JCO PO author Dr. Mark Yarchoan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, shares research on the four distinct subsets of biliary tract cancers (BTCs) and their varying immune responses and mutations. Dr. Naqash and Dr. Yarchoan discuss the article’s study of intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer. Click here to read the article! Dr. Naqash: Welcome to ASCO's JCO Precision Oncology Conversations where we bring you the highlights and overview of precision oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly impactful and significant JCO PO articles. These articles can be accessed at ascopubs.org/journals/po. Hi, I am Dr. Rafeh Naqash, Assistant Professor of Medicine at Oklahoma University Stephenson Cancer Center, where I focus on Phase I clinical trials and lung cancer. You're listening to JCO Precision Oncology Conversations podcast. Today, I will be talking with Dr. Mark Yarchoan about his recent paper, Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures. Dr. Yarchoan is an Associate Professor of Medicine in the GI Medical Oncology branch at the Johns Hopkins, Sydney Kimmel Comprehensive Cancer Center. Full disclosure for our guests will be linked in the show notes and can be found on the article's publication page. Dr. Yarchoan, thank you so much for joining us today. Dr. Yarchoan: Thank you for having me. Dr. Naqash: For the sake of our listeners, Mark, could you tell us about your professional background and your research interests? Dr. Yarchoan: Sure. I'm a medical oncologist by training focused on hepatobiliary malignancies at the Johns Hopkins Hospital, a co-director of Liver Multidisciplinary Clinic, and I'm interested in novel immunotherapeutic approaches to treating liver cancers. Dr. Naqash: That is definitely an unmet need, which we're going to talk about more as we discuss your paper. Again, for the sake of our listeners, before we take a deeper dive into the published paper, could you provide us a one-minute overview of the main findings from your manuscript that was published in JCO Precision Oncology? Dr. Yarchoan: Absolutely. So, we looked at the molecular subtypes of cholangiocarcinoma. So, there are essentially two common forms of liver cancer. There's hepatocellular carcinoma and biliary tract cancers, also sometimes called cholangiocarcinomas. Cholangiocarcinomas are the rarer of the two types of liver cancer and we know that cholangiocarcinoma’s not really one cancer, it's a number of different cancers that all anatomically start within the bile ducts of the liver. And what we did working with a number of different collaborators and then also, with Tempus, which is a major molecular profiling company, is we looked at the landscape of mutations that occur in cholangiocarcinoma, and then tried to correlate these mutations with features of the tumor immune microenvironment using RNA data from the same tumors. Dr. Naqash: Thank you so much. So, again, being a thoracic oncologist myself, we have a lot of excitement associated with immune checkpoint alone or immune checkpoint in combination with chemotherapy, similar to what has been seen in some of the upper GI cancers in the last couple of years. Now, before you started this paper or this work with Tempus, what was known about the landscape of biliary tract cancers and what have been the standard approaches of management for advanced biliary tract cancers? Dr. Yarchoan: You know, many of us who treat biliary tract cancers have joked for years that we treat the lung cancer of the GI cancer world because so many of these cancers have actionable molecular alterations. I think that's something that has been known for a long time. Over the last couple of years, for the first time, we have multiple drug approvals in cholangiocarcinoma for molecularly defined subsets of disease. So, for example, we have now inhibitors of FGFR2 that have been approved for FGFR2 fusions or rearrangements. We have an IDH1 inhibitor approved for cholangiocarcinoma. There are some tumor agnostic approvals like for BRAF and NTRK, all of which we do occasionally find in biliary tract cancer. So, you know I think it's been known for a long time that looking for molecular alterations is fruitful in cholangiocarcinoma. You often find these things and these cancers often respond to these agents. I think what is unique here is we've taken this knowledge and first of all, this is the largest series of biliary tract cancer that has ever been profiled to our knowledge, and other profiling efforts have been international. But we know that biliary tract cancer in Southeast Asia can sometimes be different from what we see here in the U.S. because there, those cancers are often caused by liver flukes, which we don't tend to see as much in the U.S. So, the genetics can be somewhat different. And finally, I think what is unique about our paper is that we have actually correlated these molecular differences, these molecular drivers of cholangiocarcinoma. And we've correlated these drivers with the RNA from the same tumor to really understand when you have a tumor that is for example, FGFR2 fusion or rearrangement, what is typically found in the immune microenvironment from that same tumor. Dr. Naqash: Thank you for that explanation. Now, going back to why biliary tract cancer’s potentially not as responsive to immune checkpoint inhibitors as some of the other GI-based tumors — pancreatic cancer, as you very well know, has a certain tumor microenvironment associated with presence of fibroblasts and other immunosuppressive macrophages that result in lack of response to immunotherapy-based combinations. What is unique in biliary tract cancers, as you've nicely explained in the discussion or your introduction, that based on Keynote-158, the response rates have generally been in the range of 2 to 10%. So, what is unique here that results in tumors being not so responsive to immunotherapy-based combinations? Dr. Yarchoan: Yeah, biliary tract cancers tend to be fairly immune resistant cancers. As you mentioned, the response rate to single agent anti PD-1 immunotherapy is probably in a range of about 5 to 10% in most studies. We do have new data now from the TOPAZ-1 study, this is a randomized first line study of Gemcitabine Platinum with or without durvalumab, which is a PDL1 inhibitor where the addition of durvalumab did modestly improve survival. So, there is some activity for immunotherapy, but it's quite low as you mentioned. And again, I think that we're still learning why this is, but cholangiocarcinoma tends to have, number one, a very low tumor mutation burden. So, the total number of mutations, which is a surrogate for the number of neoantigens that the immune system can see tends to be low. But also, when we look at the immune microenvironment at these cancers, we tend to find relatively low numbers of effector T cells in the microenvironment, which are an anti-tumor subset. We tend to find high numbers of immunosuppressive cell types, M2 macrophages and T regulatory cells. And these tumors also tend to have a lot of stroma which can impede the immune system coming in. So, the two major accesses that can determine immune sensitivity, the mutational burden in the immune cells, and the microenvironment, both point to an immune suppressed tumor type. Dr. Naqash:  Totally agree. And I think that's why findings that you describe in this paper have a lot of relevance to precision medicine and how we can approach biliary tract cancers, not just anatomically but also from a molecular standpoint. Going back to lung cancer analogy, small cell lung cancer until a few years back was considered one entity and now, it is three to four different entities based on some transcriptional factors which determine how patients respond. And I believe there is something similar going on here like you described. So, now taking a deeper dive into the paper, you did mutational signature analysis clustering, and then you also assessed RNA. What would some of the mutation-specific findings associated with whether tumors were intrahepatic or extrahepatic gallbladder in this manuscript? Dr. Yarchoan: Sure. So, we, as you mentioned, did some cluster analysis looking at the driver mutations in cholangiocarcinoma. And what we found were essentially, there appeared to be four distinct subsets of these cancers. One subset which has been reported in other similar cluster analyses, including an international cluster analysis; one subset really appears to be driven by FGFR2 fusions or rearrangements and is entirely an intrahepatic cholangiocarcinoma subset. And we found that this subset tended to have the lowest immune infiltration of any of the four subsets that we looked at. A second subset, which we called mutational cluster three, was both intrahepatic and extrahepatic disease. And the most common mutation was really in CDKN2A or N2B. The second cluster that we looked at, clusters 1, 2, 3, 4 — I think is one of the most interesting clusters. And this is a cluster that was enriched for genes that seemed to alter the epigenome of the tumor. So, for example, IDH1 mutations, which we know result in an oncometabolite 2HG were common in the subset also ARID1A and PBRM1 were common. And then finally, the largest subset of all were the tumors that had frequent mutations in KRAS, TP53 among other mutations. We found that this was the most inflamed cluster, had the highest PD-L1 expression, slightly enriched in the extrahepatic subset versus intrahepatic subset. Dr. Naqash: Definitely interesting findings based on the cluster analysis and the mutations in each cluster. Going to cluster one where you have found that TP53, ATM, et cetera, mutations are commonly altered genes, are you suggesting based on some of this work that the immune inflamed tumor microenvironment could potentially be linked to TP53, which is cell cycle checkpoint, which when altered could result in higher DNA damage similarly with ATM being in the DNA damage pathway. Could that be a potential explanation for why these alterations are resulting in a hot tumor immune microenvironment? Dr. Yarchoan: Certainly, could be. You know, obviously, we can't prove that. This was correlative, but I think that would certainly explain what we found. Dr. Naqash: And again, going back to cluster four with FGFR2 and BAP1 alterations, which had the lowest PD-L1 and lowest immune microenvironment inflammatory signature, is that potentially a cluster that you think would most commonly benefit from targeted therapies rather than immune checkpoint-based therapies? Dr. Yarchoan: That's our hypothesis here. This was a subgroup that appeared to be non-inflamed, had a low mutational burden. Genomically, I would call this a stupid cancer in the sense that there's a very powerful driver mutation and not a whole lot else going on here. It seems like the sort of tumor that may benefit from targeted therapy. I think what we don't know, and one of the questions that immediately comes out of this work is, is FGFR2 itself immunosuppressive and that's why we don't find a lot of immune cells. And if so, it raises the question whether these sort of cluster four tumors would benefit from a combination approach of targeted therapy plus immunotherapy. And so, I think that's an open question, something that we hope to look into. Dr. Naqash: Definitely, leads to potential subsequent work in this field to expand more on these findings. Now, going back to some of the other important findings in your paper, you described actionable biomarkers in the biliary tract cancers based on proven trials with specific therapies. One of the questions that I had was you take TMB ≥10 as a potentially actionable biomarker. Is that true for biliary tract cancers? Because there's data from different groups showing that different TMB cutoffs have different meaning for different types of tumors. So, is 10 a cutoff where you are reasonably comfortable in saying that potentially, single agent immunotherapy may work and TMB here is predictive of outcomes, or do you think a higher TMB is probably more relevant in these cancers that are generally not immune responsive? Dr. Yarchoan: Yeah, the approval for pembrolizumab in high TMB tumors has been controversial. I think probably more controversial than it should be. But Keynote-158, which was sort of a prospectively analyzed study of pembrolizumab and multiple tumor histologies, actually included biliary tract cancers. And the response rate in that study for biliary tract cancer in the TMB high group again, small numbers of patients but, was consistent with pembrolizumab being very active. I have to say in my own clinic, I've had some absolutely spectacular responses for high TMB biliary tract cancer, and so I tend to believe the data. I've actually had complete responses. I've had patients downstage to surgery who went on single agent anti PD-1. So, I think this is an important group of patients and I think it is a group that we shouldn't miss for biliary tract cancer. Dr. Naqash: Definitely agree with you. All of us strive as medical oncologists to get some of those complete responses that don't come often very commonly or easily. But it's always nice to see those responses and individuals especially with these biomarker-specific tumors with high TMB or high PD-L1. Now, other findings from your paper, you describe mutual exclusivity of two mutations in a certain subgroup, which was TP53 and BAP1. Could you explain the clinical relevance or the molecular significance of these mutually exclusive mutations and what they might mean in the context of this tumor? Dr. Yarchoan:The short answer is these were clearly in different immune subsets and different molecular subsets. Again, the TP53 belonged to what we called cluster one. Usually, went with KRAS, was more common in extrahepatic disease. The BAP1 mutations tended to go along with FGFR2 fusions or rearrangements, was intrahepatic. But exactly why these were mutually exclusive, why was it not evolutionarily advantageous for tumors to have both of these things at once? You know, I think remains an unanswered question. There’s certainly a hypothesis for why the tumor wouldn't need both, but I don't know. Dr. Naqash:  And you also looked at PD-L1 and tumor mutational burden across the biliary tract tumor subtypes. Could you tell us more about some of those findings? Dr. Yarchoan: Yeah, for sure. I mean, I think our cluster one, which again was the most inflamed cluster, had more KRAS, more TP53 — not surprisingly seemed to have the most immune infiltration, the highest PD-L1 expression in a trend towards a higher tumor mutation burden as well. Not totally surprising. I don't want to over-interpret that finding though because we've looked now at the prospective data from TOPAZ-1 where patients got GemCis with or without durvalumab. As a matter of fact, PD-L1 was not a very strong predictor for durvalumab benefit in that study. So, I wouldn't over-interpret the trend towards higher PD-L1 expression in that subset. It may not be very clinically actionable. Dr. Naqash:  Sure. Now, another finding is the TMB comparisons across the biliary tract cancer subtypes. And to me, it seemed like the TMB, median TMB, was slightly different but not significantly different that may not necessarily have a huge clinical relevance. Do you agree with that? What are your thoughts on that side? Dr. Yarchoan: We’re in an era now where we just get TMB at an individual patient level. So, I don't think we're going to be relying on cluster analysis to figure out a patient's TMB. So, I don't think it's necessarily clinically actionable. I do think there were some findings here that are interesting from a research perspective. For example, ARID1A was associated with a higher tumor mutation burden; something that's been reported in other tumor types and that's certainly interesting and something that should be followed up on, I think, from a research standpoint. Dr. Naqash: Excellent. Now, last figure that I came across, which was again, very interesting, was that you analyze association between all the different mutations and different immune gene signatures. And it seemed based on the figure that TP53, again, stood out when you correlated with PD-L1 or CDA T cell or other immune inflammatory gene signatures. Is there something going on with TP53 here that you think is potentially relevant co-mutation in this tumor, which could lead to some novel therapeutic combination approaches? Dr. Yarchoan: Yeah, I don't want to over-interpret our work, but I agree, it's very interesting and this is a topic that is being investigated in many tumor types because TP53 is something that appears in many tumors including the ones that you treat. So, I think this is particularly relevant because we have a bunch of TP53 targeted therapies coming down the pike. How those will modulate the tumor immune microenvironment is an interesting topic. So, maybe just for sake of discussion, are you finding the same thing in lung cancer and what's the thought process in lung cancer now? Dr. Naqash:  Yes, again, very interesting question. So, we actually had some data last year that we presented in the context of lung cancer in STK11, which is again, commonly found in pancreatic and biliary cancers also. And we saw TP53 co-mutated tumors had a very high immune inflammatory gene signature with all the different aspects of immune infiltration or Interferon gamma upregulation (IFN-γ). So, likely, our assessment was that this was potentially linked to the cell cycle aspect and higher neoantigens for DNA damage. So, something common probably going on here in this tumor type as well as you mentioned. So, one of the other things that I came across, which is interesting and I've come across a patient actually a few years back with cholangiocarcinoma, but that was associated with a liver fluke. The tumors that you assess using the Tempus database obviously, were from North America and did not have Asian patients. And from my understanding, TOPAZ-1 did include a decent number of patients from Asia. So, have you looked at or is there a potential reason to believe that liver fluke-associated tumors may have a higher inflammatory signature or has there been any data in comparing liver fluke versus non-liver fluke-associated biliary tract tumors to see what could be the genomic transcriptomic differences there? Dr. Yarchoan: Yeah, as you mentioned, our study was purely for North American patients. It's not that there were no Asian patients. There certainly were Asian patients, including patients who may have been born in Southeast Asia but immigrated here. There have been other analyses of the molecular landscape of biliary tract cancer that were international and included more patients from Asia, including a paper in Cancer Discovery a couple of years ago that I think is worth reading. Overall, I think there is some data that this subgroup of patients may have a unique tumor immune microenvironment and unique mutational landscape. We tend to find more for two in these patients. They do tend to be, I think, a little more inflamed, have more PD-L1 expression. Interestingly, in the TOPAZ-1 study, which again, was the prospective study of durvalumab, there appeared to be more benefit to durvalumab in patients in Asia than patients in the West. And it does raise the question whether that could be mediated in part by this liver fluke ideology. So, again, certainly not a settled question, but something interesting that should be followed up on. Dr. Naqash:Definitely interesting. I would again like to thank you Dr. Yarchoan and your team for this excellent work and sharing all your thoughts with us today, and giving us more insights into biliary tract cancers. On behalf of JCO PO, I'd like to thank you for considering JCO PO as the final destination for this interesting work, and hopefully, you consider JCO PO for future work as well. Dr. Yarchoan: Well, thank you for highlighting our work and for the opportunity to publish, and thanks for this discussion. Dr. Naqash: Absolutely. It's been a pleasure talking to you today, and hopefully, our audience will find this conversation equally intriguing and interesting. Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one at asco.org/podcasts or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter. Our Twitter handle is @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journals/po.   Voiceover:  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 Mark Yarchoan  Consulting or Advisory Role: Eisai, Exelixis, AstraZeneca, Genentech/Roche, Replimune, Hepion Pharmaceuticals  Research Funding: Bristol Myers Squibb (Inst), Merck (Inst), Exelixis (Inst), Incyte (Inst)   Guest Bio Dr. Mark Yarchoan, MD, is a medical oncologist focused on hepatobiliary malignancies at the Johns Hopkins Hospital and co-director of Liver Multidisciplinary Clinic.

In this JCO Precision Oncology Conversations podcast, JCO PO author Dr. Thanh Dellinger of City of Hope National Medical Center shares insights into the research published in her article, “Hyperthermic Intraperitoneal Chemotherapy–Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.” Podcast host Dr. Abdul Rafeh Naqash talks with Dr. Dellinger about hyperthermic intraperitoneal chemotherapy (HIPEC) and the various challenges of the treatment of epithelial ovarian cancer (EOC). The study described in this JCO PO article discusses protein expression, RNAseq alterations and signature, and whole-transcriptome sequencing and signatures. Read here  https://ascopubs.org/doi/full/10.1200/PO.21.00239   TRANSCRIPT Dr. Abdul Rafeh Naqash: Welcome to ASCO’s Precision Oncology Conversations where we bring you the highlights and overview of precision oncology. This podcast is here to provide interactive dialogue focusing on the excellent research published in the JCO Precision Oncology. Our episodes will feature engaging conversations regarding precision oncology with the authors of a clinically relevant and highly significant JCO Precision Oncology article. You can find all our shows including this one at asco.org/podcasts, or wherever you get your podcasts. Hello, I am Dr. Abdul Rafeh Naqash. I’m a medical oncologist and a phase one clinical trialist at the OU Stephenson Cancer Center. You're listening to JCO Precision Oncology Conversations. I have no conflicts of interest related to this podcast. A complete list of disclosures is available at the end of each episode. Today, I will be talking with Dr. Thanh Dellinger from the City of Hope Comprehensive Cancer Center, who's a gynecological oncologist, and we'll be talking about her JCO Precision Oncology article, ‘Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.’ Dr. Dellinger does not have any conflicts of interest. Hi, Dr. Dellinger, welcome to our podcast! Dr. Thanh Dellinger: Hi, Dr. Naqash! It’s such a pleasure to be on with you. Dr. Abdul Rafeh Naqash: We recently saw your paper published. It's one of those interesting, clinical translational papers that we felt needed to be highlighted in our Precision Oncology Podcast series. So, we're really excited to have you here today to take a deeper dive into the findings and some of the novel approaches that you used in your recent publication. So, for starters, could you give our listeners a brief idea of what HIPEC is, where it's used, and when it's used in ovarian cancer? Dr. Thanh Dellinger: Right! Thank you very much for this great introduction. So, HIPEC or Hyperthermic Intraperitoneal Chemotherapy has been used in ovarian cancer for quite some time. The most relevant data giving us an indication for ovarian cancer was published by Dr. van Driel in the OVHIPEC-1 randomized trial several years ago in the New England Journal of Medicine, which demonstrated that in stage 3 ovarian cancer patients who undergo an interval tumor debulking with HIPEC, that those patients appear to enjoy both progression-free and overall survival benefit. In fact, the overall survival benefit is nearly 12 months for those patients. So, with this in mind and a number of other data, the HIPEC treatment for those patients that interval debulking has been incorporated into the NCCN guidelines. Nonetheless, there have been some criticisms of HIPEC and it still remains to be seen who those patients are, the ovarian cancer patients who really best benefit from HIPEC, given the morbidity of HIPEC. We now know also that HIPEC is probably equivalent to just cytoreductive surgery alone in terms of morbidity. Dr. Abdul Rafeh Naqash: Thank you for that explanation. And especially for people like myself, who are not surgeons or gynecological oncologists, that was very helpful. So, my next question, and you probably partly answered it, but I'm going to still ask the question is: what is the reason you think that intraperitoneal chemotherapy overall, has not been as widely adopted? Dr. Thanh Dellinger: You touch on a very good point there. As many of the listeners may understand, IP chemotherapy has demonstrated a lot of efficacies in multiple clinical trials over the last decade or two decades even. And part of why, despite its benefit, it has not been taken up in the overall community may really be the difficulty and the complexity of doing IP chemotherapy in the community, especially the side effects are difficult sometimes to take care of. There's increased abdominal pain and there are catheter issues. And so, especially with more recent data, that with the presence of Avastin, IP chemotherapy may not necessarily be as beneficial. Unfortunately, IP chemotherapy hasn't been really taken up in daily oncologic care with ovarian cancer. Nonetheless, we know that there are a lot of theoretical benefits because of the peritoneal metastasis not being as best treated with intravenous chemotherapy as with regional therapy. Dr. Abdul Rafeh Naqash: Thank you! So, now going to the data that you published. I was very intrigued with some of the findings. And from what I understood, your main aim was to understand predictive biomarkers to identify patients or basically identify molecular characteristics for patients' selection for HIPEC. So, could you tell us more about why you initiated this study? And I understand this is one of the, I believe the first study in humans to evaluate some of these interesting biomarkers, both pre- and post-. So, what was the background of doing this trial? And what led to this interesting study? Dr. Thanh Dellinger: Thank you for pointing out this aim. There's a lot of criticism of HIPEC and part of it is that we may not exactly understand the mechanisms of HIPEC, why is it that it works so well in some patients? There's a lot of preclinical data supporting hyperthermia, especially with cisplatin. There's synergy between cisplatin and hyperthermia, and improving the DNA adduct formation. There's increased cytotoxicity seen when the temperature increases up to 43 degrees. And there's also a T-cell activation and immune response that occurs during hyperthermia. So, a lot of this, however, has been done in preclinical studies, in vitro data as well as preclinical mouse models. There hasn't been much or really anything published that, as far as I know, has been done in humans. And so, this particular study looked at both pre-treatments, pre-HIPEC specimens, peritoneal biopsies, as well as immediate post-operative peritoneal biopsies, tumors, and normal samples, and we wanted to look both at the whole transcriptomic sequencing profile, but also at the tumor microenvironment. Dr. Abdul Rafeh Naqash: From a logistic standpoint, from a trial design standpoint, was this a phase 1 study? I know you use the term pilot in the publication. So, were you trying to look at safety also, or was this primarily I would say, a biomarker, pharmacodynamic biomarker-driven study that you were trying to evaluate? Dr. Thanh Dellinger: You're correct. This was essentially a feasibility study. But we additionally looked at safety and feasibility with HIPEC at our institution. And in some respects, we also looked at the feasibility of giving intraperitoneal chemotherapy normothermically early after HIPEC, and so it was also an endpoint to look at safety. Dr. Abdul Rafeh Naqash: Understand! I believe there was some difference in the dose for the cisplatin, I believe, is the chemotherapy that you use. What was the rationale for the difference in the dose for 75 milligrams per meter square that you use in your study? Dr. Thanh Dellinger: The study was initiated at a time before the OVHIPEC-1 trial was published. And so, at that time, the HIPEC dose for cisplatin was still not established. 75 milligrams per meter square for cisplatin was actually used in other trials, and has been noted to be effective in other clinical trials. Dr. Abdul Rafeh Naqash: Thank you! Now going to the patient population for this trial. What type of patients were you enrolling? Was it just epithelial ovarian cancer patients, did these patients need to have peritoneal metastases when you were doing this cytoreductive surgery? What was the patient population that you were targeting in this trial? Dr. Thanh Dellinger: The majority of the patients did have epithelial ovarian cancer. We did enroll a few, actually 5, uterine cancer patients as well, which were not included in this specific publication. But the majority of them were epithelial ovarian cancer patients. Dr. Abdul Rafeh Naqash: Going to the interesting translational analysis. So, you had three subsets of patients based on the biopsy collection. What were your hypotheses, and what drove some of those translational studies to understand the biomarkers? Dr. Thanh Dellinger: The first translational analysis we conducted was the whole transcriptomic sequencing, and specifically, we wanted to look, one, for any potential transcriptomic signatures that may correlate with survival or improved response to HIPEC. The second one was to look at whole exome sequencing. Thirdly, we looked at whole transcriptomic sequencing differences before and after HIPEC treatment. And lastly, we looked at the tumor microenvironment through multiplexing of certain markers associated with T-cell response. Dr. Abdul Rafeh Naqash: From a clinical outcome standpoint - and we'll discuss the biomarkers in more detail - from a clinical standpoint, when I briefly looked over the PFS curves, were the results, as far as expected outcomes, were they similar to what you see with the current standard? Or were there any unusual safety signals? Or would you attribute any of the adverse events that you saw to intraperitoneal chemotherapy specifically? Because I believe some patients did have some chemotherapy pre-surgery, neoadjuvant if I'm correct. So, how would you attribute some of those AEs, and if at all, did you see any interesting safety signals of concern and outcomes as far as PFS is concerned? Dr. Thanh Dellinger: So, one of the major toxicities that we saw in the first half of our trial were actually renal toxicities. In fact, there were actually two patients who could not go on to adjuvant chemotherapy because they suffered chronic renal failure. And because of that, halfway through the trial, we did actually add a nephro protectant called sodium thiosulfate. And this actually dramatically improved those renal toxicities. And for the second half of our study, no patients suffered grade three or grade four renal adverse events. And so, that did change significantly. Dr. Abdul Rafeh Naqash: From a genomic standpoint, it's very interesting that you were able to do all these very cool and interesting translational biomarker studies, including multiplex immunofluorescence. From a genomic standpoint, though, would you say it's fair to say that there was no significant correlation based on the baseline genomics for some of the patients and their outcomes? Is that a fair assessment? Dr. Thanh Dellinger: Yes, that is a very fair assessment. I think that our cohort was really too small to make those kinds of assessments. I don't know whether you saw there recently was a paper published by the OVHIPEC-1 group looking at their cohort of over 200 patients that underwent the interval cytoreductive surgery in HIPEC and they did actually demonstrate benefit in patients who are HIV-positive but BRCA wild-type, but not necessarily in BRCA mutated patients. So, I think that I would point to that study to look for genomic effects with HIPEC patients. Dr. Abdul Rafeh Naqash: Understand. Now, again, going to the biomarkers that your team evaluated, it seems from among good responders especially, you saw an increase in tumor necrosis factor, alpha signaling, NF-kappa B signaling, KRAS signaling, and then you also saw some pathways that were downregulated, especially the G2-M checkpoint, and Myc targets. What would you say the correlation of these is in terms of future drug development in this specific setting? Dr. Thanh Dellinger: I think that we did see some increase in immune pathways in patients who did better in the end. And also, our multiplex results did demonstrate that E1 expression was increased in patients who had better responses after HIPEC. So, our hypothesis is that potentially, there's an activation of T-cell response with HIPEC and that potentially PD-1 inhibitor could be added in the future. This is a hypothesis that certainly would need to have more work, but it's something that is interesting enough to really look at in ways of how to improve HIPEC. Dr. Abdul Rafeh Naqash: Going to your point on the PD-1, I found really intriguing that you were able to see an increase in PD-1 expression on CD8+ T cells but no actual increase in the number of CD8+ T cells suggesting there's some sort of activation of this marker and this may not necessarily be a marker for T-cell exhaustion. So, would you interpret it in a way that in a different setting, perhaps a new adjuvant approach with immunotherapy, would perhaps somehow augment this and then you could see more upregulation? Is there any work being done in that field? How would you put this in the context of your findings? Dr. Thanh Dellinger: You bring up a really great point because to date HIPEC has been demonstrated to have benefit in the interval setting. But there was a more recent study done by, well not recent, a more recently published study by a Korean group that demonstrated no benefit in the adjuvant setting for HIPEC and still some benefit in the interval setting. And the question is, are these really two different types of cohorts who respond differently because of potential differences in immune response and tumor microenvironment? I think that that would be a great way of delving further into this. What are really the differences in tumor microenvironment changes in those two different settings? Dr. Abdul Rafeh Naqash: Definitely! It’s very exciting. You've also shown upregulation of, as you mentioned earlier, immune pathways, as well as upregulation of genes related to heat shock proteins. Does that play into future drug development as far as HSP Inhibitors are concerned? Dr. Thanh Dellinger: That is a really great question. Certainly, in preclinical models, heat shock proteins are known to be elevated and they do activate dendritic cells and result in T-cell activation. Now, whether that can be spelled out into actually some future drug therapy definitely remains to be seen. To date, there hasn't been any success in using heat shock types of agents or inhibitors, unfortunately. So, I think while this is of great interest, I'm not entirely sure that this will translate into any drug therapy in the future. Dr. Abdul Rafeh Naqash: And I totally connect with you there as a phase 1 trialist. I completely agree that we see a lot of translational data, more often than not, going into the phase 1 site because many of these targets are not actionable. Now, from a DNA repair standpoint, you did see that there was interference with DNA repair, as far as some of the analyses that you did, but I did not specifically see any markers for DNA damage that were assessed on the biopsies such as Gamma-H2AX, RAD 51, or Phospho-NBS. Was there a reason why that was not looked at? Dr. Thanh Dellinger: I think that we did look at that and there weren't really any significant results. We did put some of the data into the supplementary data. I think that in the end, our cohort was really too small to really make any meaningful data. But I absolutely agree with you looking at HSP and DNA repair is really important. And as I mentioned that most recently published paper does address that. Dr. Abdul Rafeh Naqash: Excellent! Do you think that there could be any confounders in this analysis that could have led to the upregulation of some of these pathways and may not necessarily have been the intraperitoneal chemotherapy? Could you think of some other reasons that this could have been a confounding factor? Or would it primarily be attributed to the intraperitoneal chemotherapy that you guys have looked at in this interesting paper? Dr. Thanh Dellinger: Yeah, it is a rather small cohort. So, I think that more data is required to potentially repeat this in the larger cohort. But what is interesting is that we did have paired analysis. So, we had matched peritoneal samples from the same patients looking before the HIPEC and after the HIPEC, which is very unique and hasn't really been done in the setting before. And while you couldn't necessarily repeat the same exact peritoneal tumor it was very close. And so, in the best setting, I think that we did have a good paired analysis. Dr. Abdul Rafeh Naqash: That was one of the very interesting aspects of this study that I very much appreciated, that you were able to get some of those paired biopsies and do the analyses on samples and look at all these markers. So, this was all excellent work and definitely intrigues the mind into what other ways one could use some of these findings to develop future combination-based approaches, whether it's the neoadjuvant or the adjuvant setting for patients with ovarian cancer. Are there any next steps as part of this project that you are excited about that you can share? Dr. Thanh Dellinger: Right! I'm definitely very excited about trying to build on this and essentially developing a much larger predictive study using hundreds of ovarian cancer HIPEC-treated tumors in collaboration with others. We have definitely developed a great community of HIPEC investigators who are very interested in developing somewhat of a predictive signature for ovarian cancer undergoing HIPEC. So, I’m very excited to hopefully be able to develop this consortium of HIPEC transcriptomic research. And so, I’m looking forward to collaborating with my co-investigators on that. Dr. Abdul Rafeh Naqash: It was definitely exciting to talk to you about your work. Now, I want to ask you about you as an investigator or as a researcher. How did you end up in this field? What was your background while you were pursuing science and medicine? How did you end up in this field and how are you mentoring the next generation? Dr. Thanh Dellinger: When I was a fellow at UCI, my mentor Robert Bristow introduced me to HIPEC and that has really stuck. As a GYN oncologist, it is hard to really do both chemo and be a good surgeon. And in many ways, I have really specialized in surgical oncology more than in medical oncology. And HIPEC is really a very nice blend of the two. It allows you to do clinical trials while still doing surgery and giving some chemotherapy. Really, it was for the introduction of my more recent mentor, Elena Rodriguez, who really introduced me to genomics and applying this to HIPEC samples that this all came about. And so, I think that there are a lot of opportunities for surgical oncologists who do not give chemo and may think that clinical research is not for them, but there are a lot of translational opportunities and clinical trial opportunities for those who don't give chemotherapy, but are surgical oncologists. Dr. Abdul Rafeh Naqash: Thank you so much. We are really excited for all the work that you're doing and will continue to do and hopefully, we'll see more of this evolve as time progresses. Dr. Thanh Dellinger: Thank you so much, Dr. Naqash. It was such a pleasure meeting you and talking to you. Dr. Abdul Rafeh Naqash: Same here. Thank you for listening to JCO Precision Oncology Conversations. To listen to more, visit asco.org/podcasts, or find them on Google Play Spotify and Apple podcasts. To stay up to date, be sure to follow and share JCO Precision Oncology content on Twitter. The Twitter handle is @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journals/PO.       The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  Guest Bio Dr. Thanh Dellinger, MD, is a gynecologic oncologist and physician-scientist who specializes in ovarian and uterine cancer. She is an expert in hyperthermic (HIPEC) and pressurized aerosolized intraperitoneal chemotherapy (PIPAC), and is the primary investigator of clinical and translational studies focusing on these therapies. She received her medical degree at University of California Irvine, where she also completed a gynecologic oncology fellowship. She is leading the first U.S. clinical trial in PIPAC (pressurized intraperitoneal aerosolized chemotherapy), a novel therapy using pressurized aerosolized chemotherapy for ovarian cancer. Her current research focuses on innovative therapies for ovarian cancer using intraoperative chemotherapy, and novel antibody and nanoparticle therapies.

"In this introductory episode of the JCO Precision Oncology Conversations podcast, host Dr. Abdul Rafeh Naqash, MD, from the University of Oklahoma Stephenson Cancer Center, speaks with JCO Precision Oncology’s founding Editor in Chief, Dr. James Ford, MD, of Stanford University. Dr. Naqash and Dr. Ford discuss how JCO Precision Oncology (JCO PO) started as a journal and how it has progressed since its launch in 2017. Dr. Ford dives into numerous JCO PO areas of interest, including liquid biopsy, genomics, biostatistics, and JCO PO-offered opportunities like the editorial fellowship program. GUEST BIO Dr. James Ford, MD, founding Editor in Chief of JCO Precision Oncology, received his MD degree from Yale University School of Medicine. He is currently Professor of Medicine (Oncology) and Genetics at Stanford University, and Director of the Stanford Cancer Genetics Clinic and the Cancer Genomics Program at the Stanford University Medical Center." TRANSCRIPT Dr. Abdul Rafeh Naqash: Welcome to ASCO’s JCO Precision Oncology Conversations, where we bring you the highlights and overview of precision oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant articles in JCO Precision Oncology. These articles can be accessed at ascopubs.org/Journal/PO. Hi, my name is Dr. Abdul Rafeh Naqash and you are listening to the JCO Precision Oncology Conversations podcast. Today, I will be talking with Dr. James Ford, about JCO Precision Oncology. Dr. Ford is the editor-in-chief for JCO Precision Oncology. It's great to have you here today, Dr. Ford. Dr. James Ford: Thanks, Rafeh, so much for hosting me and for running this podcast series. I think it's going to be great for the journal and for our audience. Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Ford. For the sake of our audience, could you introduce yourself with respect to your interest in medicine, oncology, and precision medicine specifically? Dr. James Ford: Sure! Well, I'm a physician-scientist, I trained at Stanford in medical oncology in genetics, and have spent my whole career here over 30 years. So, currently, I'm a professor of medicine in the division of oncology and genetics. I have focused my scholarly activities on cancer genetics and run a lab that's worked mostly in the field of DNA repair, and of course, this has evolved through the era of discovering and taking advantage of the fact that DNA damage response genes have turned out to be excellent targets for therapy in cancer. And so, this really combined my interest in the genetics of cancer and in targeting those biomarkers for therapy, which really has become the field of precision oncology. So, I run the Molecular Tumor Board here at Stanford and our Hereditary Cancer Genetics Program. So, that's really led to my interest in understanding both hereditary and somatic cancer genetics, and how we can use new targeted therapies to take advantage of understanding those biomarkers. Dr. Abdul Rafeh Naqash: Thank you so much for letting our audience know about all the work that you've done. You've definitely have been a leader in this field of cancer genomics and precision medicine. Talking about the intersection of where your interests met with starting JCO Precision Oncology, could you tell us since this is one of the sentinel episodes for our podcast series, could you elaborate on how you decided to start JCO Precision Oncology as a journal? And what was your vision of how you would shape the journal as it continued to progress over the subsequent years? Dr. James Ford: Sure! Well, the credit really goes to ASCO for the vision to start this journal about 6 or 7 years ago. ASCO decided to start adding some sister journals to its very successful flagship journal, the Journal of Clinical Oncology. And one of those, it was decided that an area, burgeoning area of interest that would be useful to our community is around precision oncology. And so, they launched a search release for a founding editor for what was named then JCO Precision Oncology, and I was fortunate enough to be chosen to be that founding editor. So, the journal started publishing just 5 years ago, right about now, this is our 5th anniversary, really, with the goal of focusing on research and reports, particularly around the clinical use of profiling tumors in individuals, as a way to advance therapies as a general scope. So, this was to add to the value that JCO, the parent journal, already has in thinking about this field that's taking advantage of n-of-1 study or of sometimes small series of studies because of the rarity of some of these genomic changes. So, scientific advances that we can take advantage of clinically, that perhaps don't fit into the traditional large phase three randomized study that reached the level of JCO, or some other journals. And I think we've seen since starting that this really has addressed an excellent niche in the field and allowed an area to publish really excellent research that doesn't always fit into some of the other journals. So, I guess the first step really then 5 years ago, 5-6 years ago, when we started this journal, was really with the truly excellent staff at ASCO and JCO, which helped launch this journal to put together our initial associate editors and board of editors, which I think truly has been one of the best parts of this whole general experience. We have the leaders in the younger generation of cancer therapy researchers and oncologists focused on precision oncology, all gathered together in this journal. And it's actually one of the most fun things about doing this is working with this great group. Of course, we've been adding to that over the years, but really, our initial core group has stayed with us. And together with the great staff and all the reviewers that have helped with this really started to put a focus on the sorts of papers and the kind of areas that it's really useful for us to publish them. Dr. Abdul Rafeh Naqash: Definitely, as you mentioned, Dr. Ford, the success of a journal, like JCO PO involves a large team that works behind the scene, including yourself and many others, as well as the reviewers who do their due diligence in helping us get the right content out there. So, you mentioned about your interest in DNA damage and you mentioned about your interest in cancer genomics. Based on how you have seen this whole field evolve, what is your understanding of how we can incorporate more and more precision medicine from an early therapeutics’ standpoint and also from a standard of care standpoint? Where do you see all that going from a testing standpoint, as well as a clinical application standpoint? Dr. James Ford: Well, I think one of the really interesting aspects of the tenure of this journal has been moving from what still is and largely was a research-based approach to cancer therapeutics using genomic and other types of molecular profiling of tumors to try to select therapies in the best way for individual patients to taking that to hopefully becoming standard of care, a better understanding how to apply that to certain individual patients, as well as have groups of patients, how to best use genomic biomarkers, and how to best encourage the development of new targeted cancer therapies for that type of use. So, I think an exciting aspect has been also profiling new clinical trial methods, and new biostatistical ways of looking at this kind of data that can't always be done in traditional large randomized trials – how to advance the field clinically, based on really the incredible technological underpinnings of the field. And so, that's required, I think, some novel and different ways of looking at and publishing data. So, of course, we are publishing original reports of excellent science, often based on preclinical findings, but always trying to find those that certainly have applications to the clinic and preferably have been tried in the clinic and shown advancements that we can take advantage of, but also, I think, importantly, has been publishing case reports, and other ways of highlighting smaller successes in the field that can lead to further larger clinical investigations. And as you know, it's hard to find journals and places where that can be published. Of course, we're quite restrictive in the kind of case reports we publish, we want to do those that have really high educational value or high predictive value for future clinical use. But I think precision oncology is one area of medicine, where looking at individual cases can be very revealing for future clinical benefit. Another thing we're doing and we founded was a series of what we call molecular tumor boards, and that really is just a description of a case or cases that are written from a Molecular Tumor Board group and describes the process of using very complicated genomic test reports and expertise from a number of physicians and scientists in interpreting that to best try to advance the therapy for a patient or group of patients. And I think that helps show to clinicians the value of a molecular tumor board or this kind of approach to analyzing both the lab-based genomic data and clinical experience and use of molecular pathology and pathologist experience, to synthesize these kinds of cases, and I think these have been very revealing as well and useful to the literature. Dr. Abdul Rafeh Naqash: Absolutely! I completely agree with you. And based on everything that you mentioned JCO Precision Oncology has definitely had a lot of significant and important submissions that have come out, and as our viewers might know, we have our most recent impact factor which is close to 5.5. So, congratulations to you Dr. Ford, and I guess the rest of the team that worked behind the scene for accomplishing this. Do you have any additional thoughts on anything that the listeners should know on the kind of content that you'd be interested in getting submissions for over the next 6 months to a year so that we have an understanding from the listeners of what kind of content is most acceptable like you mentioned earlier? Dr. James Ford: Sure! Well, as I said, we publish a number of types of articles, obviously, original scholarly reports and investigations, case reports, Molecular Tumor Board discussions, editorials, and commentaries on papers in our journal or others or areas in the field that are interesting. I think we have a healthy dialogue happening in the journal with discussions and responses from authors regarding papers we publish. This is an online journal and so we really try to publish in real-time and have an interactive forum for that. So, of course, anyone is welcome to submit ideas or commentaries on areas in the field that we think are important or should be advanced. So, we serve as a forum for that discussion as well as publishing traditional articles. I would say something that we've tried to focus on and we'll continue to do so is every year having one or several particular areas of interest that we're recruiting articles or commentaries, review articles about. Over the last couple of years, for example, we had a series very much focused on liquid biopsies and how the use of circulating tumor DNA is really revolutionizing precision oncology. We had a wonderful set of articles from our biostats editor, Ying Lu, on new biostatistical approaches to clinical trials in the area of precision oncology, thinking about the particular needs in that area. I think in the next year or so, we are launching a series right now on the use of genomic profiling, molecular profiling in earlier-stage cancer, and how to use that information for choosing or defining the correct adjuvant therapy in early cancers or using it before the metastatic setting, trying to move the process up. Is it appropriate? Where should it be used? How best to use that? It is quite an open area that I think we're going to make great advances on in the next few years. I think an area of great interest is how to think about combining targeted therapies in a precision oncology approach. How do you test preclinically? And then, of course, clinically, multiple agents together to take advantage of genomic biomarkers to advance therapies and how to test that in the clinic which is, of course, a great challenge. How to rationally pick those agents that we think might provide synergy. Of course, an area of great interest for everybody is thoughts around diversity, equity, and inclusion in clinical medicine in general, but for us, specifically, in best understanding genetics and genomics of diverse populations, how to be most inclusive in our clinical trial process, and testing of these approaches. And I think we've had a number of very thoughtful articles in this space and encourage more in this area as well. Dr. Abdul Rafeh Naqash: Thank you so much. Those are all amazing things that the journal is trying to implement. All those topics that you mentioned are extremely important and very interesting as far as precision medicine goes. Shifting gears a little bit. Dr. Ford, could you tell us about the JCO Precision Oncology Editorial Fellowship? As you know, I am a product of that editorial fellowship, where I was paired with Dr. Rodrigo Dienstmann, and it was an amazing experience. For the sake of our listeners, early career investigators, fellows, could you tell us a little bit about what this fellowship is and how that integrates into how we are trying to shape JCO Precision Oncology and the next generation of precision medicine specialists? Dr. James Ford: Sure! Well, I think this has been a really exciting and fun area for the journal. And in fact, for all the ASCO journals. ASCO instituted a fellowship program several years ago, in which mostly senior fellows, and junior faculty members in related fields, apply to work with one of the journals over the course of a year. And so, for the past several years, we've been fortunate enough to have two editorial fellows assigned to JCO PO that have worked with our associated editors throughout the process, really to learn how to not only review and manage manuscript submissions, but to best think about some of the issues we've been talking about like, how to show tape the direction of a journal, how to think about what are the most important areas in a field that we want to highlight, and hopefully can support. And it's been a great experience. We the editors have loved working with the fellows, really all of the fellows have gone on and continued in this field in academics across the country, and across the world, and a number have gone on to continue working with the journal like you, Rafeh. It's been terrific, as our audience knows. And you mentioned you were a fellow and now joined the journal as part of the editorial staff to run this whole social media program. And a number of our other fellows have joined the editorial board and continue to work with us and to really contribute to the field. So, I think that program has not only been really helpful to the folks who participated in it but to the field and to our journal in developing new talent and recruiting them to the field, so, very successful! We've even taken another step in the journals towards this and the board of editors themselves are serving as mentors to other folks and mostly fellows in medical oncology and related fields, simply to learn how to become better reviewers of papers, and go through that process with a little guidance from the editorial group. And of course, this really helps us to deepen our pool of expert reviewers and referees for journals. So, I think this process has been iterative and very beneficial to the journal. Dr. Abdul Rafeh Naqash: Definitely, I totally connected with that, Dr. Ford, as you mentioned, I was a JCO PO editorial fellow, worked with Dr. Dienstmann and yourself, and it led to subsequent interactions and roles within JCO PO, which has been amazing. I would definitely encourage all the listeners, whoever is interested in applying, if they fit the eligibility criteria to definitely apply, to the ASCO Editorial Fellowship, especially JCO Precision Oncology, given my bias towards the journal. It was amazing talking to you, Dr. Ford. Do you have any closing thoughts on what our listeners should be expecting as far as the journal or any other suggestions that you have for potential submissions out there, any other thoughts that you would like to share with our audience? Dr. James Ford: Well, thanks, Rafeh, for having me and for conducting this interview. It's been a pleasure to talk about the journal. I would conclude by saying that this has been a great experience for me, and I think our whole editorial group, to start and to develop this journal, and really see how both it can grow itself and how I think it contributes to the growth of the field and serve as a nidus for our field in exchanging information and developing new ideas and thoughts that can benefit our patients. So, I just would like to thank all of our group, our reviewers, and certainly the authors and folks that have submitted articles and ideas to the journal. I think it's making a difference. And I think the field, in general, is at a very exciting point and is making a difference for patient care, and will continue to do so with new technologies and new therapies and new ways to incorporate those. So, I think we've shown that this has been a useful journal for the field and I think I'm very excited about where things are going to go. Dr. Abdul Rafeh Naqash: Thank you so much. I completely echo your thoughts. I would like to encourage the listeners to stay tuned for subsequent author conversations, and other interactive conversations that we'll have on our JCO Precision Oncology Conversations podcast, subsequently. Thank you so much for joining us today, Dr. Ford. Dr. James Ford: Thank you. Dr. Abdul Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one, at asco.org/podcasts, or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter. The Twitter handle is @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/Journal/PO.   The purpose of this podcast is to educate and 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. James Ford’s institution receives research funding from Genentech, AstraZeneca, Puma Biotechnology, Pfizer, Merus, Bayer, and Incyte.