JCO PO author Dr. Mohamed Salem shares insights into his JCO PO article, “Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers” and the article’s findings of a large-scale, pan-cancer genomic characterization of KRASG12C. Host Dr. Rafeh Naqash and Dr. Salem discuss KRASG12C mutation, KRASG12C -mutated tumors and comutation with STK11 and KEAP1. Click here to read the article!   TRANSCRIPT

Dr. Abdul Rafeh Naqash:  Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology and assistant professor of Medical Oncology at the OU Stephenson Cancer Center. 

Today I'm thrilled to be joined by Dr. Mohamed Salem, Gastrointestinal Medical Oncologist, and Research Director at the Levine Cancer Institute in Charlotte, North Carolina. Dr. Salem is the lead author of the JCO Precision Oncology article ‘Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers’. 

Our guest’s disclosures will be linked in the transcript. 

Dr. Salem, welcome to our podcast, and thank you for joining us today.

Dr. Mohamed Salem: Thank you for having me. A pleasure and honor.

Dr. Abdul Rafeh Naqash: For the sake of this podcast, we'll be referring to each other using our first names. So thank you for coming on to our podcast and discussing this very interesting paper. And one of the reasons why we decided to incorporate this is because, as you very well know, KRAS is one of the most common altered genes in cancer, and I'm pretty confident and sure that oncologists, whether it's academic oncologists or community oncologists, have treated patients in different settings having tumors that harbor KRAS alterations. So give us a little bit of a background on where KRAS alterations stand currently and where is drug development in the space of KRAS to give our listeners some idea of why we're interested in this gene.

Dr. Mohamed Salem: Sure, thanks again for having me. And as you mentioned, KRAS mutation happens to be, I think, by far the most common oncogenic mutation we see in oncology and solid tumors. The problem with KRAS is that, for a long, long time, there was very much nothing we could do about it; it was, in fact, called an undruggable target. Until recently, we started to realize this might not be true, and, in fact, we start to see successful efforts trying to target KRAS mutation. Currently, there are several KRAS inhibitors. I think it started with G12C. I personally don't think there was anything specific about G12C, but it just happened to be one of the first targets that we were able to approach. And the initial result from using anti-G12C therapy that was published in the New England Journal of Medicine, I think, a year ago now, showed this is feasible and perhaps effective.

Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Salem, for that explanation. And being a Phase I trialist, I personally have seen a lot of exciting combination-based approaches in the setting of KRAS-altered tumors, especially KRASG12C. 

Now, specifically delving into your paper, given the extensive length and breadth of data that you've covered here, could you tell us a little bit about why you decided to use KRAS as an interesting topic for your study and the kind of data set that you chose to explore this question? 

Dr. Mohamed Salem: What happened once we started to realize how important it is to figure out which KRAS mutation we're dealing with because, at least in colorectal cancer, it's a very common mutation, almost like 40-50% of patients with colorectal cancer tumors carry KRAS mutation. Until very recently, we really didn't pay close attention to which variant it is. Is it KRAS G12D, 13, or G12C? And so on and so forth. And the reason we didn't really pay much attention to that is because there was nothing to do about it; whether the patient has this or that variant was really nothing therapeutically wise it really didn't have an impact. But once we started to realize now there is a therapeutic option and, in fact, now there is a change in the way we think about KRAS mutation, there is a proof of concept that we actually can target KRAS mutation, we started to pay closer attention to this. 

And I think this was a paradigm shift in our thinking. So for patients who have KRAS mutation, now we have data showing that KRASG12C is something we can target, whether with single agent or with combination therapy. But it was a new era for us because most of us realized it's not going to stop there. It’s not going to be just G12C; I think G12C is the tip of the iceberg, and likely the science is going to go forward, try to target the other variants. So one of the obvious questions was what are the other variants and how commonly those exist, and which tumor types also carry those variants. Because as we were talking before the recording for Phase I, now it is not like one approach fits all; it started to kind of like focus on either molecularly driven or disease-type approaches. And it was very important for us to try to figure out, okay, which tumor type carries the most KRAS variants and, within that tumor, which variants are the most common. And this is what we're trying to answer in this paper. 

Dr. Abdul Rafeh Naqash: Thank you so much, Mohamed. I looked at your data set that you had access to, very large data set of around 79,000 tumor samples and close to 14,000 KRAS mutated tumors. Could you tell us a little more about this data set and how you started with looking at the distribution of KRAS across different tumors, and what were the kind of interesting results that you came across as far as KRAS distribution is concerned?

Dr. Mohamed Salem: It's very obvious to all of us now that the field is moving from one size fits all to a targeted approach or treatment target approach. And this is very important and very interesting because usually, when we do that, we achieve better outcomes and lesser toxicity. But the problem that comes with this is that none of us, as a single, even two centers, will have enough data to ask and answer questions. And when you are talking about something like MSI-high or BRAF or KRAS, usually it becomes very challenging for one single institution, doesn't matter how big they are, to try to answer either prevalent or therapeutic approaches. Because of that, most of us now start to understand that cooperation is very important across centers and also across nations. 

So, like as you see here in this paper, there was a global cooperation between investigators in the U.S. and in Europe and Austria, and other countries. And what we did as a group we worked with one of the third-party profiling companies. Our group tried to answer what is the prevalence, just a very simple question, what is the prevalence of KRAS mutation, and what is the prevalence of each variant type in each tumor? And none of us could have answered that question on their own. Because of that, we actually collaborated with one of the third-party companies that do next-generation sequencing for tumors, and we were able to collaborate with them to have access to that database and answer some of those questions. 

Dr. Abdul Rafeh Naqash: Excellent. As everybody knows, NGS is a standard of care testing that oncologists do, especially for advanced settings, to identify driver alterations or therapeutic interventions that may be relevant for patients. So in this data set, it seems you had access to NGS data, tumor mutational burden, and PD-L1 data for these tumor types. Could you tell us about the differences in the distribution for KRAS and the KRAS subtypes that you identified in this data set?

Dr. Mohamed Salem: Sure. So, as you mentioned, we looked actually at almost 79,000 tumor samples that underwent next-generation sequencing by our collaborator. And it appears that about 17% of the tumors or so had some kind of KRAS mutation. And then, after that, we start to see G12C when we start looking at each variant. G12C were about 11%, 12%, and about 88% of the remaining KRAS mutant tumors harbored some different kind of KRAS mutation. 

The next question was, in general, in all tumors, what was the most common KRAS variant seen? I think it mimicked what was already out there. It appears that G12D happened to be perhaps the most frequent mutation seen in KRAS mutation tumors, followed by G12V, followed by G12C, and then G12/13, and then others. What was very interesting, actually, an observation we saw, is that we were able to realize the distribution of KRAS variants varies according to the tumor subtype. So, for example, in pancreatic cancer, we could see patients who had G12R KRAS mutation variants. This was not seen commonly in other tumors. And the reason that's important is because maybe that will be something in pancreatic cancer tumors that will be worth looking at and do therapeutic approach there. But also, I'm sure you're already dealing with this in your clinic quite often. It was interesting, obviously, that non-small cell lung cancer was the most common organ that actually carries G12C, followed by colorectal cancer; followed by a very interesting actual observation that was very interesting for us to see was in appendiceal cancer. As you know, appendiceal cancer is not a common disease; it's a relatively rare disease. And we were surprised to see some of them actually have G12C mutation. And again, the reason that's important is that it just opens the door for possible therapeutic options and in context of clinical trials.

Dr. Abdul Rafeh Naqash: Excellent. Definitely, the advantage of having such a rich data set like you did enabled you to look into some of these unique distributions across rare tumors, which makes it very interesting. 

Now, one thing that I realized in the paper is that these tumors of unknown origin, where you identified or your group identified that they had a certain percentage of KRAS alterations, suggesting maybe their tumor of origin is perhaps lung or upper diaphragm, which could have therapeutic implications. Could you tell us a little more about this?

Dr. Mohamed Salem: Yeah, this was another very interesting observation we saw because it is not uncommon for us in the clinic, we get like a cancer biopsy, but we cannot tell where it's coming from. And there are multiple ongoing efforts to try to identify that for the obvious reasons. But it was very interesting when we looked at those groups that when you had cancer adenocarcinoma but of no identified origin, it was the fourth common tumor that we see G12C. I think if you can just make the assumption - I don't think we have proved that - but since lung cancer was the most common tumor that exhibited G12C mutation, and now we have tumors of unknown origin also, many of them exhibit G12C mutation, we thought this could be a lung primary. As you know, there are also now a few platforms trying to identify the tumor origin based on the agent sequencing, but we didn't try to associate it with that.

Dr. Abdul Rafeh Naqash: Thank you for that explanation. Now, one of the other things I observed is you tried to delve into smoking status, very interestingly, and how that correlated with KRAS alterations. And as we know, lung cancer, obviously there is a strong predilection in patients who are smokers, but irrespective of smoking, there can be other alterations that drive lung cancer. But interestingly, in your paper, you identified a unique correlation between smoking and G12C and also found out something on those lines in colorectal cancer, which, to my understanding, has not been described before. What is your understanding of why that happens? What could be the mutational events that lead to something like that, and how could that be potentially therapeutically exploited?

Dr. Mohamed Salem: I think this was one of the very interesting findings we observed. And you are right; just because the nature of lung cancer, we know many of patients are either active smokers or former smokers. So it was not a surprise for us to see that there is some kind of association with smoking status and lung cancer. But to your point, what was really surprising and, in a way, interesting for us to see, actually, that association for patients with colorectal cancer. Smoking actually happens to be one of the risk factors, like in colon cancer, but obviously not as high as lung cancer. But when we looked at the data, demographic, and clinical features, it was obvious actually that current smoking status, whether a current smoker or prior smoker, had an association with G12C. And also, with gender as well, females tend to have more G12C, or G12C mutation was more likely to be seen in females than males. So the fact that we were able to identify the smoking status and gender as more likely to harbor G12C mutation was interesting. 

I have to tell you, the reviewer, when we submitted the paper for review, the reviewer came back and asked us, did this happen just because you had too many lung cancer, and most lung cancer patients smoke, that's why you're seeing that association? And we went back and looked at the data again and spoke with our biostat team in the study, and we were able to actually run the analysis and show that, no, it is not just because of the enrichment; it's actually a real association between the smoking status and G12C. It's very interesting to see, at least in colorectal cancer, it's following the same trend in lung cancer.

Dr. Abdul Rafeh Naqash: Right. And one of the other things I remember when I was reading through your paper and smoking status, I remembered this paper that was published in Science Magazine 2016, looking at how mutational burden changes in patients that have a history of smoking. But when you connect the dots here, interestingly, it seems like, especially in lung cancer, from what you guys have described here, is that the smoking status impacts what kind of KRAS alteration is present. But at the same time, you didn't see a tumor mutational burden that was significantly higher in G12C, mutated non-small cell lung cancer, where you would expect a lot of these G12Cs to be related to smoking. But on the other hand, the tumor mutational burden was not necessarily increased. And I understand you may not have an explanation for that through the data that you've published on, but that was kind of an interesting observation that I had. I don't know if you have any specific comments on that.

Dr. Mohamed Salem: No, it's absolutely correct. What we thought is that we should see that because the obvious rationale is just cited, but it wasn't. And until today, we're actually trying to figure out why the disconnect because you have people who smoke usually you expect like PD-L1 is positive, you expect higher tumor burden, but it didn't show at least a statistically significant correlation. 

Dr. Abdul Rafeh Naqash: Thank you. And I guess it's notable to mention that you did have some interesting correlations for tumor mutational burden overall, and with PD-L1. Could you tell us about that for different KRAS genetic alterations? 

Dr. Mohamed Salem: There were few papers published before by our colleagues trying also to understand the correlation between G12C mutation and immunostatus or immune microenvironment and some biomarkers. And I think, at least to my understanding, there was not one consensus. I think it was different findings to some degree. So, in general, when we actually looked at the entire cohort, regardless of the tumor type, it appears that tumors that carry G12C mutation also happened to have higher PD-L1 expression. What was very interesting was that once we started to look at different tumor types, this was not seen across all tumors. So some tumors did actually carry that, and some other tumor types didn't show that correlation. And to be honest with you, I'm still, until today, I'm not sure why. Is this just a function of number, or actually there is more tumor biology that reflects that? I have to say my own feeling, and that's something we need to study further, is that I think it is tumor biology. One thing was also very interesting to us from the clinical side. You have G12C mutation in lung, and you have G12C mutation in colorectal, and in the New England Phase I study, you could see very clearly that targeted G12C is more effective in the lung compared to colorectal. It's the same target, the same drug, yet the response is different once you start to have two different tumor types. So that just got me to think there must be something with the tumor type and microenvironment of the tumor and also associated co-mutations and other factors that impact that. 

Dr. Abdul Rafeh Naqash: I couldn't agree with you more, and I totally have seen that in some of the work that has been published or data that I've been part of where different tumor biology, the tumor microenvironments, even sites of metastasis make a difference in how a certain mutation behaves. So definitely something that needs further validation with perhaps proteomic and transcriptomic data to understand functional characterization of the downstream consequences for some of these mutations. And you pointed out co-mutation status. That's an ever-emerging question for some of the potentially druggable alterations, whether combination approaches targeting some other co-occurring common co-mutation would have more benefit. Could you tell us about some of the unique, interesting commutations that you identified in your cohort that were more common in certain KRAS subtypes?

Dr. Mohamed Salem: Sure. I think that's also something we try to look at for the reason I just mentioned. We know that tumor origin and tumor type influence response and sensitivity to therapy. I think the best example we have, at least in colorectal cancer, is the BRAF mutation. When we saw the BRAF inhibitor having very nice response rate and control of BRAF mutant melanoma in colorectal cancer, we saw that it’s going to be the same thing, the same drug, the same target, same thing’s going to happen. And obviously, it was not the case. And this was a lesson for all of us to understand. Even if it is the same target, even if it's the same drug, tumor origin matters, and that’s likely because of the associated co-mutations that will influence the pathway of the tumor and perhaps either the sensitivity to the drug or maybe resistance to the drug. 

So it was very important for us to look also at the associated co-mutations. And I think one of the KEAP1, and perhaps you will comment on this more than me, but the KEAP1 gene was likely to be mutated in those tumors who have G12C mutation than others. Another one was STK11. And there were a few other ones, it depends on which tumor type, but KEAP1 was a very interesting finding for us too. Because as you're aware, it's important, at least in lung cancer, and maybe will impact therapeutic approach too.

Dr. Abdul Rafeh Naqash: You're definitely right. It is important in lung cancer, and there's data that has shown both the STK11 and KEAP1 tumors have inferior outcomes to checkpoint inhibitors and are partly involved in metabolic reprogramming of the tumors. So there's definitely emerging targets that are trying to see if combination approaches in STK11 mutant lung cancer will demonstrate some level of benefit. But I think the co-mutation status would potentially have some sort of impact. But again, functional studies that help us understand what are the downstream consequences of one mutation versus another need to be further performed to get a better understanding of this space.  

But I think this is definitely interesting work and very interesting results. Hopefully, our listeners will feel the same and maybe even try to go through the paper to understand some of the other additional results that you have published as part of this extensive paper. 

We thank you on behalf of JCO Precision Oncology for submitting your work to JCO Precision Oncology, and hopefully, you'll consider us for further subsequent work in this space. Thank you so much for being with us today.

Dr. Mohamed Salem:  No, thank you for having me, and actually, on behalf of my co-authors, I also wanted to thank JCO Precision Oncology for their interest in our paper. And, of course, for the reviewers, because there was no doubt they actually made our paper a much better one. So thank you for having me today, thank you for the entire team.

Dr. Abdul Rafeh Naqash:  Reviewers definitely remain the people hidden behind the scenes who help in getting work refined and eventually published. So thank you again.

And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or a review, and be sure to subscribe, so you never miss an episode. You can find all ASCO shows at asco.org/podcasts  

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.

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Guest Bio

Mohamed E. Salem, MD, is Research Director, Associate Professor of Medicine, and Gastrointestinal Medical Oncologist in the Department of Solid Tumor Oncology at the Levine Cancer Institute. 

Guest Disclosures (See also: Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers)

Mohamed Salem:

Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca, Merck 

Speakers' Bureau: Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck, Pfizer 

JCO PO authors Dr. Edward Esplin and Professor Heather Hampel share insights into their JCO PO commentary, “Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer” and discuss practical implications of testing for patients, geneticists, and clinicians. Host Dr. Rafeh Naqash, Dr. Esplin, and Professor Hampel discuss standard of care guidelines, insurance coverage, and benefits of testing. Click here to read the article!

TRANSCRIPT

Dr. Abdul Rafeh Naqash: Welcome to ASCO's JCO Precision Oncology Conversations, where we bring you the highlights and overview of Precision Oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant JCO PO articles. These articles can be accessed at ascopubs.org/journal/po.

Hello and welcome. My name is Dr. Abdul Rafeh Naqash. I'm a medical oncologist and assistant professor at the OU Health Stephenson Cancer Center. I'm also the social media editor for JCO Precision Oncology, and you're listening to JCO Precision Oncology Conversations podcast. 

Today I am thrilled to be talking with Dr. Edward Esplin and Professor Heather Hampel about their recent paper, ‘Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers’. Heather Hampel is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Dr. Edward Esplin is a clinical geneticist and also the Head of Clinical Trials at Invitae in San Francisco, California. 

For the purpose of this podcast, we'll be referring to each other using our first names. So welcome both Heather and Ed. Thank you for joining us today.

 Dr. Edward Esplin: Thank you, Rafeh.

 Professor Heather Hampel: Thanks for having us.

 Dr. Abdul Rafeh Naqash: Well, first of all, I'd like to start by discussing some of the context behind this very interesting commentary. For the sake of our listeners, this is one of our first commentaries that we're doing a podcast on because this is very clinically relevant, especially for patients with cancer and without cancer, as I was reading through this commentary. So could you tell us, Ed, what prompted you to start this commentary, and what was the context of and the importance behind why something like this would make a difference in the clinical care of patients with cancer?

 Dr. Edward Esplin: Yes, I'd be glad to. I think that we have seen over the past couple of years an ever-growing application and opportunity for application of precision therapies in patients with cancer of various kinds. And there has been with that a growing amount of evidence connecting germline genetic variants of a pathogenic nature with various types of cancer, breast cancer being one of the ones that is the most prominent. And as we've seen this evidence accrue in cancer types such as breast, which has probably got the longest history of a connection to germline genetics, but also accruing in other cancer types such as pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, it became clearer and clearer that there is evidence to support a broader application of germline genetic testing than is currently the standard of practice. In part driven by the desire for access to these precision therapies that are driven in part by patients' germline genetic makeup and for the opportunity that germline genetic testing results have for affording patients potential access to clinical treatment trials - so the cutting edge of what is driving some of these treatment opportunities - and reviewing the amazing amount of work that has been done by a number of people across the country and across the world to support these opportunities and support this becoming more and more the standard of care really motivated us to do this project together, and we've been fortunate to have been involved in a number of the studies that we review in this commentary.

 Dr. Abdul Rafeh Naqash: Thank you so much for that explanation, Ed. So, Heather, you, and both Ed, have obviously led and been part of a lot of work in this space and have developed guidelines in this space. For the sake of our listeners, whether they are clinicians or patient advocates, what are the current guidelines behind germline testing for patients with cancer and patients without cancer?

 Professor Heather Hampel: That's a really good question, and that's a lot of what's driving it for me, just from a clinical perspective.

 So currently, we mainly use the NCCN guidelines in the US for deciding when a patient is appropriate for germline genetic testing. And they only recommend or suggest considering germline genetic testing for all cases of three particular cancers: all cases of ovarian, pancreatic, and, most recently, this summer, all cases of colorectal cancer, they've said you could consider offering germline testing to. The other one that has a recommendation is prostate cancer, but that's restricted to patients with metastatic or advanced prostate cancer, so it's not all prostate cancers. When you look at the guidelines, you ask yourself, how did they decide that? Was it based on the prevalence of finding a germline mutation? Because if it was, there are several other cancers where germline mutations are just as prevalent, but that recommendation has not been made.

 And what is happening really on the front lines is that some patients are not having access to genetic testing because we have very complex criteria requiring ages of diagnosis, certain tumor markers, particular family history constellations that make the criteria difficult to use for frontline primary care physicians and patients deciding who needs referred, and do I need to see cancer genetics? And how much more straightforward would it be if we just said everybody with cancer needs gene testing? At this point, we pulled the data together for this commentary. We feel like the odds of testing positive are high enough in every single solid tumor to support a change in the recommendations like that.

 Dr. Abdul Rafeh Naqash: Thank you. And from the data that you highlight in this commentary, apart from the tumors that you mentioned, Heather, that have recommendations for germline testing, what other tumors would you try to incorporate this in subsequently as a first, second, third approach, maybe if you can't get to all tumors at the same time?

 Dr. Edward Esplin: I would say that one of the ones that we would highlight, I think, also, is breast cancer, right? That's one that there's a clear link. And as Heather appropriately noted, while a universal guideline per se has not been established by the NCCN for breast cancer, about three years ago now, based on a publication in Journal of Clinical Oncology, there was the observation that the guidelines that existed at that time did not find a significantly increased number of pathogenic germline findings in patients who met the criteria as they existed at that time compared to those patients who did not meet the criteria. And based in part upon that data, the American Society of Breast Surgeons came out with guidelines that recommended, indeed, the time is now for universal germline genetic testing for all patients who have been diagnosed with breast cancer. So I think that one's another one that there's a great deal of opportunity for that to be implemented, consistent with what Heather has already noted.

 And I think there is also data that's been presented at ASCO here very recently, suggesting that similar evidence supports testing not just for metastatic prostate cancer but possibly for a broader collection of prostate cancer patients as well, perhaps all of them with a similar finding where in a prospective observational cohort of unselected patients with prostate cancer. Again, when you applied the current guidelines for testing, there was no statistically significant difference in the number of actionable pathogenic germline findings in patients who met the current criteria compared to those who do not. Which unfortunately suggests that all those patients who are being excluded when we adhere to these guidelines are not able to access the genetic information that could be crucial to their treatment. And it's just because they're not being considered, even though there is a significant fraction of those individuals who do have germline genetic information that could impact their care and possibly the preventive care of their at-risk family members as well.

 Professor Heather Hampel: And, Ed, let me add a study I did with you and your team on endometrial cancer. So the truth is, Rafeh, we don't want to pick. We want all solid tumor patients to get germline genetic testing through a multigene panel. But I think if we did have to pick, I would also add endometrial. We did a study of nearly 1000 unselected endometrial cancer patients in the state of Ohio and found just over 10% had a pathogenic variant in a cancer susceptibility gene. And you really could not predict, based on personal or family history factors, who was going to test positive.

 Dr. Abdul Rafeh Naqash: And that was definitely something interesting that I caught in this commentary as I was going through it. One of the sentences that was definitely interesting for me was where you mentioned that these guidelines should include risk factors beyond family history and just testing for genes beyond BRCA1 and BRCA2, which are commonly identified entities associated with germline testing, that prompt germline testing.

 But one of the other things is the financial aspect of it, which you have highlighted in your commentary. So, I wanted to briefly touch on that and understand what are the policies. It seems like different coverage policies cover different aspects of germline testing, so that's number one. Could you comment on that? And number two, a few years back, there has been an effort you might have heard of related to TMB or Tumor Mutational Burden Harmonization. Could there be some sort of harmonization to identify what are the most important testing genes that are or should be covered by some of these insurance policies? And could you highlight some of the aspects around that?

 Dr. Edward Esplin: That's an excellent point. And what we have found has been the course this usually proceeds through is when the guidelines have established what the criteria should be for testing, then, over a certain period of time, naturally, the various insurance payers will then incorporate this into their medical policies. And, for better or for worse, this takes time. I think, in the opinion of most, the time that it takes is unfortunately prolonged for reasons that I don't personally understand.

 But noting a bright spot, I'll highlight that UnitedHealthcare has actually taken the step of instituting a very patient-first medical policy. They did this back in 2020, where they recommend and consider medically necessary standard of care germline genetic testing for any patient who has a diagnosis of any cancer that is associated with Lynch syndrome. So meaning that any patient covered by their policy who has a personal diagnosis of colon cancer, endometrial  cancer, the long list of cancers associated with Lynch syndrome, qualifies for germline genetic testing. And that's covered as part of the standard of care, which is a great move in the right direction for this, the largest private commercial insurance provider in the United States.

 Now, do we need to see more of that? We absolutely do, because, as Heather’s already noted, there is an access issue, and there is a disparity issue for those individuals that don't meet the criteria of their own insurance policies, medical policy, they don't have access. And that requires them, if they choose, to get germline genetic testing, to pay an out-of-pocket cost of $250 or more, depending. And that may be something that is simply not accessible to individuals. And so there's a tremendous amount of effort that needs to be done to incorporate the guidelines as they currently exist into medical policy.

 And I think, to your point as well, the discrepancies between various medical policies is certainly a challenge, and I don't have a good answer for how to address that. But it is frustrating, to say the least, that any clinician has to guess what their own particular patient that's sitting in front of them right now has in terms of medical policy coverage for germline genetic testing. And then that should in any way cause them to have to second guess ‘How am I going to get the standard of care to this patient?’ One of the other challenges that that potentially raises is, as we noted in our commentary as well, unfortunately, even for those cancer types where there is an established recommendation for universal germline testing, there is nowhere near the implementation of that that there ought to be.

 For ovarian cancer, I think it's in the neighborhood of 30% of patients with ovarian cancer are getting this testing. For breast cancer, I think it's 25%. I can't remember if this was cited in this paper or not, but in a recent publication that we did with collaborators from Optum Health, we found that 5% or less of colorectal cancer patients who fell under this very progressive UnitedHealthcare policy were getting testing where everyone qualified for it under the medical policy. And so it really raises concerns about these missed opportunities in the setting of not effectively implementing germline genetic testing even when it is already recommended as the standard of care for the guidelines as they currently exist and not to be available to many more patients with various cancer types, as we've already noted.

 Dr. Abdul Rafeh Naqash: Thanks for highlighting some of those very extremely important points. And, to your point, it's not implemented as much as it should.

 Heather, have you, or others in this field, tried to understand what are those exact barriers that maybe me, as a clinician who sees at least patients with cancer, should know, or any other community-based oncology practice physician, should know that these are patients where testing is important and will have clinical implications. But what would be the barriers that potentially do not result in as much of a higher implementation of this testing than one would expect?

 Professor Heather Hampel: Well, you may be surprised to hear this coming from a genetic counselor, but I've become convinced over the years that requiring pretest genetic counseling is one of the biggest barriers that actually keeps patients from getting genetic testing when it's appropriate. And not that we're trying to be, but just that we have long wait times. Patients may have a lot of appointments because of a new cancer diagnosis, and they’re overwhelmed. It just adds one more thing that's a little difficult.

 And so, I really am interested in flipping the paradigm, and this is what we're doing at City of Hope now, currently, which is offering a precision medicine or a mainstreaming approach, where every single patient at the institution is offered germline genetic testing regardless of age, regardless of family history, regardless of tumor type. And then, believe it or not, this actually supports hiring more genetic counselors because you're dealing then with thousands of results that need to be hand-reviewed, and all positives, of course, get invited in for full post-test genetic counseling. And that saves that resource, that scarce resource of genetic counseling for the people who need it the most, the people who tested positive, whose family members need testing, who need to implement all the management that comes with testing positive.

 I find those sessions much more rewarding because I can be much more helpful for the patient and the family, and our negative patients, or patients with variants of uncertain significance, get templated letters. We've got a team of genetic counseling assistants that are helping get those out because, of course, that's the majority of patients. But if they have questions or concerns or a strong family history, they can, of course, come in for post-test genetic counseling, too. But I think we're on the cusp of switching the paradigm of how cancer genetics is delivered, and that's really the only way to get it at scale to the large number of patients who actually need it.

 Dr. Abdul Rafeh Naqash: Thank you. And, to that point, I wanted to say that, as cancer care becomes more and more multidisciplinary, it's right there in front of us that, I think, genetic counselors or clinical geneticists need to be part of these multidisciplinary teams, whether it's through molecular tumor boards or outside of molecular tumor boards. But I think that's where the gap is, at least from what I see on my end. And that's where communication gaps create issues. I recently had at least two patients in their 30s and 40s, one with a PALB2 and another with the CHEK2 alteration and initially identified on liquid biopsy, actually, and that prompted me to check for germline testing. And lo and behold, both were positive. And that resulted, as Ed, you mentioned, cascade testing and eligibility for trials, both ended up on different DNA damage-based trials. So, definitely a lot of clinical implications.

 In your practice, when you were on the academic side, Ed, did you have instances where you definitely could see a lot of difference with respect to clinical management of a patient when such an event was identified when a pathogenic germline alteration was identified? And could you give us a few examples so that listeners maybe could try to understand better how some of these things can have significant clinical implications?

 Dr. Edward Esplin: Well, I practiced when I was at Stanford in perhaps a little bit of a skewed environment, skewed to the better, where much of my interaction with patients with cancer and with molecular tumor board as well was in the setting of the Stanford Cancer Genetics Clinic. And so that's certainly highly enriched for well-informed individuals, very genetic-savvy medical oncologists. Obviously, the genetic counselors were the foundation there, and me, as a clinical geneticist, was actively involved in such a way that, yes, I think it made a lot of difference from the standpoint of patients with cancer, knowing what all of their options were. And in a number of cases also, the first thing, I think that at least from my standpoint, thinking about genetics a lot that many patients want to know is: why do I have this cancer? Did I do something to cause this? What's the underlying reason for this? And being able to either provide them reassurance that this was not something that was genetic, that this was not something that anyone in their family needed to be particularly concerned about, or that there was anything further that needed to be done about that. Versus the alternative, each of those answers was incredibly valuable to the patient and the patient's family for the reasons I think that you already alluded to.

 If there is a genetic cause, then there are known actions that can be taken, whether it's an approved precision therapy or a clinical treatment trial. But then I think equally important, especially in those families where there was a known history of various cancers, and this is the first person who had any genetics done, then being able to share with that patient and with the patient's family that they're going through an excruciating disease course, but there is an opportunity for some of that to be mitigated, some of that risk to be mitigated in their family members; I think brought a certain amount of, I don't know if reassurance is the right word, but it was valuable and was greatly appreciated by those individuals.

 One situation that I recall actually was a patient that– I can't remember what her age was, she was probably in her 40s or 50s, but she had developed a colorectal cancer. She had had appropriate germline genetic testing performed and had had a variant identified; I believe it was one of the Lynch syndrome genes, I’m not recalling exactly right now. But while she was undergoing her treatment, I mean, to her credit, she went right away to her family in particular, to, it happened to be her son who was one that got tested, and he was, I think, late teens, maybe early 20s, he had tested positive for the same thing. She made sure that he went in, he got his colonoscopy right away, and lo and behold, right, they find an advanced polyp in this 20-year-old kid that, had that not been done, that would have been identified in just a very tragic way. And yet, as a result of her taking charge and having the information that she needed to take charge for herself and for her family members, a cancer was literally prevented. And that individual's life was prolonged, if not saved, because of that action being taken on behalf of that individual who had the information they needed to do that.

 Professor Heather Hampel: Yeah, I would just add I was talking to some of the docs at one of our network sites recently and talking about all of these benefits, which are 100% clear and really also hitting on the targeted therapy benefit quite a bit. And they reminded me of another benefit which we all often forget, and that is even surgical decision-making. So if we got this done early enough, there are certainly patients who have BRCA mutations who might elect to have bilateral mastectomies instead of a unilateral mastectomy or a lumpectomy and patients with Lynch syndrome who might elect to have a subtotal colectomy instead of a segmental resection. And again, this is where not only do we need to be offering this to everybody, but we need to be offering it early at the time of biopsy-proven cancer in some cases, where it could actually affect even their surgery.

 Dr. Abdul Rafeh Naqash: Absolutely. And thanks, Ed, for highlighting some of those interesting and important examples.

 Now, Heather, when we talk about 80%-85% of the places in the country, at least in the US, they may or may not likely have access to experts like yourself or elaborate, broad, experienced teams that you guys have been part of. So on the oncology side, in a clinic, we get a patient who gets next-generation sequencing done, a 500-600 gene panel where we may or may not have a geneticist, or the wait times are longer. What is your suggestion for individuals, both clinicians and for patients, in that setup? What are the things that one should think of to mitigate some of those delays in that setup where you may not get a geneticist to see that patient or a counselor to see that patient immediately? Looking at that sequencing panel, what couple of things would you think of should prompt a physician to refer a patient to a genetic counselor if it's on a need basis and not available for everybody?

 Professor Heather Hampel: And you're talking about a tumor panel that's coming back.

 Dr. Abdul Rafeh Naqash: Correct. I'm talking about NGS 600 gene panel because that's what gets done clinically every day, all day, when you're talking about patients with cancer. What are the few things that one should look out for?

 Professor Heather Hampel: So there's some nice ESMO guidelines around this, and that's what we were using. Where I used to work, I would actually hand-review the tumor test that came in and kind of send an email to the docs when I said, "Hey, this may be germline. I think this patient needs a referral." Some of the labs are now calling those out themselves, which is nice. So if they're calling it out themselves, definitely pay attention to those boxes that say "Potential germline finding," and make sure you refer any patients with anything there. If you're using a lab that's not calling it out, certainly some of the rules—there's already guidelines - anyone with a BRCA1 or BRCA2 mutation found in their tumor should be referred, regardless of what kind of tumor they have. So that one's easy.

 Some of the things I like to look at is what was the variant allele fraction. If it's around 50% or anything over 35%, you start thinking maybe that's germline, that's a nice red flag. Cautionary tales - every colon tumor has an APC mutation in it, so we don't want those referred to genetics. Most of them don't have familial adenomatous polyposis. So only send a patient with an APC mutation in their colon tumor if they– in the setting of polyposis. Same goes for TP53. You're going to find that in almost every tumor, and very few of them are going to have Li-Fraumeni Syndrome.

 So in the ESMO guidelines, I believe in addition to having a TP53 and an APC around a VAF of over 35%, they want to see it in a young age tumor so that you have an indication that you might be dealing actually with Li-Fraumeni syndrome. The Lynch syndrome genes, I think the common genes, if you see a mutation in them, go ahead and refer. Consider the variant allele fraction and then beware of genes that are commonly mutated in all cancers because most of those won't be hereditary, and genetics can't handle seeing every single patient who has a TP53 mutation in their tumor. So we need to see an early age or some strong family history in those cases.

 The other thing just to point out, because there are long waits and not everybody has a genetic counselor or geneticist on staff is COVID turned out to have a little silver lining for the genetics community, and that is cancer genetics transition very well to televideo medicine. And there are now multiple companies providing televideo medicine. And you can usually get your patient in within a day or two for a televideo genetic counseling appointment. And so, just be aware if you can't get them to an in-person clinic in a timely manner, there are many, many televideo companies now providing genetic counseling services remotely from the comfort of their own home within two days' notice, evening appointments, weekend appointments to make it convenient for the patient. I don't work for any of those companies, but I would say just that people should be aware that those options exist so that their patients don't have to have a long wait time.

Dr. Edward Esplin: Just one quick thought along those lines. And in the context of the commentary that we talked about, I think there is a good rationale that if the patient that we're talking about with respect to receiving the tumor profiling NGS they're having any of those solid tumor types that we're discussing, it does make a lot of sense now to order that Germline genetic test at the same time that they're getting that tumor test. And doing that via what I've heard described in the literature is a mainstream approach where the clinical oncologist can be the person who is initiating both the tumor test and that germline genetic test. Get both those things cooking at the same time, such that when you're getting those results back, and in many cases, you'll probably get the germline results back sooner, then you don't have to ask those questions. And the referral to genetics can take place at the same time as well, potentially, where those results can then be discussed in detail. And I say that in part because testing all these patients with these tumor types that we've described and taking a more universal approach can make a lot of difference, for example, in patients having the information they need to actually prevent or mitigate the risk for a second primary cancer. 

We did a retrospective here a little while ago where we looked at patients who had received germline testing as a reflex to the tumor testing they’d received already. And appropriately so, I think, these savvy clinicians doing exactly what Heather described and referring them for germline testing. The unfortunate thing we found is in about 10% of the individuals that had a positive finding in their germline genetic test that was done as a downstream effect from their tumor profiling test, they had had this done on the second cancer that they had developed. And the genetic result that they received in their germline test was consistent with their first cancer that they had developed. In fact, if they had the germline testing done with the first cancer that they had developed, they would have the opportunity to have had that second cancer either downstaged by screening or completely avoided in its entirety with that information being at hand. And of course, it’s practically unconscionable that a patient who has successfully defeated cancer, beat it back into remission, would need to be at unknown increased risk of a second primary tumor simply for lack of getting germline genetic testing at the time when they were first diagnosed with cancer. 

Professor Heather Hampel: And not to pile on, but I'm a big fan of paired tumor and germline testing as well. And I'll just mention a Memorial Sloan Kettering paper which showed that about 10% of the mutations found on germline testing had been missed on the tumor testing because they were large rearrangements or some other type of mutation that tumor testing is really not designed to detect. So you also can't feel reassured by a normal tumor test that there isn't a germline mutation because that's not the purpose of the test, and it doesn't find every type of mutation. And so I am also a big fan of paired testing when you can get it. I also think it gives you some potential for sorting out variants of uncertain significance because you can look for second hits, et cetera. So again, I think that's the future of cancer genetics.

Dr. Abdul Rafeh Naqash: Absolutely. And I learned a lot from all the stuff that you guys mentioned. And one of the things that you just mentioned that was on my mind was VUSs or Variants of Undetermined Significance. And briefly, I wanted to touch on VUSs. If I have a BRCA1, BRCA2 VUS, what should I do? 

Dr. Edward Esplin: Nothing. Absolutely nothing. 

Dr. Abdul Rafeh Naqash: Should I refer to genetics or just wait and watch?

Dr. Edward Esplin: Well, I'll speak with my Invitae hat on. The waiting and watching, like you describe, I think, is very relevant because Invitae and other labs are actively involved in interrogating these VUSs on a routine basis. We see thousands of patients every day, and we see these VUSs popping up, and we're combing the literature on an ongoing basis. We're depositing new variants into ClinVar all the time, and that is part of what we consider to be our responsibility to continuously review the evidence underlying these VUSs. 

And in fact, in a paper published, I think it was in JCO Global Oncology here pretty recently, we noted that over the course of about, I think it was a five-year retrospective of patients who had undergone breast cancer testing, that we looked at how many of those individuals had a variant of uncertain significance, for example, in BRCA 1 and BRCA 2, and over that period of time how many of them got reclassified, and if so, what was the reclassification. There was some small fraction that over that time period got reclassified. I think I'm going to say it's in the order of like 10% or 20% and I'm saying that wrong. But more importantly, of all of the ones that got reclassified over that five-year period of time, 10% or less ended up being pathogenic or likely pathogenic. The vast majority of them ended up being benign or likely benign, which just underscores there's nothing that needs to be done for VUS when the evidence might ever accrue that would help to reclassify that. The vast majority of the time, it's going to end up downgrading it. That's not even the right term to use for a VUS. It's going to reclassify it as a benign or likely benign variant. And if it is something that should be actionable at some point in time, all of the reputable labs out there will notify clinicians of that change in status, and that is the time when action ought to be taken.

Professor Heather Hampel: Yeah, I think that's one of the biggest cons people will have against offering germline testing to every patient is the high variant of uncertain significance rate and a fear that those patients will be mismanaged as positives, particularly in settings where there aren't genetics professionals on staff. And so I think that's a really important point. I remember when Mary-Claire King was with her Lasker Award recommending germline genetic testing for all breast cancer, all women actually, unaffected, to try and prevent breast cancer. She had suggested that in that setting, they maybe should not report variants out at all because of the risk of them being mismanaged, and I think it's an interesting idea. Most of the academic centers like to have them; sometimes, they like to work on getting some of them reclassified. But I think it's something we need to consider if we start doing testing at this large of a scale or just being sure that everybody knows that a variant of uncertain significance should be treated like a negative until proven otherwise.

Dr. Edward Esplin: I'll pile on that just briefly to note that at ASHG American Society of Human Genetics just last year there was an entire session devoted to exactly that kind of topic, and it was broadly discussed, the potential opportunity to, for example, within a cancer gene multigene panel is that a panel where returning VUS is just not a useful thing to do, restricted to pathogenic, likely pathogenic. We do that on other panels already. We do that on panels for ostensibly healthy folks and other situations. So I think that is a very worthwhile approach to consider. 

And at the same time, we've also seen in the literature, Heather brings up a concern that is broadly raised and repeatedly raised, we've seen evidence that clinicians are not acting inappropriately as much as they had done, perhaps in the past, that we're getting our house in order. Breast surgeons and other physicians are treating these things like the negative results that they, in reality, are, and so that in my opinion, the potential for increased VUS identification should not be an obstacle to folks getting clinically indicated testing because that's what's needed for them to have appropriate treatment and appropriate prevention.

Dr. Abdul Rafeh Naqash: Absolutely. Well, this has been very engaging and very interesting, and hopefully, our listeners will feel the same. Thank you, both Heather and Ed, for joining us today and especially choosing JCO PO as one of the destinations for your very interesting commentary. 

Thank you for listening to JCO Precision Oncology Conversations. If you like today's episode, please leave a rating and review. You can find all our shows, including this one, at asco.org/podcasts and continue to stay updated by following JCO PO on Twitter with the handle @jcopo_asco. All JCO PO articles and series can be found at ascopubs.org/journal/po.

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Guest bios

Prof. Heather Hampel, MS, is an Associate Editor of JCO Precision Oncology. She is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center.

Dr. Edward D. Esplin, MD, PhD, FACMG, CGAF, FACP is board-certified in clinical genetics and internal medicine and completed his clinical fellowship training in medical genetics at Stanford University. He now works at Invitae.

Guest disclosures (See also: Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers)

Heather Hampel

Stock and Other Ownership Interests: Genome Medical, GI OnDemand

Consulting or Advisory Role: InVitae, Genome Medical, Pomega, 23andMe, GI OnDemand, Natera

Edward D. Esplin

Employment: Invitae

Stock and Other Ownership Interests: Invitae

Consulting or Advisory Role: Taproot Health Inc

JCO PO author Dr. Shilpa Gupta, MD, Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director, shares analysis on outcomes in real-world settings for metastatic urothelial carcinoma (mUC) patients. Host Dr. Rafeh Naqash and Dr. Gupta discuss the utility of tumor mutational burden (TMB) to determine treatment, and mUC patient response from immune checkpoint inhibitors (ICPI) as compared with carboplatin. Click here to read the article!

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations. I am Dr. Rafeh Naqash, assistant professor of medicine at OU Stephenson Cancer Center. You're listening to the JCO Precision Oncology Conversations podcast.

Today I'll be talking with Dr. Shilpa Gupta, who is an associate professor of medicine at the Cleveland Clinic and also the GU Medical Oncology Director. And we'll be talking about their group's recent paper, ‘Tumor Mutational Burden as a Predictor of First-Line Immune Checkpoint Inhibitor Versus Carboplatin Benefit in Cisplatin-Unfit Patients With Urothelial Carcinoma’.

Full disclosures for our guest can be found on the article’s publication page.

Hello and welcome to the podcast, Dr. Gupta. It's nice to have you here. For the sake of this podcast, we'll be referring to each other using our first names. So welcome and thanks for joining us today.

Dr. Shilpa Gupta: It's my pleasure to be here, Rafeh, I’m really excited about chatting about this paper with you. Thank you for the opportunity.

Dr. Rafeh Naqash: Thank you so much. So today we'll be discussing this interesting publication of yours, talking about biomarkers. And I often refer to biomarkers as the Pandora's Box for immune checkpoint inhibitors because definitely one size does not fit all. And reading through your paper, I saw a lot of interesting findings that you have defined in this publication. But for starters, what was the premise and background of why you wanted to study this question of tumor mutational burden as a biomarker in this patient population?

Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. The treatment paradigm for urothelial cancer patients has really evolved over the last many years. For example, patients who are eligible to receive cisplatin-based chemotherapy, that's the treatment of choice. And for patients who are not eligible to receive cisplatin due to a variety of reasons like chronic kidney disease, heart failure, peripheral neuropathy, poor performance status, or hearing loss, in the past, we used to treat them with gemcitabine and carboplatin, but outcomes were quite dismal with median overall survival less than six months or so. And then in 2017, the approval of pembrolizumab and atezolizumab as single agents was welcome news because these patients had more durable responses and survival was longer than historically with gemcitabine-carboplatin. And this is what became the standard of care based on the FDA expedited approval.

However, in 2018, the FDA restricted the use of immunotherapy only to those patients whose tumors had high PD-L1 or who were not eligible to receive carboplatin, based on the interim analysis from the phase three trials IMvigor130, which compared atezolizumab to gemcitabine-carboplatin, one of the cohorts for cis-ineligible patients, and KEYNOTE-361, which compared pembrolizumab to gemcitabine-carboplatin in the cis-ineligible cohort. And furthermore, recently, the FDA actually further restricted the label for pembrolizumab, because in the phase 3 study, even in high PD-L1 subgroups, pembrolizumab did worse than gemcitabine-carboplatin, regardless of their PD-L1 status. There were early deaths, lower response rates, and in the IMvigor130 study, we recently saw that atezolizumab was actually withdrawn for this indication altogether.

So there has been this attraction for PD-L1 for a long time, but now multiple studies in urothelial cancer have shown that PD-L1 is not a durable biomarker. And we wanted to see if there's other biomarkers which can be accessible at the point of care. And we wanted to study how tumor mutational burden can or cannot pan out as a treatment selection or complementary to clinical criteria. Right now, there's no biomarkers to guide treatment for patients in urothelial cancer for carboplatin or immunotherapy use. And that was the premise for the study.

Dr. Rafeh Naqash: Excellent. Thank you so much for that detailed understanding of why you decided to pursue this.

Now, from the listener standpoint when you define cisplatin-ineligible patients, in your practice, what is the percentage of patients that you see who are technically cisplatin-ineligible? Does comorbidity play an important role in determining which patients, or does it depend on your discussion with the patient? What are those factors that you would describe to define what cisplatin-ineligibility would constitute?

Dr. Shilpa Gupta: So historically, Matt Galsky and colleagues described cisplatin-ineligibility as patients with a creatinine clearance less than 60 mLs per minute, hearing loss greater than grade two, poor ECOG performance status two or higher, peripheral neuropathy, which is significant or significant heart failure. Now, those all make patients ineligible for cisplatin.

Now, more recently, we know that we can safely give cisplatin as long as creatinine clearance is above 50. So for the real world, 50 is a threshold where we can use split dose cisplatin. And I'll say, given that bladder cancer or urothelial cancer is a disease of the elderly, median age being 71 years, a lot of our patients have these comorbidities, chronic kidney disease, diabetes, and whatnot, which precludes us from using cisplatin. So in the real world, I would say that around 50% of patients are ineligible to receive cisplatin.

Dr. Rafeh Naqash: Interesting. And that goes back to the point where not everything that resulted from clinical trials, or the data that we get, may not be exactly applicable to the real world patient population, as you have pointed out in this interesting paper. So going back to the manuscript now from a methodology perspective, what kind of data did you include to get to the results that we'll talk about next? What was the inclusion and what was the patient population in this analysis?

Dr. Shilpa Gupta: So the patient population basically were patients who had a confirmed diagnosis of metastatic urothelial cancer. And the databases we used were the US-wide Flatiron Foundation Medicine Clinical Genomic Database, which has patients who were listed as metastatic urothelial cancer. But in addition, they also had genomic testing performed from their tumors, and results were available. And we accessed the database between 2011 until April 2021. And all these patients had had genomic testing using Foundation Medicine assay. And this de-identified data was basically US-wide across 280 cancer clinics and that's around 800 sites of care. And there's a whole range of retrospective longitudinal clinical data that was available, derived from the electronic health records comprising patient-level structured and unstructured data and also their genomic information from the tumors. And there was clinical data including demographics, lab values, performance status, timing of treatment, exposure, as well as time of progression and survival.

We decided to include patients if they received a frontline single agent immunotherapy, no matter what it was, whether pembrolizumab, atezolizumab, Nivolumab, durvalumab or avelumab, or a carboplatin-based chemotherapy. And just for the readers, this is a retrospective review. So we just used these selected patients who got in these therapies. We also required that these patients had tumor mutational burden information available through the tissue biopsy and patients who received chemotherapy and immunotherapy together were excluded and details are present in the manuscript, but this was pretty much the broad selection criteria.

Dr. Rafeh Naqash: Thank you so much. And definitely a very representative patient population from a real world setting with different therapy and different other clinical variables that are relevant in the real world setting.

So from an analysis standpoint, you, from what I read, define both a predictive and a prognostic aspect to tumor mutational burden. Could you tell us more about those results and highlight some of the interesting findings from that perspective?

Dr. Shilpa Gupta: Yes, absolutely. So as you know, tumor mutation burden cut off of ten mutations per megabase is currently utilized by the FDA, whereby approval of pembrolizumab for tumor agnostic condition was made. So that's what we considered high versus low. And we found that in this, after propensity weighing in, the tumor mutational burden less than ten group, basically those patients did not benefit from checkpoint inhibitor single agent as compared to tumor mutational burden of ten or greater. And so basically, we found that patients who had tumor mutational burden ten or higher overall had more favorable progression-free survival time to next treatment, as well as overall survival when they got a single agent immune checkpoint inhibitor, as opposed to those who got carboplatin, and also when compared to those who had tumor mutational burden less than ten. So we also looked at PD-L1 information available from the genomic database, but it was only available for around 35% of patients and still we were able to see that PD-L1 did not correlate with any of these outcomes as we show in the paper.

Dr. Rafeh Naqash: I see. And as you mentioned, you show both time to treatment failure PFS being better in TMB high patients defined as ten mutations per megabase. I didn't specifically see results related to TMB high versus low in a carboplatin specific cohort. Is that analysis something that was looked at and trying to understand whether neoantigens in a platinum-based setting specifically make a difference whether high TMB is predictive there in the carboplatin setting. Was that looked at?

Dr. Shilpa Gupta: So yes, we looked at, in the Figure 4, for the comparison of the TMB and which we were looking at the checkpoint inhibitor versus chemo. So for TMB low the chemotherapy cohort had more favorable results. Is this what you were getting at?

Dr. Rafeh Naqash: Yeah, I think what I was specifically trying to look at, like you have shown in the paper, is TMB is predictive of benefit with checkpoint inhibitors and is also prognostic in the checkpoint inhibitor setting. So my question was more whether it had a prognostic implication in a carboplatin specific cohort. So meaning high TMB, whether it correlated with better outcomes with carboplatin therapy versus low TMB. So if that was looked at.

Dr. Shilpa Gupta: We didn't look at that specifically, we only compared whether high TMB did better with the immunotherapy or chemotherapy.

Dr. Rafeh Naqash: And some of the correlation of this in my mind comes from some data that people have looked at in the lung cancer setting, whether high TMB makes a difference and for example, resected lung cancer patients, which usually gets platinum-based adjuvant therapies. So that's why I was wondering if there's any correlation there. But this is definitely interesting.

Now, my next question was going to be in your manuscript you mentioned around 30% of patients had tumor mutational burden more than or equal to ten. Did you identify any other unique characteristics from any other mutational standpoint or a PD-L1 standpoint in the high TMB cohort?

Dr. Shilpa Gupta: Yes. So PD-L1 didn't really stand out to be a very steady biomarker in our experience. And this is also what was reflected in the phase three trials like DANUBE where they looked at the durvalumab and tremelimumab, IMvigor130 or KEYNOTE-361. So that was pretty consistent that these studies also showed TMB to be more useful in exploratory analysis. Of course, these patients were not stratified based on that. And we also looked at other emerging biomarkers, for example, F-TBRS and angiogenesis gene expression signatures as well as tGE3. And we need to evaluate them in a separate study to see what pans out.

But for now, I think as far as in the real world, we are looking at a lot of genomic testing being done and right now we really don't know how to use that for making treatment decisions, right? PD-L1 has really phased out as of any utility whatsoever. And using TMB; I think in addition to the clinical characteristics, like when possible, we should be offering patients carboplatin. There's no doubt about that for cisplatin ineligible patients. But there's those patients who, if they're refusing chemotherapy and we really can't make a case for giving them single agent immunotherapy, I think TMB can come in handy to justify and make sure that we're not doing them a disservice by not giving carboplatin. And I think future trials need to use this biomarker in a prospective setting to further establish its utility.

Dr. Rafeh Naqash: Definitely, I agree it's a case-by-case situation from a patient standpoint to determine what therapy is appropriate for the patient and what is most realistic, what is the expectation that the patient has, from that treatment.

Now, from a TMB standpoint, one of the ongoing debates is if it is a binary cut off or whether it could be tertiles for a certain tumor type or quartiles. Was there any subanalysis or any subsequent study that your team would be looking at from a TMB cut off standpoint? Maybe a higher cut off would mean a better outcome and maybe lesser duration of therapy in those patients. Is that somewhat of a consideration?

Dr. Shilpa Gupta: Yeah, that's a great question, Rafeh. And I think the reason we stuck to it as a binary end point is because that's the FDA definition, so people don't try to extrapolate based on anything higher or lower. But yeah, that's a great question. And I know in lung cancer they're looking at different ranges. As far as urothelial cancer, we just stuck to the ten mutations per megabase for now.

Dr. Rafeh Naqash: Of course. And one of the other interesting things I really like to see in the paper is your figure specifically on the ECOG performance status and how clinical trials sometimes do not include patients on the higher ECOG performance status spectrum. And your study obviously had a good representation on that standpoint. What were some of the findings from the ECOG standpoint that were somewhat different in your cohort than what you would see in clinical trials in general?

Dr. Shilpa Gupta: Yes, as we've shown in Figure 5, the ECOG in real world, it was quite an eye opener to see that there was a considerable number of patients who were documented as ECOG performance status three. And if you see the ECOG performance status two bar was around 50% and ECOG performance status one was also lower than what has traditionally been included in the phase three trials. And in the phase three trials, there's hardly any patients with ECOG performance status two compared to what we saw in the real world. And very few patients, in fact, hardly any had ECOG performance status zero in our real world analysis. So clearly the trials need to be more inclusive, as has been the ASCO message all along. And it's always very surprising to see the big gap between the real world and the clinical trial patient population.

Dr. Rafeh Naqash: Definitely, I think more and more, especially cooperative group trials that you and many others are leading, are trying to be as inclusive as possible, which is important to get a better understanding of how these therapies do in different patient populations. And one of the questions I wanted to ask you, and I've seen this a few times in different checkpoint therapy treated tumors, is this initial rapid progression in some patients where the chemotherapy arm does better, but the immunotherapy arm kind of falls rapidly and then starts plateauing. In your clinical experience, have you seen that? And if yes, what are the features of some of those patients that have this rapid progression from a clinical and both from a biomarker standpoint?

Dr. Shilpa Gupta: That's a great question, Rafeh, and we do see that every now and then, and especially in my experience, we've seen that in women in particular who have bone metastases are really challenging to treat with immunotherapy. And sometimes we find that the disease just rapidly blows through immunotherapy and we really need to do more biomarker work to understand what determines these biomarkers of hyper-progression, so to speak. I know there's a lot of work going on in the field and we are also trying to understand these by serially collecting blood and circulating tumor DNA from our patients during their treatment journey.

Dr. Rafeh Naqash: Exactly. Definitely work in progress and another unique patient population where more needs to be done to understand what are the events that lead to these hyper-progression aspects, whether it's in the bone or brain or any other compartment in the body.

Well, this has been exciting and interesting, but before we end, we try to know a little bit more about the investigator, the author. So, Shilpa, can you tell us a little bit about your journey in oncology and your journey as a trainee, your journey as faculty, as a clinical trialist, as a successful clinical trialist? And any advice for junior investigators listening to this conversation?

Dr. Shilpa Gupta: Yeah, thank you for asking. I think oncology always struck me as a very exciting field back in my residency days, 2005, 2006. And at the time, so much was going on, like just drugs like bevasizumab were just coming around for colorectal cancer and in lung cancer drugs like EGFR inhibitors were coming around. And that kind of really excited me. And talking with my mentor at the time, who was a really well-renowned transplanter, he said to me that if he had to do it all over again, he would love to get into solid tumor oncology with all the excitement that's going on. I was drawn to oncology also because of, not only it's a learning experience every day, but it can be very gratifying to see amazing responses and patients living longer despite having advanced disease, and also provides a lot of challenges every day when every patient is not the same. So I think that was the reason why I was drawn to oncology and provides us an opportunity to really develop new therapies as opposed to some of the other specialties because of how challenging the patient population is.

And as far as my journey, you know, I've now been in the US for almost 18 years and have been in a variety of places, and I think it's been a very rewarding journey despite multiple bumps along the way. And I'm really glad to be doing what I'm doing and trying to advance the field, clinical trials, and learning from people around me.

Dr. Rafeh Naqash: Thank you so much for giving us a little glimpse into your journey and your experiences. And it's always inspiring to listen to successful investigators and also try to emulate in some ways what you have done and what you've achieved. And thank you again for coming on this podcast. And thank you for choosing JCO Precision Oncology as a destination for your manuscript, and hopefully we'll see more of the same from you and your group in the subsequent years to come and more in this field of biomarkers.

Thank you for listening to JCO Precision Oncology Conversations. You can find all our shows, including this one, at ASCO.org/podcasts or wherever you get your podcasts. To stay up to date, be sure to follow and share JCO PO content on Twitter @JCOPO_ASCO. All JCO PO articles and series can be found at ascopubs.org/journal/PO.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Guest Bio

Shilpa Gupta, MD, is Associate Professor of Medicine at the Cleveland Clinic and GU Medical Oncology Director.

Guest disclosures

Stock and Other Ownership Interests: Nektar, Moderna Therapeutics

Honoraria: Bristol Myers Squibb

Consulting or Advisory Role: Gilead Sciences, Guardant Health, AVEO, EMD Serono, Pfizer, Merck, Loxo/Lilly

Speakers' Bureau: Bristol Myers Squib

JCO PO author Dr. Mark Stewart, PhD, Vice President, Science Policy at Friends of Cancer Research, shares analysis on clinical trials and the association between CT-DNA and outcomes in lung cancer. Host Dr. Rafeh Naqash and Dr. Stewart discuss dataset metrics, identification of biomarkers, timepoints, and checkpoint inhibitors, development of new medicines, and novel technologies measuring CT-DNA. Click here to read the article!

TRANSCRIPT

Dr. Rafeh Naqash: Welcome to ASCO's JCO Precision Oncology Conversations, where we bring you highlights and overview of precision oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant articles published in JCO Precision Oncology. These articles can be accessed at: ascopubs.org/journal/po.

Hi, I'm Dr. Rafeh Naqash, Medical Oncologist, and Assistant Professor of Medicine at the OU Stephenson Cancer Center, and you're listening to JCO Precision Oncology Conversations podcast.

Today, I am delighted to be talking with Dr. Mark Stewart, Vice President Science Policy at Friends of Cancer Research. We'll be talking about their group's recent paper in JCOPO, titled, 'Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors'.

At the time of this recording, my guest and I have no relevant disclosures.

Welcome to the podcast, Mark.

Dr. Mark Stewart: Thanks. Thanks so much for having me here.

Dr. Rafeh Naqash: I am excited to discuss this new publication that your group has come out with, and I see this is a significant effort involving both academia and industry, and also your organization. Could you tell us about what led to this work, and then we can go into finer details about what your findings were?

Dr. Mark Stewart: Sure. I might start with just briefly describing our organization. We are a non-profit patient advocacy organization in Washington, DC. And our mission as an organization is really to help accelerate development and access to new medicines. And we do this by doing horizon scanning to see kind of what issues, or emerging technologies, are coming down the pipe that might have implications in oncology.

And we bring together experts from universities, government, industry, patient advocacy, to help develop evidence-based policies that can pave the way for future discoveries, but also accelerate the pace of scientific progress. I think that's really embodied in the manuscript that we recently published, and that we'll be talking about today.

Dr. Rafeh Naqash: Awesome. And I have come across some of the other phenomenal work that your organization is doing, and this is definitely a step forward in developing more personalized therapies, and trying to identify relevant biomarkers so that we can treat patients and their cancers appropriately.

Moving forward, could you tell us some of the main findings from this publication, and then we'll take a deeper dive in trying to understand the kind of data that you used and the kind of analysis that was done? But just as an overview for our listeners, could you briefly explain some of the major findings from this publication?

Dr. Mark Stewart: Sure. Maybe in my last answer, I could have provided some rationale in terms of what led us to even initiate this project. So, I think if you look at trends in oncology drug development over the past decade, the use of precision medicines led to really incredible outcomes for patients. I think that's led to really transformative medicines. And with these therapies, if you look at the drug development paradigm, they've often used these expedited development programs at the agency, and that's largely driven by our improved understanding of the biology of the cancer, and the natural history of the disease, and the ability to use endpoints that can read out earlier, that provide us insights into whether a drug is working or not.

And as we continue to improve the available treatments that patients have, we're seeing the shift where drugs are starting to be investigated in patients that have earlier disease. And because of that, the length of time it takes to understand whether a drug is working or not can often take much longer because of the follow-up time needed to read out endpoints like progression-free survival, or overall survival. And so, the ability to identify new novel biomarkers that can help us understand whether a drug is working or not sooner would certainly provide a lot of value to drug development, it could help expedite the development of new, innovative therapies for cancer patients.

And I think like everyone else, when we first saw a lot of the emerging data coming out on the role of circulating tumor DNA and its potential role in clinical research and care, I think there was a lot of excitement around the potential. And when you look at all these exploratory studies, you see a lot of potential for using ctDNA changes to signal whether a drug is working. But a lot of these initial studies were conducted independently, using different methods, different technologies for measuring ctDNA, and this really left questions about the applicability of this from a more rigorous standpoint, and how this might be applied in a regulatory setting.

And so, we brought together a diverse group of scientific leaders to really design a comprehensive plan that could leverage these prior studies, and then bring them together in an effective manner to where we can increase our power, strengthen our understanding of this association that we see between changes in ctDNA and outcomes. And so, this manuscript is really a first iteration of several data readouts we have planned over the next year. This first study included five different clinical trials of patients with lung cancer that were treated with immune checkpoint inhibitors. And I think one of the figures that I think is most interesting to see in this, is actually our FIG 1., where it's a swimmer plot, where it really shows the differences across all these different trials, and it also exemplifies some of the challenges that we had to overcome when we brought all these datasets together, but yet still arrive at some meaningful data to address our core question of whether changes in ctDNA can predict treatment outcomes.

Dr. Rafeh Naqash: So, definitely an exciting endeavor that you guys have brought forward this aspect of ctDNA. So, in my other life I'm involved in a lot of early-phase clinical trials, and my patients often ask me, "How is it that you're going to assess our response? How long will we be on treatment?" And currently, as most of our listeners know, the standards are primarily using CT scans, or other imaging modalities to assess for responses, and with the innovation that's being made in the field of circulating tumor DNA, it's definitely transforming the world and innovations on the precision oncology side. For example, in GI cancers, there's been significant development, there are clinical trials in this setting. In the lung cancer setting, there are clinical trials trying to assess ctDNA-related changes, and treatment changes associated with those alterations, or decrease, or increase, in the ctDNA.

So, based on what you describe here from the understanding that I have reading through this interesting paper, you used, as you mentioned, previously-conducted clinical trials. Could you tell us a little more about what kind of clinical trials were these, and for non-small cell lung cancer, and what kind of therapies patients were treated with in these clinical trials, and how did you determine which clinical trials you would use for this project?

Dr. Mark Stewart: Sure. When we first launched this project, we basically put a call out to various drug developers, academic investigators, to see what types of data were even available. And at that time, maybe not a surprise to many, there was a lot of ongoing clinical trials that were measuring ctDNA in patients with lung cancer. And because of that, we found a number of clinical trials that kind of fit a general criteria that we felt could be brought together as part of this initial analysis. We tried to keep the criteria broad, we didn't want to be overly exclusive. So, we didn't limit the studies to having to have used a specific assay, for instance, and we thought that that was an important component here because we wanted to understand whether this phenomenon of changes in ctDNA being associated with outcomes isn't necessarily due to a specific technology. And I think the strength of this becoming a potential endpoint is that it is something that can be reproducible and repeated regardless of the kind of technology that was used.

The clinical trials, it’s also important that they had multiple timepoint collections while the patient was on treatment because there's still questions remaining around what's the right time to collect ctDNA, and which timepoints are most correlative to long term outcomes. And we thought those were important things to begin to investigate in our study. And so, it was really the availability of data that naturally led us to first starting in lung cancer.

Dr. Rafeh Naqash: Sure. Thank you for that explanation, Mark. And to the best of my understanding, when I read through some of the details in the manuscript, there's a mention that these were five clinical trials. Patients had been treated with either immunotherapy alone, or immunotherapy with chemotherapy, both being the standards of care, depending on some of the other biomarkers and disease burden. But from a ctDNA perspective, it seems that you were trying to include mostly patients that had at least two assessments done at baseline, no earlier than 14 days, and at least one within the first 70 days of treatment initiation. Is that a fair understanding from what has been described in the manuscript?

Dr. Mark Stewart: Yes. And we didn't limit as well to a specific immune checkpoint inhibitor. Again, for us, our goal was to cast a broad net and try and include as many clinical trials as we could in this first analysis.

Dr. Rafeh Naqash: Right. And I guess, based on the data that you have used in this project, there's obviously heterogeneity with the trials, with the treatment, with probably different lines of therapies that the patients had been treated with, so, that is probably why you were trying to explore different metrics of this ctDNA change. And there's a couple of metrics, it seems, that you and your team have assessed here; one of the metrics that seemed to stand out was this metric where you used three different categories of patients that, depending on the change in the ctDNA, whether they had a decrease, an intermediate category, and a category that had an increase.

So, Mark, based on the findings on the paper, it seems that you're using different ctDNA-based metrics to assess changes in responses and survival. Based on the methodology, what was the most appropriate, or the strongest one that you were able to identify that was associated with differences in survival, and responses as you've sort of explained in the manuscript? Could you describe that briefly for us?

Dr. Mark Stewart: When initiating the study, there were a lot of unknowns in terms of how we would be able to bring together these different datasets, particularly knowing that they use different ctDNA assays that potentially included targeted panels, and whole genome sequencing, and also had different kind of readouts and metrics that were used. And so, early on we explored various metrics. And the one that rose to the top was a variant allele frequency, which is simply the number of mutant alleles divided by the total number of mutant and wall-type alleles. And there's different ways you can report that out -- it could be a mean, it could be a median, or a maximum. While we didn't necessarily see large differences between those, we did observe that consistently, maximum VAF correlated with overall survival and was one that we continued to use as a primary analysis in our manuscript.

Dr. Rafeh Naqash: So, Mark, based on some of the analysis you've done here, was a landmark timepoint used to compare survival for the patients because there could be a difference in the number of timepoints of ctDNA assessment for different patients, which would, in turn, mean that some patients could have been treated longer versus some other patients? So, did you try to limit that heterogeneity by performing a landmark analysis on this cohort?

Dr. Mark Stewart: Yes. That was one of the approaches we had to take, given the heterogeneity across the different studies that we included in this analysis. In FIG 2., again, you can see across the five different studies how there are different numbers of ctDNA timepoint collections, but also that they were collected at different timepoints. And so, to try and create a more equal playing field and informative analysis here, we did use a landmark of 70 days here and used ctDNA timepoints that were around that landmark when we were looking at the association between changes at that particular time to overall survival, or progression-free survival.

Dr. Rafeh Naqash: So, Mark, based on what you've shown here as far as overall survival is concerned, could you tell us about how the specific ctDNA metric that you used was able to compartmentalize patient survival on checkpoint inhibitors?

Dr. Mark Stewart: Sure. As I'd mentioned previously, in this analysis, we used a three-level variable to differentiate response to treatment using ctDNA. This three-level ctDNA metric represented patients that had a decrease in ctDNA from baseline, an intermediate change, or an increase. And so, for each of these three ctDNA metrics, we were able to bucket patients into these three categories based on the percent change and varying allele frequency. And so, those that had the 50% decrease in ctDNA were bucketed in the 'decrease' category, and those that had a 50% change in the positive direction were bucketed in the 'increase', and then all the patients that remained were placed into the 'intermediate' category. And as you can see from the Kaplan-Meier Curves, I think a quite robust differentiation between those three groups.

Dr. Rafeh Naqash: Right. And another interesting finding on one of the forest plots that you've shown is that patients who smoked had a better survival or better outcome with therapies. And I remember a couple of years back reading an interesting paper in Science, if I remember correctly, from a group at Sloan Kettering, showing the increased neoantigens and mutational burden related to smoking, that probably predicts better responses. Is there any other interesting aspect to this from a ctDNA standpoint that your group was able to identify, or is looking at, at least in this comparison of smokers versus never-smokers?

Dr. Mark Stewart: Yeah. Actually, when we took into account all the different clinical variables that were included in these datasets, we actually saw an association between patients that were smokers or had smoked at one point, and the ctDNA levels that were present. Despite that smoking may impact the levels of ctDNA present, I think, the fact though, that we are trying to determine whether a treatment is working, or not, based on a change, or a delta, between a baseline and a subsequent timepoint, it shouldn't really matter necessarily what your baseline is, so long as you're still able to observe a decrease or an increase.

Dr. Rafeh Naqash: From, I guess a futuristic perspective since this project primarily involved pooling of data from five different clinical trials, is there a plan to validate some of this in an independent cohort of patients in the next year to two years?

Dr. Mark Stewart: Yes. As I mentioned, the CT Monitor project that we've developed into multiple different modules, and the modules have been broken up basically in terms of when data is available in different clinical trials. And so, we've continued to work with different drug sponsors and academic investigators to put together data use agreements, and I'm excited to say that we have three different modules that we plan to read out over the course of this next year. We have a module that includes patients with lung cancer that are treated with a TKI - Tyrosine Kinase Inhibitor. We have a second module that is an additional analysis in patients with lung cancer treated with immune checkpoint inhibitors. I think a key thing to highlight there is that the studies that we'll include in this next round are all randomized clinical trials, and so, we'll be able to look at the ability to differentiate between two treatments using ctDNA, and understanding its kind of predictive nature as a potential endpoint. And then the third module is really kind of a catch-all that includes multiple different cancer types, and where patients have been treated with either a Tyrosine Kinase Inhibitor or an immune checkpoint inhibitor.

And across all of those studies, we have about 22 different clinical trials that'll be included in those analyses that represent over 3000 patients. And so, I do think we'll be able to validate the findings that we've been able to show in this latest publication, and also address some additional questions. Many of these studies are newer, so I think people have learned from some of the earlier clinical trials that included ctDNA. So, in these latest studies you see many more collection timepoints. You also see earlier collection timepoints even before the first RECIST measurement. So, I think we'll be able to understand, again, get greater granularity on, what are the optimal timepoints for collecting ctDNA; how early can ctDNA predict clinical outcomes; and finally, just to add to that body of evidence that can hopefully help provide confidence to the community that this is an objective and meaningful measure, and that could hopefully be used in a regulatory standpoint as a potential early endpoint that could serve as a basis for a drug approval.

Dr. Rafeh Naqash: Those are all awesome, phenomenal things that need to be accomplished, definitely, and your organization is leading these efforts in a one-of-a-kind public-private partnership. And I completely agree with you that this could be a very important biomarker metric for patients who are treated with novel therapies, including checkpoint therapies, Tyrosine Kinase Inhibitors, or even potentially, on clinical trials.

From a practical application standpoint, Mark, has your organization also made any efforts in terms of trying to see how we can try to get both FDA and insurance approval for patients who are treated on standard of care therapies but would benefit from having serial, you know, every four to six months ctDNAs done? Because I try to do that sometimes in my practice and do face occasional challenges from insurance companies where they're not willing to pay for repeated ctDNA assessment. And I try to space it out when I'm not getting CT scans, you know, alternate it with CT scans. But is there any kind of an effort in that direction where from a regulatory standpoint, in the next one to two years, we can make progress so that clinicians are able to order ctDNA on patients, whether they're treated on checkpoint therapies or other targeted therapies?

Dr. Mark Stewart: That's a critical issue that you raise, and certainly a potential barrier that can prevent patients from benefiting from this novel technology. To date, our efforts have been mostly focused in kind of the use of ctDNA in the research space, but I think that they're not mutually exclusive. I think one important way to ultimately get coverage for these tests is to have that evidence base that really shows the utility that it is providing benefit to patients. I look at this as kind of a first step to getting there, and I think once you have this evidence, and also you have the right evidence that we know payers want to see, that hopefully, it can help address those potential concerns.

Dr. Rafeh Naqash: I could not agree with you more. And your work, definitely, is a step forward in the right direction, and I think will lead to a lot of exciting subsequent things, as you mentioned.

I congratulate you and your group again, on this exciting project, and I appreciate that you chose JCO Precision Oncology as the final destination for this phenomenal work.

Dr. Mark Stewart: Thank you for having me. And certainly I just want to extend gratitude to my fellow authors. I think we have around 34 authors on this manuscript, and I think it just, demonstrates the recognition that this truly does require collaboration across different stakeholders, and look forward to next steps.

Dr. Rafeh Naqash: Thank you so much, Mark.

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 JCOPO content on Twitter with the handle: @JCOPO_ASCO.

All JCOPO articles and series can be found at: ascopubs.org/journal/po.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Guest Bio

Mark D. Stewart, PhD, is Vice President, Science Policy at Friends of Cancer Research in Washington, DC, an advocacy organization that drives collaboration among partners from every healthcare sector to power advances in science, policy, and regulation that speed life-saving treatments to patients.

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.