think we do need to get some more information about specialty-specific screening preferences. We just had one response per site in this particular survey, and so I think we are going to need a larger sample size in order to get that data. But I think that is certainly possible that, you know, certain subspecialties may prefer, you know, screening more aggressively or not including family history. That is definitely a question that we will be asking in future studies. Dr. Rafeh Naqash: Definitely more gift cards that will be needed as well. Moving on to another aspect of the implications for early detection, from a breast cancer, colon cancer standpoint, there is health economics research that shows it saves cost in the bigger picture. Has there been anything for pancreas cancer where early detection, early identification, early treatment actually ends up saving a lot more versus detecting metastatic pancreas cancer later? Dr. Bryson Katona: It is a great question. And of course, for any screening modality, you know, we would ultimately want it to be a cost-effective measure. In pancreas cancer screening, the jury is still a little bit out about whether or not pancreas cancer screening is truly cost-effective or not. There have been several different studies that have assessed this. And I think in general, the thought is that it is a cost-effective endeavor. But I think most of these cost-effectiveness estimates are actually related to what is the risk of pancreatic cancer in the population you are studying. And so when you have very, very high-risk individuals that have over a 10% lifetime risk of pancreatic cancer, it is almost a certainty that pancreatic cancer screening is going to be cost-effective. However, you know, if you have, say for example, BRCA1 carriers where lifetime risk of pancreatic cancer may be less than 5%, likely around like 3%, those individuals, I think it is going to be a tougher sell to say that it is cost-effective. But as we get more data on pancreatic cancer screening, that will be a very important question to ask. And you know, when you mentioned how does it save money, our goal at least in pancreatic cancer screening is to really downstage pancreatic cancer at the time of diagnosis and allow someone to undergo, you know, ideally a curative-intent surgery. There is data out there showing that we can downstage the cancers, that survival after the time of diagnosis is substantially increased after detection in a pancreatic cancer screening program. But again, these are studies that are based on fairly small numbers of converters. And so I think we need more data in that space as well, which is one of the main questions that the PRECEDE Consortium is trying to answer with all of our prospective data. Dr. Rafeh Naqash: Excellent. Well, I hope we see more interesting, exciting work from the PRECEDE Consortium at meetings as well as as a publication in JCO PO. I would like to shift gears briefly for a minute or two, Bryson, to you as an individual, your career. How have you evolved over the last 5, 7 years? How did you end up doing cancer genetics? What were some of the lessons that you learned along the way and some of those that you would want to share with our listeners, especially trainees and early-career faculty? Dr. Bryson Katona: Just to give you and others listening a little bit of background, but I am a physician-scientist, gastroenterologist, but a physician-scientist. And so my clinical practice is exclusively focused on individuals with hereditary GI cancer risk. I run a basic science lab where we do a lot of studies in organoids and mouse models of these hereditary GI cancer risk syndromes. And then I also have a clinical research group where we do early-phase clinical trials and screening and early detection trials, again in these same individuals with hereditary GI cancer risk. I think probably the most important thing that kind of allowed me to get to this stage in my career where I am trying to, you know, essentially try to juggle all three of these balls at the same time is that I absolutely love what I do. And I am so incredibly interested in what I do. And I think for young individuals that are coming through the pipeline and going through training, you know, I mean, finding a specialty and a clinical niche where you truly just enjoy the work and you enjoy the patients and you enjoy your colleagues is by far the most important thing. I ended up getting into the hereditary GI cancer space because a lot of my work earlier on in my career during my PhD and then in my postdoc work in the lab really focused on colorectal cancer. And I thought that focusing on cancer genetics could allow me to really continue to think from the molecular side of things while simultaneously being a gastroenterologist and taking care of patients with hereditary cancer risk. Dr. Rafeh Naqash: Well, thank you so much for giving us a sneak peek of your journey and insights on what perhaps works best, especially when you love what you do. I think that is one of the most important reasons a work tries to keep you going and keep you interested, keep you passionate. So thank you again. Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or a review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 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. Asaf Maoz at Dana-Farber Cancer Institute shares insights into article, "Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era." Host Dr. Rafeh Naqash and Dr. Maoz discuss the causes of death in individuals with LS and the evolving role of immunotherapy. 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, podcast editor for JCO Precision Oncology and Associate Professor Medicine, at the OU Health Stephenson Cancer Center. Today, I'm super thrilled to be joined by Dr. Asaf Maoz, Medical Oncologist at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and faculty at the Harvard Medical School, and also lead author on the JCO Precision Oncology article entitled "Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era." This publication will be a concurrent publication with an oral presentation at the annual CGA meeting. At the time of this recording, our guest's disclosures will be linked in the transcript. Asaf, I'm excited to welcome you on this podcast. Thank you for joining us today. Dr. Asaf Maoz: Thank you so much for highlighting our paper. Dr. Rafeh Naqash: Absolutely. And I was just talking to you that we met several years back when you were a trainee, and it looks like you've worked a lot in this field now, and it's very exciting to see that you consider JCOPO as a relevant home for some of your work. And the topic that you have published on is of significant interest to trainees from a precision medicine standpoint, to oncologists in general, covers a lot of aspects of immunotherapy. So, I'm really excited to talk to you about all of this. Dr. Asaf Maoz: Me too, me too. And yeah, I think JCOPO has great content in the area of cancer genetics and has done a lot to disseminate the knowledge in that area. Dr. Rafeh Naqash: Wonderful. So, let's get started and start off, given that we have hosts of different kinds of individuals who listen to this podcast, especially when driving from home to work or back, for the sake of making everything simple, can we start by asking you what is Lynch syndrome? How is it diagnosed? What are some of the main things to consider when you're trying to talk an individual where you suspect Lynch syndrome? Dr. Asaf Maoz: Lynch syndrome is an inherited predisposition to cancer, and it is common. So, we used to think that, or there's a general notion in the medical community that it is a rare condition, but we actually know now from multiple studies, including studies that look at the general population and do genetic testing regardless of any clinical phenotype, that Lynch syndrome is found in about 1 in 300 people in the general population. If you think about it in the United States, that means that there are over a million people living with Lynch syndrome in the United States. Unfortunately, most individuals with Lynch syndrome don't know they have Lynch syndrome at the current time, and that's where a lot of the efforts in the community are being made to help detect more individuals who have Lynch syndrome. Lynch syndrome is caused by pathogenic germline variants in mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, or as a result of pathogenic variants in EPCAM that cause silencing of the MSH2 gene. Dr. Rafeh Naqash: Excellent. Thank you for that explanation. Now, one of the other things I also realized, similar to BRCA germline mutations, where you require a second hit for individuals with Lynch syndrome to have mismatch repair deficient cancers, you also require a second hit to have that second hit result in an MSI-high cancer. Could you help us understand the difference of these two concepts where generally Lynch syndrome is thought of to be cancers that are mismatch repair deficient, but that's not necessarily true for all cases as we see in your paper. Can you tease this out for us a little bit more? Dr. Asaf Maoz: Of course, of course. So, the germline defect is in one of the mismatch repair genes, and these genes are responsible for DNA mismatch repair, as their name implies. Now, in a normal cell, we think that one working copy is generally enough to maintain the mismatch repair machinery intact. What happens in tumors, as you alluded to, is that there is a second hit in the same mismatch repair gene that has the pathogenic germline variant, and that causes the mismatch repair machinery not to work anymore. And so what happens is that there is formation of mutations in the cancer cell that are not present in other cells in the body. And we know that there are specific types of mutations that are associated with defects in mismatch repair mechanisms, and those are associated a lot of times with frameshift mutations. And we have termed them 'microsatellites'. So there are areas in the genome that have repeats, for example, you know, if you have AAAA or GAGA, and those areas are particularly susceptible to mutations when the mismatch repair machinery is not working. And so we can measure that with DNA microsatellite instability testing. But we can also get a sense of whether the mismatch repair machinery is functioning by looking at protein expression on the surface of cancer cells and by doing immunohistochemistry. More recently, we're also able to infer whether the mismatch repair machinery is working by doing next-generation sequencing and looking at many, many microsatellites and whether they have this DNA instability in the microsatellites. Dr. Rafeh Naqash: Excellent explanation. As a segue to what you just mentioned, and this reminds me of some work that one of my good friends, collaborators, Amin Nassar, whom you also know, I believe, had done a year and a half back, was published in Cancer Cell as a brief report, I believe, where the concept was that when you look at these mismatch repair deficient cancers, there is a difference between NGS testing, IHC testing, and maybe to some extent, PCR testing, where you can have discordances. Have you seen that in your clinical experience? What are some of your thoughts there? And if a trainee were to ask, what would be the gold standard to test individuals where you suspect mismatch repair deficient-related Lynch syndrome cancers? How would you test those individuals? Dr. Asaf Maoz: We do sometimes see discordance, you know, from large series, the concordance rate is very high, and in most series it's over 95%. And so from a practical perspective, if we're thinking about the recommendation to screen all colorectal cancer and all endometrial cancer for mismatch repair deficiency, I think either PCR-based testing or immunohistochemistry is acceptable because the concordance rate is very high. There are rare cases where it is not concordant, doing multiple of the tests makes sense at that time. If you think about the difference between the tests, the immunohistochemistry looks at protein expression, which is a surrogate for whether there is mismatch repair deficiency or not, right? Because ultimately, the mismatch repair deficiency is manifested in the mutations. So if the PCR does not show microsatellite instability and now NGS does not show microsatellite instability, the IHC may be a false positive. At the end of the day, the functional analysis of whether there are actually unstable microsatellites either by PCR or by NGS is what I would consider more informative. But IHC again is an excellent test and concordant with those results in over 95% of cases. Now there is also an issue of sampling. It's possible that there's heterogeneity within the tumor. We published a case in JCOPO about heterogeneity of the mismatch repair status, and that was both by immunohistochemistry, but also by PCR. So there are some caveats and interpreting these tests does require some expertise, and I'm always happy to chat with trainees or whoever has an interesting or challenging case. Dr. Rafeh Naqash: Thanks again for that very easy to understand explanation. Now going to management strategies, could you elaborate a little bit upon the neo-adjuvant data currently, or the metastatic data which I think more people are familiar with for immunotherapy in individuals with MSI-high cancers? Dr. Asaf Maoz: Yeah, that's an excellent question and obviously a very broad topic. Individuals with Lynch syndrome typically develop tumors that are mismatch repair deficient or microsatellite unstable. And we have seen over the last 15 years or so that these tumors, because they have a lot of mutations and because these mutations are very immunogenic, we have seen that they respond very well to immunotherapy. And this has been shown across disease sites and has been shown across disease settings. And for that reason, immunotherapy was approved for MSI-high or mismatch repair deficient cancer regardless of the anatomic site. It was the first tissue-agnostic approval by the FDA in 2017. And so there are exciting studies both in the metastatic setting where we see individuals who respond to immunotherapy for many years, and one could wonder whether their cancer is going to come back or not. And also in the earlier setting, for example, the Cercek et al. study in the New England Journal from Sloan Kettering, where they showed that neoadjuvant immunotherapy can cause durable responses for rectal cancer that is mismatch repair deficient. And in that series, the patients did not require surgery or radiation, which is standard of care for rectal cancer otherwise. And there's also exciting data in the adjuvant space, as was presented in ASCO by Dr. Sinicrope, the ATOMIC study, and many more efforts to bring immunotherapy into the treatment landscape for individuals with MSI-high cancer, including individuals with Lynch syndrome. Dr. Rafeh Naqash: A lot of activity, especially in the neo-adjuvant and adjuvant space over the last two years or so. Now going to the actual reason why we are here is your study. Could you tell us why you looked at this idea of patients who had Lynch syndrome and died, and the reasons for their death? What was the thought that triggered this project? Dr. Asaf Maoz: As we were talking about, we now know that immunotherapy really has changed the treatment landscape for individuals with Lynch syndrome, and that most cancers that individuals with Lynch syndrome do have this mismatch repair deficiency. But we also know that individuals with Lynch syndrome can develop tumors that do not have mismatch repair deficiency, and we call them mismatch repair proficient or microsatellite stable. And there was a series from Memorial Sloan Kettering showing that in colorectal cancer, about 10% of the tumors that individuals with Lynch syndrome developed did not have mismatch repair deficiency. In addition to that, we anecdotally saw that some of our patients with Lynch syndrome died of causes that were not mismatch repair deficient tumors. We wanted to see how that has changed since immunotherapy was approved in a tissue-agnostic manner, meaning that we could look at this regardless of where the cancer started, because we would anticipate that if the tumor was mismatch repair deficient, the patient would be able to access immunotherapy as standard of care. Dr. Rafeh Naqash: Thank you. And then you looked at different aspects of correlations with regards to individuals that had an MSI-high cancer with Lynch syndrome or an MSS cancer with Lynch syndrome. Could you elaborate on some of the important findings that you identified as well as some of the unusual findings that perhaps we did not know about, even though the sample size is limited, but what were some of the unique things that you did identify through this project? Dr. Asaf Maoz: The first question was what cause is leading to death in individuals with Lynch syndrome? And we had 54 patients that we identified that had died since the approval of immunotherapy in 2017, 44 of which died of cancer-related causes. And when we looked at cancer-related causes of death, we wanted to know how many of those were due to mismatch repair deficient tumors versus mismatch repair proficient tumors or MS-stable tumors. And we found, somewhat surprisingly, that 43% of patients in our cohort actually died of tumors that were microsatellite stable or mismatch repair proficient, meaning of tumors that are not typically associated with Lynch syndrome. This is not entirely surprising as a cause of death because we know that immunotherapy does not typically work for tumors that are microsatellite stable. And so in the metastatic setting, there are much less cases of durable remissions with treatment. But it was helpful to have that figure as an important benchmark. There are previous studies about causes of death in Lynch syndrome, and particularly from the Prospective Lynch Syndrome Database in Europe. Those have provided really important information about cause of death by cancer site, but they typically don't have mismatch repair status and are more difficult to interpret in that regard. They also don't include a large number of individuals who have PMS2 Lynch syndrome, which is the most common, but least penetrant form of Lynch syndrome. Dr. Rafeh Naqash: As far as the subtype of pathogenic germline variants is concerned, did you notice anything unusual? And I've always had this question, and you may know more about this data, is: In the bigger context of immunotherapy, does the type of the pathogenic germline variant for Lynch syndrome associated MSI-high cancers, does that impact or have an association with the kind of outcomes, how soon a cancer progresses or how many exceptional responders perhaps with MSI-high cancers actually have a certain specific pathogenic germline variant? Dr. Asaf Maoz: That's an excellent question, and certainly we need more data in that space. We know that the type of germline mutation, or the gene in which there is a germline pathogenic variant, determines to a large degree the cancer risk, right? So we know that individuals who have germline pathogenic variants in MLH1 or MSH2 have a much higher colorectal cancer risk than, for example, PMS2. We know that for PMS2, the risks are more limited to colorectal and endometrial, and may be lower risk of other cancers. We also know that, you know, the spectrum of disease may change based on the pathogenic germline variants. For example, individuals who have MSH2 associated Lynch syndrome have more risk of additional cancers in other organs like the urinary tract and other less common Lynch-associated tumors. The question about response to therapy is one where we have much less information. There are studies that are trying to assess this, but I don't think the answer is there yet. Some of the non-clinical data looks at how many mutations there are based on the pathogenic variant and what the nature of those mutations are, whether they're more frameshift or others. But I think we still need more clinical data to understand whether the response to immunotherapy differs. It's also complicated by the fact that the immunotherapy landscape is changing, especially in the metastatic setting, now with the approval of combination ipilimumab and nivolumab for first-line treatment of colorectal cancer that is microsatellite unstable. But in our study, we did find that, as you would expect, there is an enrichment in MS-stable cancers among those with PMS2 Lynch syndrome. Again, our denominator is those who died, right? So this is not the best way to look at the question whether this is overall true, that is more addressed by the study that Sloan Kettering published. But we do see, as we would anticipate, that there are more microsatellite stable cancers among those with PMS2 Lynch syndrome that died. Dr. Rafeh Naqash: A lot to uncover there for sure. This study and perhaps some of the other work that you're doing is slowly advancing our understanding of some of these concepts. So I'd like to shift gears to a couple of provocative questions that I generally like to ask. The first is, in your opinion, and you may or may not have data to back this up, which is okay, and that's why we're having a conversation about it. In your opinion, do you think the type or the quality of the neoantigen is different based on the pathogenic germline variant and a Lynch syndrome associated MSI-high cancer? Dr. Asaf Maoz: I think there are some data out there that, you know, I can't cite off the top of my mind, but there are some data out there that suggest that that may be the case. I think the key question is the quality, right? I think that whether these differences that are found on a molecular level also translate to a clinical difference in response is something that is unknown at this moment. Some people hypothesize that if the tumor has less neoantigens, there's less of a response to immunotherapy. But I think we really need to be careful before making those assertions on a clinical level. I do think it's a really important question that needs to be answered, among others because, you know, in the colorectal space, for example, where we have both the option of doing ipilimumab with nivolumab and the option of doing pembrolizumab, we don't really know which patients need the CTLA-4 blockade versus which patients can receive PD-1 blockade alone and avoid the potential excess toxicity of the CTLA-4 blockade. There are a lot of interesting questions there that still need to be answered. And of course, individuals with Lynch syndrome are just a fraction of those individuals who have MSI-high cancer. So there's also the question about whether non-Lynch syndrome associated MSI-high cancer responds differently to immunotherapy than Lynch syndrome associated MSI-high cancer. A lot of very interesting questions in the field for sure. Dr. Rafeh Naqash: Absolutely. My second question is more about trying to understand the role of ctDNA, MRD monitoring in individuals with Lynch syndrome. If somebody has a germline, you know, Lynch syndrome MSI-high cancer, when you do a tumor-informed ctDNA assessment, what do you capture generally there? Because, and this question stems from a discussion I've had with somebody regarding EGFR lung cancer, since I treat individuals with lung cancer, and the concept generally is that even if the tissue showed EGFR, but for MRD monitoring, when you do a barcoded sequence of different tumor specific mutations, it's not actually the EGFR that they track in the blood when they do ctDNA assessment. But from a Lynch syndrome standpoint, if you have a germline, right, which is the first hit, and then you have the somatic in the tumor, which is the second hit, are you aware or have you tried to look into this where what is exactly being followed if one had to follow MRD in a Lynch syndrome MSI-high colorectal cancer? Dr. Asaf Maoz: I think a lot of the MRD assays are proprietary, and so we don't receive information about what the mutations that are being tracked are. In general, the idea is to track mutations that we would not expect to disappear as part of resistant mechanisms. We want these to be truncal mutations. We want these to be mutations in which resistance is not expected to result in reversion mutations. But what specifically is being tracked is something that I don't know because these assays, the tumor-informed ones, are proprietary, and we don't get the results regarding specific mutations. When it's circulating tumor DNA that is not necessarily tumor-informed, we do get those results, but that is less so about the specific selection of mutations. Dr. Rafeh Naqash: Thank you for clarifying that question to some extent, of course, as you said, we don't know a lot, and we don't know what we don't know. That's the most important thing that I've learned in the process of understanding precision medicine and genomics, and it's a very fast-paced evolving field. Last question related to your project, what is the next step? Are you planning any next steps as a bigger multicenter study or validation of some sort? Dr. Asaf Maoz: There are two big questions that this study raises. One, is this true across multiple other sites, right? Because this is a single center study, and we really need additional centers to look at their data and validate whether they are also seeing that a substantial portion of deaths in individuals with Lynch syndrome are attributable to mismatch repair proficient cancer. The other question is whether we can look at specifically MSI-high cancer versus MS-stable cancer and understand what the mortality rate for each of those are. From a clinical perspective, it's important to counsel individuals with Lynch syndrome about general cancer screening outside of mismatch repair deficient tumors and to understand that there is also a risk of mismatch repair proficient tumors and that treatment for those tumors would be different. There's a lot of work to be done in the future. Another major area of need is to see whether tumors that are microsatellite stable can be sensitized to immunotherapy, and that is beyond the Lynch syndrome field, but that is something that certainly would benefit these individuals with Lynch syndrome who develop mismatch repair proficient cancer. Dr. Rafeh Naqash: That's very interesting to hear, and we'll look forward to seeing some of those developments shape in the next few years. Now, I'd like to spend a minute, minute and a half on you specifically as a researcher, clinician, scientist. Could you briefly highlight - because I remember meeting you several years back as a trainee, with your interest in genomics, computational research - could you briefly tell us what led you to hereditary cancer syndromes based on your research and work? What are some of the things that you learned along the way that other early career investigators can perhaps take lessons from? Dr. Asaf Maoz: Big questions there, thanks for asking. I got interested in the field of hereditary cancer syndromes when I came to the United States and started doing lab research in Stephen Gruber's lab at the time at USC. He's now at City of Hope. And my interest was originally looking at immunotherapy and immunology, but I went to the case conferences where we were learning about individuals with hereditary cancer, and those were kind of earlier days where we were still trying to figure out how to test and what the implications for these individuals would be. And through fellowship, I was also very interested in that, and I did my senior fellowship years with Dr. Yurgelun here at Dana-Farber, who is the director of the Lynch Syndrome Center. And I I think it's the combination between being able to treat individuals based on precision medicine and what the germline mutation is, but also the ability to prevent cancer and to develop strategies to intercept cancer early that is really appealing to me in this field. It's also a great field to be in because it's a small field. If you come to the CGA-IGC meeting, you'll be able to interact with everyone. Everyone is super collaborative, super nice, and I really recommend it to trainees. The CGA-IGC annual meeting is really a great opportunity to learn more and experience some of the advancement specifically in the GI hereditary space. Lessons for trainees. I think there are a lot of lessons that I could think about, but I think finding strong and supportive mentors is one of the things that has helped me most. I think that just having close relationship with your mentor, having frequent discussions and honest discussions about what is feasible, what is going to make a difference for your patients and your research and what you want to focus on is really important. And so I think if I had to choose one thing, I would say choose a mentor that you trust, that you feel you have a good relationship with, and that has the availability to support you. Dr. Rafeh Naqash: Thank you so much for those insightful comments, and thank you for sharing with us your journey, your project, and some of your interesting thoughts on this concept of hereditary cancers. Hopefully, we'll see more of this work being published in JCOPO through your lab or work from others. Dr. Asaf Maoz: Thank you so much. I appreciate the opportunity to be here. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/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.

In this JCO Precision Oncology Article Insights episode, Dr. Jiasen He summarizes JCO PO article "Synthetic Lethal Co-Mutations in DNA Damage Response Pathways Predict Response to Immunotherapy in Pan-Cancer" by Hua Zhong et al. TRANSCRIPT Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today we will be discussing the JCO Precision Oncology article, "Synthetic Lethal Co-mutations in DNA Damage Response Pathway Predict Response to Immunotherapy in Pan-Cancer" by Dr. Zhang and colleagues. Immunotherapy has emerged as a groundbreaking treatment option for many types of cancer. However, the overall response rate to immunotherapy is low, around 10% to 30%. This highlights the critical need to identify which patients are most likely to benefit from immunotherapy. Two of the most extensively studied biomarkers are PD-L1 expression and tumor mutation burden (TMB). High levels of PD-L1 and TMB have been associated with better response to immune checkpoint inhibitors, which are now widely used in clinical practice. The predictive value of these markers is inconsistent across all settings. Some tumors with high PD-L1 or TMB still respond poorly to immunotherapy. One reason is that TMB reflects new antigen production, but recent studies suggest that new antigen levels do not always correlate with tumor immunogenicity. Many new antigens are not effectively recognized by T cells, limiting the immune response. Emerging evidence indicates that mutations in the DNA damage response (DDR) pathway play a critical role in moderating tumor immune interactions. Tumors harboring DDR pathways frequently exhibit increased genome instability, which may enhance their sensitivity to immune checkpoint inhibitors. While all these pathways are under active investigation, the optimal DDR pathway biomarkers for patient selection remain unclear. Notably, tumor cells with a defect in one DDR pathway may acquire greater reliance on alternative DDR pathways. Recent studies suggest that synthetic lethal co-mutations within DDR pathways are associated with immune-inflamed or hot tumor microenvironments. Based on this rationale, Dr. Zhang is investigating if synthetic lethal co-mutations in DDR pathway response pathway can serve as a treatment biomarker for immune checkpoint inhibitors. To address this question, Dr. Zhang and colleagues first utilized SynLethDB 2.0, a comprehensive database that integrated multiple data sets. Synthetic lethal (SL) gene pairs in this resource are identified through both experimental and computational approaches, with confidence scores assigned to each pair. These SL pairs were then mapped to gene sequencing results from several clinical cohorts. SL co-mutation status was defined as positive when both genes in a synthetic lethal pair were mutated. From this, SL co-mutation pairs specifically involving DDR pathway genes were selected. Patients were classified as DDR co-mutation positive if both genes in a synthetic lethal pair, each belonging to the defined DDR pathways, were mutated. In total, 431 DDR-related SL pairs were identified and matched to sequencing data from clinical cohorts. Clinical information was extracted from the cBioPortal, while further analysis of immune infiltration was performed using DNA mutation and RNA expression data from The Cancer Genome Atlas (TCGA) pan-cancer data set. The author first examined the correlation between SL co-mutation status and response to ICI therapy. They discovered that patients with SL co-mutation showed significantly improved outcome to ICI therapy across various clinical cohorts. Notably, in patients who did not receive ICI treatment, patients with SL co-mutation showed markedly compromised overall survival. Further analysis focused on the predictive value of SL co-mutation within DDR pathway genes. The author found that patients with DDR SL co-mutation had a longer overall survival compared to those with mutations in a single DDR gene, implying that SL co-mutations may be more effective biomarkers within the DDR pathway. To explore this further, in the TMB-MSKCC cohort, the author found that patients with DDR co-mutation constituted approximately 20% of various cancer types, including non-small cell lung cancer, melanoma, and bladder cancer. These patients demonstrated significantly better survival outcomes and disease control rates when treated with ICIs compared to DDR co-mutation negative patients. Notably, the TMB level was substantially higher in patients with DDR co-mutation, a finding consistent with data from the Miao-lung cohort. Furthermore, in cohorts not treated with ICIs, patients with DDR co-mutation had a shorter overall survival compared to their counterparts. Upon stratifying by PD-L1 expression, the author observed that patients with DDR co-mutation who were also PD-L1 positive derived the greatest clinical benefit from ICI therapy. Upon analyzing the frequency of co-mutation within the DDR pathway, the authors found that patients with SL co-mutation in the CPF-CPF pathway experienced remarkable survival benefit from ICIs. Within this group, one of the most common co-mutation combinations was TP53-ATM, observed in approximately 45% of cases, which was associated with a better response to ICI therapy. Further analysis of immune cell infiltration revealed that patients with TP53-ATM co-mutation exhibited a distinct tumor immune microenvironment. As the authors stated, the study's main limitation lies in the nature of retrospective analysis, which lacked the control over confounding variables and was subject to non-random sampling. For instance, patients with both SL co-mutations and DDR SL co-mutations exhibited high TMB, and TMB was known to be associated with improved response to ICI therapy itself. So, these findings require validation through prospective studies, and immune infiltration analysis needs confirmation via laboratory experiments. In conclusion, the authors found that patients with SL co-mutations in DDR pathways showed favorable clinical response and prolonged survival following ICI therapy. They also identified TP53-ATM co-mutations as a clinically relevant biomarker for predicting ICI treatment response. Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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 Dr. Abhishek Tripathi and Dr. Salvador Jaime-Casas at City of Hope Comprehensive Cancer Center share insights into their article, "Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma."  Host Dr. Rafeh Naqash and Drs. Tripathi and Jaime-Casas discuss a novel understanding of the genomic alterations underlying SCBC, revealing actionable mutations that could serve as potential targets for improved clinical outcomes. 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. Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today, I am thrilled to be joined by Dr. Abhishek Tripathi, Associate Professor in the Department of Medical Oncology and Experimental Therapeutics Research at the City of Hope Comprehensive Cancer Center, as well as his mentee, Dr. Salvador Jaime-Casas, postdoctoral research fellow and first author of the JCO Precision Oncology article entitled "Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared with Urothelial Carcinoma and Small Cell Lung Carcinoma". At the time of this recording, our guest disclosures will be linked in the transcript. Abhishek and Salvador, welcome to our podcast and thank you for joining us today. This is a very interesting topic given that at least the landscape for neuroendocrine carcinomas, where small cell lung cancer is on one end of the spectrum, has been changing, at least on the lung cancer side, with recent approvals and some new ADCs. So, of course, understanding the genomic and transcriptomic similarities or differences between pulmonary small cell and extrapulmonary small cell is of huge interest. Could you tell us a little bit about small cell bladder cancer, current approaches to treatment of small cell bladder cancer, and then why you wanted to investigate that in this project as far as the genomic differences or similarities are concerned? Dr. Salvador Jaime-Casas: Well, first of all, thank you very much for having me. I am very excited to be here. And really what served as backbone for this research project was the notion that there is a currently evolving genomic landscape in the area of bladder cancer. We know this is a highly heterogeneous disease when it comes to molecular underpinnings and mutational profile. Specifically, we know that the most common histologic subtype is urothelial carcinoma. Small cell bladder cancer represents a histology that is found in less than 1% of all bladder cancer cases. However, it is one of the most aggressive histologies. It presents with a very poor prognosis to patients and very poor response to treatment, which is why we attempted to really elucidate what is the mutational profile behind this and provide a comparison contrast between small cell bladder cancer, small cell lung cancer, and conventional urothelial carcinoma. As your question mentioned, in terms of treatment, the conventional urothelial carcinoma and small cell bladder cancer are two distinct pathways when it comes to treatment algorithms. We know that in the current era there are newer and newer drugs being developed for conventional urothelial carcinoma. We have perioperative immunotherapy in the context of metastatic disease. We have antibody-drug conjugates such as enfortumab vedotin. But really, this amazing track record of drug development hasn't been mirrored in small cell bladder cancer. And here most of the therapy is usually extrapolated from studies from other small cell histologies like you mentioned earlier, small cell lung cancer has given some form of background in terms of what therapies are used here. Cytotoxic chemotherapy, for some patients with localized disease and small cell bladder cancer, concurrent chemotherapy and radiotherapy or perioperative cytotoxic chemotherapy have been the cornerstone of treatment for many years now. However, like I mentioned, the oncologic outcomes are very suboptimal when it comes to comparing it with other disease histologies, which is why we really wanted to describe the landscape here and provide this comparison across three different groups. For this particular study, we leveraged the Tempus dataset. So, include patients with urothelial carcinoma with small cell bladder cancer and small cell lung cancer. We included their demographic information, as well as the frequency of most common genomic alterations identified. And really, it was a very comparable Table 1. We see the demographic data across the three groups was very similar. One key thing that we identified was the female prevalence was a little bit lower in patients with small cell bladder cancer when compared to small cell lung cancer. But other than that, the age, race, ethnicity, was comparable across groups, and even the smoking history. Most of the patients in this cohort were former smokers, which we believe comes to explain that regardless of any mutational profile that we talked about in a few minutes, there are shared commonalities between these histologies and shared environmental exposures and risk factors that are going to be implicated in the disease biology for these three histologies. Dr. Rafeh Naqash: Thank you so much, Salvador, for that useful background. I would like to shift to Abhishek real quick. Abhishek, you are a practicing clinician, you have led several studies in the GU space, especially bladder. Based on what you see in the small cell lung cancer space, how drug development is shaping up, which aligns with what you are trying to evaluate in this paper as targets, how do you see some of that being implemented for small cell bladder cancer in the current era and age? Abhishek Tripathi: Thanks so much for the excellent question, Rafeh. As a GU investigator, small cell bladder cancer has always lagged behind in some regards regarding enrollment abilities for the novel clinical trials. And small cell lung cancer has paved the way and led the development of a lot of these drugs across the board. With the most recent sort of drugs targeting DLL3 already approved and several antibody-drug conjugates currently in development. That actually translates really well to how we should approach drug development in bladder cancer. What we saw in the study is that although there are overlaps and similarities between small cell lung cancer and small cell bladder cancer, there are also certain differences. So the long-term assumption that all therapies for small cell bladder cancer can be extrapolated to small cell bladder], may or may not be true, and I think it is high time that we specifically investigate these novel agents in tissue-specific small cell carcinomas. To that effect, we are excited to be participating in trials that are looking at some of the novel DLL3 targeted agents, specifically bispecific antibodies and T cell engagers so to speak, and antibody-drug conjugates that are now starting to open enrollment specifically in non-lung cancer cohorts to evaluate its efficacy. So overall, I think studies like this have the opportunity to identify more putative targets for organ-specific development of these novel agents. Dr. Rafeh Naqash: Absolutely, I could not agree more. I think tumor-agnostic therapies definitely have a place, but not all therapies work the same in different tumors with a similar histological or genomic background because there are definitely differences. So now going to the comparison that Salvador, you guys did in this project, could you help us understand what are some of the things you looked at, what were some of the commonalities and the differences, and what were some of the conceptual thoughts that come out from those results? Dr. Salvador Jaime-Casas: Of course. So, the first thing that we identified was which were the most frequent molecular alterations across these histologies. We actually provided a table showcasing how the most common mutations that we identified were TP53, TERT, RB1. However, like Dr. Tripathi mentioned, the distinction between these histologies is notable in the sense that some are more predominant in small cell-pertaining cancers such as bladder cancer and lung cancer. While some others are more common in bladder-pertaining malignancies like urothelial carcinoma and small cell bladder cancer. For instance, we saw that TP53 and RB1 were significantly more evident in small cell histologies, both small cell bladder cancer and small cell lung cancer, as opposed to conventional urothelial carcinoma, which really this mirrors what is known about these mutations and what has been published. These are markers associated with more aggressive disease with a worse prognosis and even to resistance to treatment. We also identified how TERT mutations were characteristically more prevalent in small cell bladder cancer as opposed to small cell lung cancer, as well as in urothelial carcinoma. TERT mutations were more commonly identified than in small cell lung cancer. And we give a long list of these mutations that we identified, but really what we wanted to underscore here was, A, the most common mutations across histologies; B, the most common co-occurring mutations where we saw that these are not mutually exclusive. A lot of patients had co-occurring TP53 and RB1 or RB1 and TERT or RB1 and ARID1A, really elucidating how heterogeneous this molecular landscape is across histologies. And the third one that we believe really brings down the clinical impact of this research was evidencing the idea of clinically actionable mutations. We also provided a table here showcasing how mutations like FGFR, DLL notch pathway, HER2, were evident in these histologies, and what is the current status of some clinical trials evaluating different drug designs for these mutations. Like Dr. Tripathi mentioned in the context of FGFR, approximately 6% of our cohort with small cell bladder cancer showcased mutations in FGFR3. However, up to 14% of them had mutations in any FGFR gene, which really underscores the notion that drugs like erdafitinib, which have been introduced in the market in recent years, could potentially showcase some response in the space of small cell bladder cancer. We actually provide the description of two trials, phase two, phase three trials, that are evaluating erdafitinib in the context of high-risk non-muscle invasive bladder cancer and even metastatic urothelial carcinoma. Like Dr. Tripathi mentioned as well, antibody-drug conjugates, another very interesting area of drug development targeting HER2, we included evidence on how disitamab vedotin and trastuzumab deruxtecan are currently being explored across different phase two and phase three clinical trials, both as part of basket trial designs for solid malignancies expressing HER2, but also for patients with urothelial carcinoma where there is evidence of HER2 expression. So, we believe that the landscape is shifting in the right direction in the sense that therapies are becoming much more personalized and targeted against these known molecular profiles. Dr. Rafeh Naqash: Thank you, Salvador, for summarizing some of those very interesting results and providing a very unique conceptual context to that. I would like to go to Abhishek this last portion. Of course, I am sure you guys will expand on this work and there are a lot of other interesting things that will likely come out from this work and hopefully you will publish that in JCO PO. But one of the very important things that I wanted to highlight from this podcast specifically was the science is obviously very interesting, but I feel the more important interesting aspect is giving trainees and fellows, residents, mentorship opportunities, mentoring them and giving them lead roles in projects like this, which is what Dr. Tripathi has successfully done for you in this project, Salvador. So, Abhishek, as somebody I have known for a couple of years now, more than a couple of years, as a very successful clinical translational investigator in the GU space in the early phase setting, Abhishek, really briefly, within a minute, could you tell us about your journey and what are some of the things that have worked for you as an early career investigator that you have learned from, and then your journey of mentorship, how has that been for you and what are some of the things that you take home from your mentorship role? Abhishek Tripathi: Absolutely. And as you mentioned, mentorship has been pivotal for all early career investigators for them to really succeed. So, my journey, as you know, I started off as an early career investigator at another institution, and I think I owe it to my mentors even at that time and even now who are helping me develop some of these newer translational and clinical trial ideas, creating opportunities where we could really showcase some of the interesting work that we are doing. That actually goes a long way in terms of creating independence as an established investigator. And I think the sooner we start off with mentorship prospects, I think the better it is. And paying it forward, I think I have been lucky to have mentees like Salvador who are just extremely talented, really committed, and goal-oriented. He really led the project right from the beginning in terms of initial analyses and looking up all the sort of correlative studies that we could do and the contextual data between small cell lung cancer and bladder cancer that we have delved into for the past several years. And it really showcases the ability of young mentees like Salvador to really excel given the right guidance and the support. As a mentor, it has been a really rewarding experience. It is really helpful to actually learn from some of these mentees as well as to approach the same problem from a different angle and different thought process and guide them through the study. So, it has been incredibly helpful and rewarding both being a mentee and a mentor over the past several years as I have transitioned. Dr. Rafeh Naqash: Thank you, Abhishek, for those very insightful comments on how both being a mentee and being a mentor helps shape you as an individual as well. And then you take a lot of pride in the success of your mentees. Now real quick, Salvador, could you tell us a little bit about yourself, you know, how you ended up at City of Hope under Dr. Tripathi's mentorship and what are some of the next important things that you are looking forward to doing? Dr. Salvador Jaime-Casas: So, a little bit about who I am. I did medical school in Mexico City. I was born and raised there, and towards the end of my medical training, I started to be engaged in research projects. And through one of my mentors in Mexico, I was actually introduced to the team here at City of Hope, including Dr. Tripathi. And through this, we got the opportunity to have some conversations about what I wanted to do, become a physician-researcher in the area of genitourinary oncology and hopefully my transition to residency in a few years. And that is how I came to be his mentee here at City of Hope. I think it has been a very rewarding experience, like Dr. Tripathi said, having such an incredible mentor and really being with him both in the academic setting and in the clinical setting, in patients with clinic, seeing this curiosity and all these clinical trials, all of this evidence that we have coming together to generate this insight. Dr. Rafeh Naqash: Thank you so much for both the scientific insights, as well as the journey of being a mentee for you, Salvador, and as a mentor for you, Abhishek. I really enjoyed talking to you guys about both aspects here today and hopefully we will see more of your work, Abhishek and Salvador, as far as understanding the transcriptomic heterogeneity in neuroendocrine tumors or neuroendocrine cancers of the bladder. Dr. Salvador Jaime-Casas: Thank you very much. Thank you for having us. Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. Abhishek Tripathi Disclosures Consulting or Advisory Role:  Company: Aadi biosciences, Seattle Genetics/Astellas, Exelixis, Bayer, Gilead Sciences, Pfizer, Deka biosciences Speakers' Bureau: Company: Sanofi

In this JCO PO Article insights episode, Dr. Jiasen He summarized the JCO PO article "Mucin 16–Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implications for Other Sarcoma Subtypes" by Connolly et al. TRANSCRIPT Jiasen He: Hello, and welcome to JCO Precision Oncology Article Insights. I'm your host, Jiasen He, and today we'll be discussing the JCO Precision Oncology article, "Mucin 16-Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implication for Other Sarcoma Subtypes" by Connolly et al. Epithelioid sarcoma and malignant rhabdoid tumor are rare pediatric soft tissue sarcomas, characterized by INI1 loss, high recurrence rates, and poor outcome despite multimodal treatments. Emerging evidence has shown that Mucin 16 is expressed in both tumor types. Mucin 16 is a transmembrane glycoprotein whose extracellular domain can be cleaved and released as CA-125. Both Mucin 16 and CA-125 are well-established biomarkers in several adult epithelioid malignancies, particularly ovarian cancer. Ubamatamab is a specific T-cell engager targeting CD3 and Mucin 16. It has demonstrated antitumor activity in patients with recurrent ovarian cancer, and clinical trials are ongoing to evaluate its efficacy as monotherapy or in combination regimens. In this manuscript, Connolly et al. present the first reported case of a heavily pretreated patient with epithelioid sarcoma who responded to ubamatamab, followed by an investigation into mechanisms of resistance after disease progression. Furthermore, the authors retrospectively assessed Mucin 16 expression in a cohort of pediatric and young adult sarcomas, finding high expression in both epithelioid sarcoma and malignant rhabdoid tumor. In this case report, the authors describe a 23-year-old woman with relapsed metastatic epithelioid sarcoma. Initially diagnosed at age 12, she had received multiple lines of treatments, including surgery, radiotherapy, targeted therapy, and immunotherapy. Following disease progression after all these treatments, her tumor was tested for Mucin 16 expression and it demonstrated 100% positivity with markedly elevated CA-125 levels, providing a rationale for treatment with the Mucin 16-CD3 bispecific T-cell engager, ubamatamab. Ubamatamab was administered in an escalating dose schedule up to 250 mg once weekly during cycle one and continued for a total of 162 weeks. The best response was observed at week 11, with a 40% reduction and a marked decline in CA-125 levels. Disease progression was first detected in a single left lower lobe lung nodule, which on biopsy showed a reduction in Mucin 16 expression from 100% to less than 5%. Post-treatment analysis revealed changes in the tumor microenvironment, including increased expression of T-cell exhaustion markers such as PD-1 and LAG-3. Ubamatamab was generally well tolerated. Cytokine release syndrome occurred during the escalating phase of cycle one, presenting with fever and hypoxia. Other notable adverse events included pleural and pericardial effusion, both of which resolved spontaneously. Given its favorable safety profile and limited alternative treatment options, ubamatamab was continued beyond the initial progression. The patient ultimately received 28 cycles of treatment before she passed away due to disease progression. In the second part of the paper, the authors examined Mucin 16 expression in a cohort of pediatric and young adult sarcomas. Among 91 samples, Mucin 16 was expressed in six out of eight epithelioid sarcomas and two out of four malignant rhabdoid tumors. H-score analysis showed that all Mucin 16-positive tumors showed moderate to high expression levels. In conclusion, this manuscript presents the first reported use of a Mucin 16-CD3 bispecific T-cell engager for epithelioid sarcoma, along with an investigation into resistance mechanisms following progression. The treatment achieved a substantial partial response with a favorable safety profile. The findings suggest that resistance may be associated with loss of Mucin 16 expression and T-cell exhaustion. Follow-up studies are needed to confirm these mechanisms. Notably, the study also identifies INI1-deficient sarcoma as a group with high Mucin 16 expression, warranting additional validation and mechanism exploration. These findings offer valuable insight for future therapeutic strategies and support the use of Mucin 16/CA-125 as both a treatment target and a biomarker for patient selection and disease monitoring. Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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.