JCO Precision Oncology Conversations – Détails, épisodes et analyse

In this episode of JCO PO Article Insights, host Dr. Jiasen He summarizes the article, "Somatic Mutation Profiles of Colorectal Cancer by Birth Cohort" by Gilad, et al published October 11, 2025.

TRANSCRIPT

Jiasen He: Hello, and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today, we will be discussing the JCO Precision Oncology article, "Somatic Mutation Profiles of Colorectal Cancer by Birth Cohort," by Dr. Gilad and colleagues.

Early-onset colorectal cancer is defined as colorectal cancer diagnosed before the age of 50. Several reports have suggested that early-onset colorectal cancer has unique characteristics. Compared with late-onset colorectal cancer, early-onset colorectal cancer cases are more commonly found in the distal colon or rectum, tend to be diagnosed at more advanced stages, and may display unfavorable histologic features.

Although the overall incidence of colorectal cancer has declined in recent decades, the incidence of early-onset colorectal cancer continues to rise. This increase appears to be driven by birth cohort effects. The reasons behind this rise remain unclear but are likely multifactorial, involving changes in demographics, diet, lifestyle, environmental exposures, and genetic predisposition. At the same time, studies have shown conflicting results regarding whether there are differences in the mutation profiles between early-onset and late-onset colorectal cancer. Therefore, it is crucial to explore whether colorectal cancer somatic mutational landscape differs across birth cohorts, as this could provide important insight into generational shifts in colorectal cancer incidence.

To address this question, the authors conducted a retrospective study to characterize the mutation spectrum of colorectal cancer across different birth cohorts. Consecutive colorectal cancer patients who underwent somatic next-generation sequencing at the University of Chicago pathology laboratory between 2015 and 2022 were retrospectively identified. Tumors were tested for 154 to 168 genes and categorized as either microsatellite stable or high according to established thresholds. Patients with hereditary cancer syndromes or inflammatory bowel disease were excluded. Participants were then grouped into birth cohorts by decades, as well as into two major groups: those born before 1960 and after 1960. Genes that were identified in at least 5% of the sample were selected and grouped into 10 canonical cancer signaling pathways. These genes and pathways were then included in the analysis to explore their association with colorectal cancer across different birth cohorts and age groups.

A total of 369 patients were included in the study, with a median birth year of 1955 and a median age at colorectal cancer diagnosis of 62.9 years. 5.4% were identified as having microsatellite-high tumors. The median tumor mutational burden was 5 mutations per megabase for microsatellite-stable tumors and 57.7 mutations per megabase for microsatellite-high tumors. Patients with microsatellite-high tumors tended to have earlier birth years and were diagnosed at an older age. However, after adjusting for potential confounders, neither birth year nor age remained statistically significant. Similarly, after controlling for confounders, no significant associations were observed between birth year or age and mutation burden.

In this cohort, APC, TP53, and KRAS were the most frequently mutated genes. No statistically significant differences in the prevalence of gene mutations were observed across birth cohorts. Correspondingly, the most affected signaling pathways were the Wnt, TP53, and (RTK)/RAS pathways. Similar to the gene-level finding, no significant differences in the prevalence of these pathways were identified among birth cohorts.

When examining patients born before and after 1960, the authors found that the older birth cohorts were diagnosed at an older age and had higher tumor mutational burden. However, no significant differences were observed in any of the genes or pathways analyzed. Among microsatellite-stable tumors, 18.3% were classified as early-onset colorectal cancer, while 81.1% were late-onset colorectal cancer. Consistent with previous reports, early-onset colorectal cancers in this cohort were more likely to be left-sided and more common among more recent birth cohorts. However, no significant differences were identified in any of the examined genes or pathways when comparing early-onset to late-onset colorectal cancer.

In this cohort, a higher prevalence of early-onset colorectal cancer was observed among more recent birth cohorts, consistent with previous reports. Still, no distinct mutational signature was identified between the early and late birth cohorts. The authors proposed that the lack of distinct mutational profile by age or birth cohort may be due to the limited number of key molecular pathways driving colorectal cancer. Although environmental exposures likely differ across generations, the downstream effects may have converged on similar biological mechanisms, leading to comparable somatic mutations across cohorts. Alternately, they proposed that the observed birth cohort differences in colorectal incidence may be driven by distinct mutation signatures, epigenetic alterations, or changes in the immune microenvironment rather than variations in canonical gene mutations.

As the authors noted, given the retrospective nature of this study, its modest sample size, and the predominance of advanced-stage tumors, larger prospective studies are needed to validate these findings.

In summary, this study found no significant differences in the mutational landscape of colorectal cancer across birth cohorts or age groups. The authors proposed that the generational shift in colorectal cancer incidence is unlikely to be driven by changes in the underlying tumor genomics. However, larger prospective studies are needed to validate these findings.

Thank you for tuning in to JCO Precision Oncology Article Insights. Do not forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology.

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

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

JCO PO author Dr. Bryson Katona at the University of Pennsylvania Perelman School of Medicine shares insights into his article, "Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection (PRECEDE) Consortium" Host Dr. Rafeh Naqash and Dr. Katona discuss how, given differing guidelines as well as lack of detail about how PC surveillance should be performed, approaches to PC surveillance across centers often differs.

TRANSCRIPT

Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.

Today, I am thrilled to be joined by Dr. Bryson Katona, Director of the Gastrointestinal Cancer Genetics Program and Director of the Lynch Syndrome Program at the Penn Medicine's Abramson Cancer Center, and also lead author of the JCO PO article entitled "Areas of Uncertainty in Pancreatic Cancer Surveillance: A Survey Across the International Pancreatic Cancer Early Detection or PRECEDE Consortium."

Bryson, thanks for joining us again.

Dr. Bryson Katona: Well, thank you so much for having me. I appreciate the opportunity.

Dr. Rafeh Naqash: It is exciting to see that this work will be presented concurrently with the upcoming CGA meeting.

Dr. Bryson Katona: Yes, it has been a fantastic partnership between JCO PO and the CGA-IGC and their annual meeting. And for those who may not be familiar, the CGA-IGC is the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. It is basically a professional organization dedicated to individuals who have hereditary GI cancer risk and focusing on providing education, promoting research, and really bringing together providers in this space from not just throughout the US but from across the globe as well.

Dr. Rafeh Naqash: That is exciting to hear the kind of work you guys are doing. These are definitely interesting, exciting things. Now, going to what you have published, it is an area that is very evolving in the space of cancer screening, cancer surveillance, especially for a very aggressive cancer such as pancreatic cancer. Could you tell us currently, what are the general consensus? I know there are a lot of differences between different guidelines or societies, but what are the some of the commonalities if we were to start there first for pancreas cancer screening? If you are not a GI oncologist, you may not be aware that there is something with regards to pancreas cancer screening. Could you give us an overview and a background on that?

Dr. Bryson Katona: Yeah, I think that pancreatic cancer screening really is one of the most controversial areas of all cancer screening. Part of that controversy is just because all the guidelines, the many different guidelines that are out there, do not always match up with one another, which I think leads to a lot of confusion, not just for providers but for patients who are trying to go through this, and then also the insurance companies in trying to get these screening tests covered.

You know, when we think about who is eligible for pancreatic cancer screening, you know, it is important that these are not average-risk individuals. So really, we are only offering screening to high-risk individuals. And those can include people that have a strong family history of pancreatic cancer without a germline genetic susceptibility that has been identified. And those individuals we refer to as having familial pancreatic cancer. And the other big cohort is those individuals that carry hereditary pancreatic cancer predisposition. These are due to cancer risk mutations in many different genes, including many of the breast cancer risk genes like BRCA1 and BRCA2, as well as ATM and PALB2, but then other genes such as the Lynch syndrome genes, and then some of the higher risk genes such as those leading to Peutz-Jeghers syndrome as well as FAM, which is due to CDKN2A mutations.

Dr. Rafeh Naqash: Thank you for that. Again, another practical question, and this may or may not be exactly related to your specific topic here, but perhaps to some extent there might be an overlap. If I get a patient from a colleague, and I see people in the early-phase clinical trial setting, so many different tumors for novel drugs, and I find an individual with, let us say, lung cancer who has a pathogenic BRCA2, which is somatic, should I be worried about pancreas cancer screening in that individual? Or have we not met that threshold yet in that circumstance?

Dr. Bryson Katona: A lot of times these variants or these genes that are associated with pancreatic cancer risk get picked up on the somatic tumor profiles. Now, you know, whether or not those are truly germline variants typically requires the next step of referring the patient for germline genetic testing. So you know, I would not screen or make any kind of screening choices based on a somatic variant alone, but nowadays germline testing is so easy, so efficient, and relatively cheap that it is easy enough to confirm whether or not these somatic hits are in fact just somatic or may confer some germline risk in addition.

Dr. Rafeh Naqash: So from what I understand from what you have said, there is debate about it, but it is something that should be done or is important enough that you need to figure out a path moving forward. Was that one of the reasons why you performed this project through this very interesting consortium called the PRECEDE Consortium?

Dr. Bryson Katona: Yeah, that was one of our main reasons for doing this. And for those who do not know about the PRECEDE Consortium, this is a very large international, multi-institutional organization really focused on reducing death and improving survival from pancreatic cancer, primarily through increased and more effective use of screening and early detection strategies. This is an international consortium. There are over 50 sites now with nearly 10,000 patients who are enrolled in the consortium. So it really is at this point the largest prospective study of individuals who are at high risk for pancreatic cancer who are undergoing screening.

And you know, I think amongst all of us in the consortium, just amongst discussions between colleagues and then, you know, often times when I see patients that are transferring their care to Penn who maybe had their screening done in another center before, what we were realizing is that, you know, although we all do a lot of screening, it seems that people are doing it slightly differently. And it does not seem that there is a real consensus approach across all centers about how pancreatic cancer screening should really be done. And it is one thing if you are thinking comparing, okay, well, maybe in the US we do it differently than, you know, in Europe or in other locations, but even among centers within the United States, we were still seeing very large differences in how pancreatic cancer screening in high-risk individuals were done. And so that led us to really pursue this survey of pancreatic cancer screening practices across the PRECEDE Consortium. So for this survey, we actually have 57 centers who the survey was sent out to. As you know, surveys are oftentimes very difficult to get good response rates back on, but we were fortunate to have 54 of the 57, or 95% of the centers, actually get back to us about their screening practices for this particular project.

Dr. Rafeh Naqash: That is good to know. I hope you did not have to use any kind of gift cards for people to respond to the survey. But nevertheless, you got the information that you needed. Could you tell us what are some of the common denominators that you did identify and some of the differences that you identified? From your perspective, it sounds like there is no established consensus guidelines. There are different societies that have different perspectives on it. So I am sure some of what you found will probably have implications in maybe creating some guidelines. Is that a fair statement?

Dr. Bryson Katona: Definitely a fair statement, and we found some very interesting results. I think one important result is really just the heterogeneity in the consortium. And so even before we got into pancreatic cancer screening practices, we also, we were asking consortium sites, "At your particular site, who is the individual that is leading these in-depth discussions about pancreatic cancer screening?" And while about 50% of the sites had a gastroenterologist leading it, about a quarter of the sites had a medical oncologist, a quarter had a surgeon leading these discussions as well. And we also found heterogeneity in who is the physician or the provider actually ordering these screening tests, again, with multiple different specialties across the different sites.

But really one of the main areas that we wanted to hone in and focus on was how the different pancreatic cancer screening guidelines were actually utilized in each of the particular centers. The biggest controversial area in the field is for the gene mutation carriers, whether or not we should be requiring that a family history of pancreatic cancer be present in order for those individuals to qualify for pancreatic cancer screening. And the reason that is so controversial, let us take an example of BRCA1 and BRCA2 carriers. Currently, if you look through the guidelines, NCCN and the ASGE guidelines recommend that really all BRCA2 carriers undergo pancreatic cancer screening regardless of whether or not there is a family history, starting at age 50. However, other guidelines such as the AGA guidelines, or the AGA Clinical Practice Statement, as well as guidelines from the CAPS consortium, do recommend that a family history of pancreatic cancer be present in order to qualify for screening.

But then we have different things for other genes. So for BRCA1 carriers, in fact, it is the ASGE guidelines that recommend all BRCA1 and 2 carriers undergo screening, whereas NCCN and the other guidelines that are out there do not recommend those individuals undergo screening. Again, this huge heterogeneity in guidelines is quite striking. And so when we assessed all the sites in the PRECEDE Consortium, we found some really interesting results with respect to these particular genes. For BRCA2 carriers specifically, we found that about half of the sites required a family history for recommending pancreatic cancer screening, but about half of the sites would offer it to all BRCA2 carriers regardless of if there was a family history of pancreatic cancer screening. Rates for BRCA1, PALB2, and ATM carriers were a little bit lower, where about a third of sites would offer screening really regardless of whether or not there is a family history of pancreatic cancer. And for Lynch syndrome, those rates were very, very low, with only about 13% of sites offering screening to Lynch patients in the absence of a family history. But I think, you know, we are all in the same consortium, but there is still just a lot of heterogeneity in how our own individual practices are run.

Dr. Rafeh Naqash: Definitely different thoughts, different practices. But from what you saw, did it matter as far as outcomes are concerned whether it was a gastroenterologist doing the screening, or it was a medical oncologist, or a geneticist? Or is it a combination of all of these that actually makes the most difference?

Dr. Bryson Katona: So I think we do need to get some more information about specialty-specific screening preferences. We just had one response per site in this particular survey, and so I think we are going to need a larger sample size in order to get that data. But I think that is certainly possible that, you know, certain subspecialties may prefer, you know, screening more aggressively or not including family history. That is definitely a question that we will be asking in future studies.

Dr. Rafeh Naqash: Definitely more gift cards that will be needed as well.

Moving on to another aspect of the implications for early detection, from a breast cancer, colon cancer standpoint, there is health economics research that shows it saves cost in the bigger picture. Has there been anything for pancreas cancer where early detection, early identification, early treatment actually ends up saving a lot more versus detecting metastatic pancreas cancer later?

Dr. Bryson Katona: It is a great question. And of course, for any screening modality, you know, we would ultimately want it to be a cost-effective measure. In pancreas cancer screening, the jury is still a little bit out about whether or not pancreas cancer screening is truly cost-effective or not. There have been several different studies that have assessed this. And I think in general, the thought is that it is a cost-effective endeavor. But I think most of these cost-effectiveness estimates are actually related to what is the risk of pancreatic cancer in the population you are studying. And so when you have very, very high-risk individuals that have over a 10% lifetime risk of pancreatic cancer, it is almost a certainty that pancreatic cancer screening is going to be cost-effective. However, you know, if you have, say for example, BRCA1 carriers where lifetime risk of pancreatic cancer may be less than 5%, likely around like 3%, those individuals, I think it is going to be a tougher sell to say that it is cost-effective.

But as we get more data on pancreatic cancer screening, that will be a very important question to ask. And you know, when you mentioned how does it save money, our goal at least in pancreatic cancer screening is to really downstage pancreatic cancer at the time of diagnosis and allow someone to undergo, you know, ideally a curative-intent surgery. There is data out there showing that we can downstage the cancers, that survival after the time of diagnosis is substantially increased after detection in a pancreatic cancer screening program. But again, these are studies that are based on fairly small numbers of converters. And so I think we need more data in that space as well, which is one of the main questions that the PRECEDE Consortium is trying to answer with all of our prospective data.

Dr. Rafeh Naqash: Excellent. Well, I hope we see more interesting, exciting work from the PRECEDE Consortium at meetings as well as as a publication in JCO PO.

I would like to shift gears briefly for a minute or two, Bryson, to you as an individual, your career. How have you evolved over the last 5, 7 years? How did you end up doing cancer genetics? What were some of the lessons that you learned along the way and some of those that you would want to share with our listeners, especially trainees and early-career faculty?

Dr. Bryson Katona: Just to give you and others listening a little bit of background, but I am a physician-scientist, gastroenterologist, but a physician-scientist. And so my clinical practice is exclusively focused on individuals with hereditary GI cancer risk. I run a basic science lab where we do a lot of studies in organoids and mouse models of these hereditary GI cancer risk syndromes. And then I also have a clinical research group where we do early-phase clinical trials and screening and early detection trials, again in these same individuals with hereditary GI cancer risk.

I think probably the most important thing that kind of allowed me to get to this stage in my career where I am trying to, you know, essentially try to juggle all three of these balls at the same time is that I absolutely love what I do. And I am so incredibly interested in what I do. And I think for young individuals that are coming through the pipeline and going through training, you know, I mean, finding a specialty and a clinical niche where you truly just enjoy the work and you enjoy the patients and you enjoy your colleagues is by far the most important thing.

I ended up getting into the hereditary GI cancer space because a lot of my work earlier on in my career during my PhD and then in my postdoc work in the lab really focused on colorectal cancer. And I thought that focusing on cancer genetics could allow me to really continue to think from the molecular side of things while simultaneously being a gastroenterologist and taking care of patients with hereditary cancer risk.

Dr. Rafeh Naqash: Well, thank you so much for giving us a sneak peek of your journey and insights on what perhaps works best, especially when you love what you do. I think that is one of the most important reasons a work tries to keep you going and keep you interested, keep you passionate. So thank you again.

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

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

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

JCO PO author Dr. Philip Philip at Henry Ford Cancer Institute and Wayne State University shares insights into his JCO PO article, "Incorporating Circulating Tumor DNA Testing Into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group." Host Dr. Rafeh Naqash and Dr. Philip discuss how prospective trials are required to clarify the role of ctDNA as a valid surrogate end point for progression-free or overall survival in GI cancers.

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.

Today, we are excited to be joined by Dr. Philip Philip, Chair of Hematology and Oncology, as well as leader of GI and Neuroendocrine Oncology. He's also the Professor of Oncology and Pharmacology, as well as Co-Leader of the Pancreatic Cancer Program and Medical Director of the Cancer Clinical Trial and Translational Research Office at the Henry Ford Cancer Institute at Wayne State University. Dr. Philip is also the Senior Corresponding Author of the JCO Precision Oncology article entitled, "Incorporating Circulating Tumor DNA Testing into Clinical Trials: A Position Paper by the National Cancer Institute GI Oncology Circulating Tumor DNA Working Group."

At the time of this recording, our guest's disclosures will be linked in the transcript.

Dr. Philip, welcome to our podcast, and thank you so much for joining us today.

Dr. Philip Philip: Thank you so much, Dr. Naqash, for providing me this opportunity to be discussing this with you.

Dr. Rafeh Naqash: This is a very timely and interesting topic. We've done a couple of podcasts on ctDNA before, but none that is an opinion piece or a guidance piece based on what you guys have done. Could you tell us what led to this perspective piece or guidance manuscript being published? There is some background to this. Could you tell us, for the sake of our listeners, what was the initial thought process of why you all wanted to do this?

Dr. Philip Philip: The major reason for this was the fact that investigators were considering using ctDNA as a primary endpoint in clinical trials. Obviously, you hear my focus will be on gastrointestinal cancers. So, the idea was, can we use ctDNA instead of using the traditional endpoints such as disease-free survival, progression-free survival, or overall survival? And the question was, do we have enough data to support that in patients with gastrointestinal cancers? Now, the article obviously goes over some review of the data available, but the core of the article was not to do a comprehensive review of ctDNA use and the evidence so far, although we used that in really putting our recommendations. So, we really had to evaluate available data. But the focus was, what are the gaps? What do we need to do? And are we ready to use ctDNA as a primary endpoint in clinical trials?

Dr. Rafeh Naqash: Thank you for giving us that background. Obviously, a very broad, complicated topic with a bunch of emerging data that you've highlighted. But most importantly, for the sake of, again, trainees and listeners, could you help us understand the difference between tumor-informed and non-tumor-based ctDNA assessments?

Dr. Philip Philip: Sure. So, the tumor-informed is simply meaning that you're taking the genomic makeup or the DNA fingerprint of the cancer in a given patient, and you create a profile, and then use that profile to see whether that DNA is present in the blood. So, it's very simple. It's like barcoding DNA and then going and looking for it in the blood, which means that you have to have the primary tumor. When I say primary tumor, you need to have the tumor to start off with. It doesn't really apply, maybe easily, if you just have a fine-needle aspirate and things like that. So, you really have to have a good amount of the tumor for you to be able to do that. So, that's a tumor-informed, and from the name, you can easily understand how it's done, compared to the other one, which is uninformed, whereby off-the-shelf probes are used to look for tumor DNA. And again, they're based on prior experience and prior identification of the key DNA changes that will be seen in tumors. So, that's the difference between the two in terms of the principle of the test.

The uninformed will not require you to send the original tumor that you're trying to test. However, the informed, you do. The turnaround time is, again, a bit different because, as you would expect, it's shorter in the uninformed. And the reason for that, again, is the initial preparation of the profile that is going to be used in the future when you do serial testing. The sensitivity has been a bit of a discussion. Initially, people have thought that tumor-informed assays are more sensitive, more specific, more sensitive, et cetera. But in our review, we come to the conclusion saying that we don't think that's going to be a major difference. And there are obviously improvements happening in both types of assays. The sensitivities have been improving. So, at this point in time, we do feel that you have two types of assays, and we didn't feel strongly about recommending one over the other.

Dr. Rafeh Naqash: Thank you for that description. You mentioned something about sensitivity, specificity. Obviously, many of us who have ordered both tumor-informed and tumor-uninformed, we understand the differences with respect to the timing. The tumor-informed one can take more time. The uninformed one, being a sort of a liquid biopsy, may not necessarily have as much of a turnaround time. Could you briefly speak to those limitations or advantages in the context of the two versions?

Dr. Philip Philip: I just really want to also highlight that when we say turnaround time, so for the tumor-informed assays, the first assay that we do will be requiring a turnaround time. But once the pattern has been set and the profile has been documented, the subsequent testing doesn't require much in the way of waiting. However, when you're using this for the minimal residual disease, then you have a window of opportunity to work at. That's number one. So, it means that in patients who have resected cancer, you may end up having to wait longer than the tumor-uninformed assay, especially if you don't have easy access to your material for the baseline material to send.

And also, what we'd like to do is not do the test immediately after the operation or soon after the operation. Give it some time. There's a window where you can work at, and starting minimally two weeks after the surgery. But in my experience, I'd like to wait at least four weeks just to make sure that we got an accurate reading. Sometimes when you do it very early after surgery, because of the effect of the surgery and the release of the normal DNA is also, it may dilute the tumor DNA, and then you may get a false negative. So, basically, it depends on the clinical situation.

And your question is, is one better to be used than the other? I think ultimately, it ends up with the turnaround time not being as much of an issue. It might be in certain situations, depending on when you see the patients after the operation or any definitive treatment you've done and you want to look for minimal residual disease. But in general, I don't think that's going to be a real major issue.

Dr. Rafeh Naqash: I remember discussing this with one of the tumor-informed platforms with regards to this barcode you mentioned. They generate a fingerprint of sorts for the tumor on the tissue, then they map it out in the blood and try to assess it longitudinally. And one of the questions and discussions we had was around the fact that most of the time, these barcoded genes are not the driver genes. If you have a KRAS mutant tumor, it's not going to be the KRAS gene that they map out. It's something that is specific.

So, is there a possibility that when you are mapping out, let's say, a metastatic tumor where there is truncal and subclonal mutations at different sites, that you capture something that is not necessarily truncal, and that does not necessarily reflect some other metastatic site having a recurrence? So basically, over time, you don't see a specific mutational pattern or the signature on the tumor-informed, and then you see something on the scan which makes you think, "Well, it was not the right test," but actually it could be a different subclone or a clone mutation at a different site. Is there a concept that could help us understand that better?

Dr. Philip Philip: I think you raise a very important point. Although, I have to say from my practical experience, that is not a common thing to see. In fact, for some reason, we don't see it that often in any frequency that should, at this point in time, make us concerned about the serial testing. But what you were mentioning is a real challenge which can happen. Now, the question is, how often does the clonal evolution or the divergence happen to the point that it's going to be like a false negative, is what you're saying. At this point in time, we don't really have good information on that, or any good information, practical information. And when we went through the literature and we were looking for the evidence, that wasn't something which was there clearly telling us. Although, this is something that has to be studied further prospectively. And I don't know of a study, but I might be missing it, I don't know of a study which is systematically looking at this. Although it's a very valid hypothesis and theoretical basis for it, but in real life, we still have to see how much does it really interfere with the validity of this kind of testing.

Dr. Rafeh Naqash: Which brings us to the more important discussion around your manuscript. And I think that the overarching theme here is the consensus panel that you guys had recommended that ctDNA-based metrics be used as a co-primary endpoint.

Could you tell us, for early-phase trials, maybe phase two studies for that matter, could you tell us what were some of the aspects that led to this consensus being formed from your working group?

Dr. Philip Philip: Well, there were a number of reasons, in any order of priority, but one of them is we don't have a good sense of dynamics of the ctDNA. And again, remember this article was about gastrointestinal cancers. Maybe we know more about colon cancer, but, or colorectal cancer, but we don't know that well about the upper GI, like gastroesophageal, pancreatic, et cetera. So, we don't know what is the false negative percentages. And in fact, we know that there are certain sites of the disease, metastases, that do not lead to enough shedding of the DNA into the circulation. So, that was something else. I mean, false negativity, not knowing exactly what the dynamics are, especially in different disease types. So, that was another reason, which we felt that it may not be at this time primetime to really have those ctDNA tests as a primary endpoint.

We wanted to make sure that, on the other hand, we wanted to make sure that people consider including ctDNA more like a secondary endpoint so that we can gain the information that we're lacking, at least the ones I mentioned to you. So, that was an important point of our discussions and deliberations when we were writing the article.

Dr. Rafeh Naqash: And I myself have been on both sides of the aisle where - I treat people with lung cancer, you mentioned appropriately that most of the data that we have for ctDNA is generated from GI cancers, especially colorectal - on the lung cancer side, I myself had a patient with an early-stage cancer, had treatment, surgery, immunotherapy, and then had ctDNA that was tumor-informed, was positive four to five months before the imaging actually showed up. And on the other side, I've also had an individual where early-stage lung cancer, surgery, immunotherapy, and then had PET scans that showed a positive finding, but the ctDNA, tumor-informed ctDNA, was negative multiple times. So, I've seen both aspects of it, and your paper tries to address some of these questions on how to approach a negative, radiologically negative imaging but positive ctDNA potentially, and vice versa. Could you elaborate upon that a little bit?

Dr. Philip Philip: Well, obviously, we do see this in practice. Again, I do GI oncology. I have patients who, you do ctDNA. I mean, my advice to anyone, when you order a test, you have to make sure that you know what you're going to do with the test, because that's the most important thing. You get a positive test, you do something. You get a negative test, you do something. But most importantly, our patients who you're following up, they are very anxious for a diagnosis they have that is not- I mean, it's cancer. If you're doing these tests, if we get continuous, repeatedly negative testing, then you really have to also tell the patient that there's a false negativity. And I mentioned to you earlier, there are certain sites of disease, like peritoneal, they may not be producing enough, or there are some tumors, their biology is such that they don't release as much to be detected in the blood. Now, one day we will get maybe a more sensitive test, but I'm talking about the tests we have now.

On the other hand, if you get a positive testing, you have to make a distinction for ctDNA in the minimal residual disease situation. If you get a positive test, there is enough evidence that the patient has a worse prognosis. There's evidence for that. No one can dispute that. Again, I'm talking about colorectal cancer where there are a lot of data for that. So, in that situation, there are studies that are looking, if you get a positive test in someone who you're not intending to give any adjuvant treatment, there are studies looking into that, both in terms of intensifying, like chemotherapy, in certain patients. And also, there's work being done, if you have a negative test in someone who has stage III disease, for example, or definitely stage II disease, they may not need to give them chemo. Those things are happening. But in metastatic disease, it's a different situation. Or even in someone who has received surgery, adjuvant chemotherapy, in those patients where they, whether they're now under, in the surveillance mode, those patients, if you have a positive, it may be positive. I had a recent patient like those, eight months before we saw anything on the scans. So, the question is, if you have a positive test, is there any advantage in giving them treatment, systemic treatment? Of course, we're assuming that the PET scan is negative. So, is there really any advantage in giving someone treatment ahead of time, before you see the imaging changes? That kind of data, in my opinion, is not really available or strong. You can always think of it in different ways, explain it in different ways. It's minimal disease, maybe you get a better response. But I don't know if we really can justify at this time. Therefore, in my practice, my own practice, I do not treat just a positive ctDNA. Again, that's different than after surgery when you're thinking of whether to give adjuvant treatment, no adjuvant treatment. But someone who's finished treatments and then you're just serially monitoring the disease, those patients, I do not treat them with chemotherapy. And that was something which, based on the literature we reviewed, there was nothing out there to definitely- I mean, if you see something positive, you will do a scan earlier, you will talk to the patient, examine the patient, whatever. But if there's nothing there, starting a treatment, that's not justified at this point in time.

Now, you need to do a study like that. Definitely, you need to do a study. But I can tell you that from my experience, having been involved with study design and all that, it's not an easy trial to do. It's going to be a trial- at a minimum, it will take many patients, it will take longer time to complete, and there are a number of variables there. If someone is willing to put a lot of money into it, it can be done. But I can tell you that that kind of intention to do a study like that has been very much a challenge at this time.

Dr. Rafeh Naqash: Of course, as you mentioned, the follow-up time that you need for a study like that is going to be very long to get to meaningful outcomes.

Dr. Philip Philip: You need to be very patient to do such a study. But the problem with a very long study is that things change, standard of care changes with time, and the assays will change. So, that's why we don't have that kind of data. I'm not sure if there are people in the community or in the academic centers who do treat based on only positive ctDNA.

The other thing is that you really have to always consider the psychological impact of these tests on patients and caregivers. Sometimes it can be really very stressful, burdensome to people to sit there just waiting for the disease to show up on a scan. And therefore, in my opinion, I'm not saying definitely don't use it in that situation, I'm just saying that you have to personalize it also, to see the patient who you would like to do it and then other patients who may not do it, or you think that it's not good for them to do it. And the patient also has to understand the outcome of the test and how you're going to be interpreting it.

Dr. Rafeh Naqash: That's a lot of great insights, Dr. Philip, and I know you've been involved in trial designs. I'm sure NCT and cooperative groups are actively thinking and incorporating ctDNA-based metrics as one of the endpoints in their trial. I know of a GU study that's, I think it's an Alliance study, trying to de-escalate treatment based on ctDNA. I have one of my colleagues who's also a GU investigator at OU, he's doing a ctDNA-based, tumor-informed-based de-escalation. So, obviously, more and more data, hopefully, that'll be generated in the next couple of years.

Dr. Philip Philip: But remember, these studies are not using it as an endpoint. They're using it as a means of optimizing treatment, which is a bit different. So, as an endpoint, can you do a phase III trial of, let's say, a thousand patients, and your primary endpoint is not survival, but you're saying, "Can I reduce the ctDNA, clear it earlier, or whatever?" That's the sort of thing this article was about. We can't do that at this time.

Dr. Rafeh Naqash: I totally understand. Thank you for explaining the difference, and hopefully more to come in this space in the next couple of years.

I briefly wanted to touch upon your personal career and journey based on all that you've done and accomplished. Could you tell us about how you started, what your journey has been like, and how that connects with what you're doing right now, including mentoring other trainees and junior faculty?

Dr. Philip Philip: Well, when I was in high school, I wanted to be an engineer, but I grew up in Baghdad, and all my friends wanted to do medicine, so I went with the tide, so I did medicine. I don't regret that. I would do it again if I had the opportunity. The reason why I did oncology was, I left the country and did a PhD in clinical pharmacology at the University of London. And that really got me, it was a topic which included, which was on cancer. So, I really got interested in a disease that is really a lot of science, and things are new, or were new at the time. And if I want to look back what I was doing, the beginning of my training in the 80s, second half of the 80s, and now, it's unbelievable how things have changed.

But one of the things which I really have to say is that almost all my life I've been in what we call academic institutions. But I firmly believe that for people, whether academic or not, you have to be a very good, astute clinician, because many of the things we do, really, we're trying to put the patients in the center. It's not only doing fancy science, it's to do things that help the patients. And you can bring in bits and pieces of fancy science or less fancy science, but that's something which is really extremely important for us to think about, being a very good clinician, very good doctor, because medicine is a science, whether you're practicing as a solo practitioner or you're part of a large academic center. It's the way you think, the way you interrogate things that you're not sure of, the way you collaborate, the way you learn every day. I mean, at my age, I still don't like to miss any tumor board, because in each tumor board, there's something you learn, even if you think that you know everything. So, that's really the whole thing of it, is that be a very good clinician, be open-minded. Always, you have to think of things that, they look interesting, they look somehow unexplained. Always try to help find the solutions and do that.

One of the major things that I feel that people should do is being also very focused on things. I mean, you have to also know what you want to do in the next 5, 10, 15 years. Because although everyone is in it in the same way when we start, but there are different things that drive people, people who want to do more of the formal research, like being an academic-like institution. But there are also a lot of people who are very successful outside of a- what we call an academic setting. In the United States, most people are not working in an academic kind of setting. Although, for me, the distinction between academic and community is getting less and less, because if you think that you do phase I trials in academia only, that's not true, because there are, in fact, in the state of Michigan, the most active phase I doctor is not even in academia, he's in private practice. So, you can do all these things. It's a matter of what you like to do, and you really have to make sure you know what you want to do. Because sometimes people are, especially early on, they get a bit confused, "What I want to do." There's an issue of doing general oncology versus subspecialist. If you're a subspecialist doing only GI, you have to make sure that you really also have some kind of recognition that you're only a GI oncologist, recognition regional, national, international, but some degree of recognition that you feel that people are coming to you for advice as a second opinion or whatever it is. But again, you have to decide what you think you want to be, how you want to be, because there's a lot of options here between community practice, academic practice, industry, and of course, there's always the administrative thing. Some people tend to be more like going into the line of being an administrator. So, there's a lot of options for you.

Dr. Rafeh Naqash: Well, thank you again, Dr. Philip, for those pearls of wisdom. I think that was very insightful. I'm sure all the trainees and early-career investigators will find all that advice very helpful. Thank you again for joining us today.

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

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In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma" by Dr. Miles C. Andrews, et al. published on June 07, 2024.

The guest on this podcast episode has no disclosures to declare.

Jiasen He:

Hello and welcome to the JCO Precision Oncology Article Insights. I'm your host, Jiasen, and today we'll be discussing the JCO Precision Oncology article, "Predictive Impact of Tumor Mutational Burden on Real-World Outcomes of First-Line Immune Checkpoint Inhibition in Metastatic Melanoma," by Dr. Miles C. Andrews and colleagues. This study was supported by Foundation Medicine, a for-profit company that conducts FDA-regulated molecular diagnostics, including assays used to measure tumor mutational burdens, or TMB, as described in this article.

Immune checkpoint inhibitor (ICI) therapy has become a cornerstone in the treatment of metastatic melanoma. They work by activating the patient's own immune system, representing a fundamentally different approach from traditional chemotherapy. Several biomarkers have emerged as promising tools to predict ICI therapy response, and TMB is one of the most extensively studied. TMB is defined as the number of somatic mutations per megabase of an interrogated genome sequence. In the KEYNOTE-158 study, patients with high TMB showed better response rates and longer progression-free survival compared to those with low TMB, which led to the FDA tumor-agnostic approval of TMB as a biomarker to guide ICI therapy.

In this manuscript, Dr. Andrews and colleagues set out to answer an important question: does TMB predict outcomes of ICI therapy in real-world patients with advanced melanoma? To explore this, they analyzed de-identified data from the nationwide Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). To be included, patients needed to have had at least two visits to a Flatiron Health clinic and a Foundation Medicine Comprehensive Genomic Profiling report. Eligible patients had received first-line treatment with either monotherapy (nivolumab or pembrolizumab) or dual therapy with the combination of ipilimumab and nivolumab for metastatic melanoma. They also needed a tissue-based TMB score from either the FoundationOne or FoundationOne CDx genomic test. For this study, TMB less than 10 mutations per megabase was considered low TMB; TMB equal to or more than 10 mutations per megabase was considered high TMB; and TMB equal to or more than 20 mutations per megabase was considered very high TMB. Of the 497 patients in the final cohort, 29% had low TMB, while 71% had high TMB, and 50% had very high TMB.

The authors observed that patients with very high TMB were more often male, had BRAF wild-type tumors, and were more likely to receive anti-PD-1 monotherapy. This group also had tumors more commonly sampled from brain and lung metastases. Patients with high TMB but not very high TMB were more likely to carry the BRAF V600K mutation and were least likely to have lung metastases. Meanwhile, those with low TMB tended to be younger and had disease limited to non-visceral sites. As expected, the presence of ultraviolet mutation signatures, a known driver of melanoma, was strongly associated with TMB. UV signatures were found in just 18% of the low TMB group, but in 89% of the high TMB and 93% of the very high TMB group. High TMB was found to be prognostic of improved real-world progression-free survival (PFS) and overall survival (OS) in patients receiving both monotherapy and dual immune checkpoint inhibitors, even after adjusting for other established prognostic factors. Interestingly, in the low TMB group, overall survival was likely confounded by the availability of effective second-line targeted therapy, particularly for BRAF-mutant patients. These patients had better outcomes compared to their BRAF wild-type counterparts, likely reflecting a greater reliance on salvage therapy in low TMB patients who derived less benefit from first-line immunotherapy.

The authors then further examined the ICI outcomes using stepwise TMB thresholds, with TMB less than 10 as low, 10 to 19 as high, and equal to or more than 20 as very high. For those receiving ICI monotherapy, both PFS and OS were highest in the very high TMB group, followed by the high TMB group, and lowest in the low TMB group. However, in patients treated with dual ICI therapy, the results diverged. While low TMB patients still had the poorest outcomes, those with high TMB (mutations 10 to 19 per megabase) had better PFS and overall survival than those with very high TMB (mutations equal to or more than 20 per megabase).

The authors then conducted exploratory multivariable modeling, showing that among very high TMB patients with BRAF mutations, dual ICI therapy was associated with a significantly higher hazard ratio compared to monotherapy. They concluded that dual ICI may not benefit, and could even harm, patients with very high TMB, whereas those with TMB between 10 and 20 mutations per megabase may get more from the intensified regimen. Importantly, as the authors stated in the manuscript, we need to note that in this cohort, very high TMB patients were more likely to have brain metastases at treatment initiation, be male, and lack BRAF V600E/K mutations—all factors associated with poorer prognosis. This might partially explain inferior outcomes to dual ICI in very high TMB patients, as patients were not randomly assigned to therapy in this retrospective, real-world study. As such, these findings should be interpreted with caution and validated in future studies.

In summary, this study showed that in a real-world setting, high tumor mutational burden predicts better outcomes with immune checkpoint inhibitor therapy in patients with advanced melanoma. Interestingly, the authors found that dual ICI therapy may offer no added benefit for patients with very high TMB compared to ICI monotherapy. However, this was a retrospective, non-randomized study, and the cohorts were imbalanced for some known risk factors, which could confound outcomes. As a result, these findings should be interpreted with caution and will need to be validated in future prospective studies.

Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.

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

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

JCO PO author Dr. Dean A. Regier at the Academy of Translational Medicine, University of British Columbia (UBC), and the School of Population and Public Health, BC Cancer Research Institute shares insights into his JCO PO article, "Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation."

Host Dr. Rafeh Naqash and Dr. Regier discuss the real-world clinical effectiveness and cost-effectiveness of multigene panels compared with single-gene BRAF testing to guide therapeutic decisions in advanced melanoma.

Dr. Rafeh Naqash:
Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center in the University of Oklahoma.

Today, we are excited to be joined by Dr. Dean A. Regier, Director at the Academy of Translational Medicine, Associate Professor at the School of Population and Public Health, UBC Senior Scientist at the British Columbia Cancer Research Institute, and also the senior author of the JCO Precision Oncology article entitled "Clinical Effectiveness and Cost-Effectiveness of Multigene Panel Sequencing in Advanced Melanoma: A Population-Level Real-World Target Trial Emulation."

At the time of this recording, our guest's disclosures will be linked in the transcript.
Dean, welcome to our podcast and thank you for joining us today.

Dr. Dean Regier:
Thank you. I'm delighted to be here.

Dr. Rafeh Naqash:
So, obviously, you are from Canada, and medicine, or approvals of drugs to some extent, and in fact approvals of gene testing to some extent is slightly different, which we'll come to learn about more today, compared to what we do in the US—and in fact, similarly, Europe versus North America to a large extent as well.

Most of the time, we end up talking about gene testing in lung cancer. There is a lot of data, a lot of papers around single-gene panel testing in non-small cell lung cancer versus multigene testing. In fact, a couple of those papers have been published in JCO PO, and it has shown significant cost-effectiveness and benefit and outcomes benefit in terms of multigene testing. So this is slightly, you know, on a similar approach, but in a different tumor type. So, could you tell us first why you wanted to investigate this question? What was the background to investigating this question? And given your expertise in health economics and policy, what are some of the aspects that one tends or should tend to understand in terms of cost-effectiveness before we go into the results for this very interesting manuscript?

Dr. Dean Regier:
Yeah, of course, delighted to. So, one of the reasons why we're deeply interested in looking at comparative outcomes with respect to single- versus multigene testing— whether that's in a public payer system like Canada or an insurer system, a private system in the United States— is that the question around does multigene versus single-gene testing work, has not typically tested in randomized controlled trials. You don't have people randomized to multigene versus single-gene testing.

And what that does, it makes the resulting evidence base, whether it's efficacy, safety, or comparative cost-effectiveness, highly uncertain. So, the consequence of that has been uneven uptake around the world of next-generation sequencing panels. And so if we believe that next-gen sequencing panels are indeed effective for our patients, we really need to generate that comparative evidence around effectiveness and cost-effectiveness. So we can go to payers, whether it be single payer or a private insurer, to say, "Here are the comparative outcomes." And when I say that uptake has been uneven, uptake there's been actually plenty, as you know, publications around that uneven uptake, whether it be in Europe, in the United States, in Canada. And so we're really interested in trying to produce that evidence to create the type of deliberations that are needed to have these types of technologies accessible to patients. And part of those deliberations, of course, is the clinical, but also in some contexts, cost-effectiveness.

And so, we really start from the perspective of, can we use our healthcare system data, our learning healthcare system, to generate that evidence in a way that emulates a randomized controlled trial? We won't be able to do these randomized controlled trials for various, like really important and and reasons that make sense, quite frankly. So how can we mimic or emulate randomized controlled trials in a way that allows us to make inference around those outcomes? And for my research lab, we usually think through how do we do causal inference to address some of those biases that are inherent in observational data. So in terms of advanced melanoma, we were really interested in this question because first of all, there have been no randomized controlled trials around next-gen sequencing versus single-gene testing. And secondly, these products, these ICIs, immune checkpoint inhibitors, and BRAF and MEK inhibitors, they are quite expensive. And so the question really becomes: are they effective? And if so, to what extent are they cost-effective? Do they provide a good reason to have information around value for money?

Dr. Rafeh Naqash:
So now going to the biology of melanoma, so we know that BRAF is one of the tumor-agnostic therapies, it has approvals for melanoma as well as several other tumor types. And in fact, I do trials with different RAF-RAS kinase inhibitors. Now, one of the things that I do know is, and I'm sure some of the listeners know, is the DREAMseq trial, which was a melanoma study that was an NCI Cooperative Group trial that was led by Dr. Mike Atkins from Georgetown a couple of years back, that did show survival benefit of first-line immunotherapy sequencing. It was a sequencing study of whether to do first-line BRAF in BRAF-mutant melanoma followed by checkpoint inhibitors, or vice versa. And the immune checkpoint inhibitors followed by BRAF was actually the one that showed benefit, and the trial had to stop early, was stopped early because of the significant benefit seen.

So in that context, before we approach the question of single-gene versus multigene testing in melanoma, one would imagine that it's already established that upfront nivolumab plus ipilimumab, for that matter, doublet checkpoint inhibitor therapy is better for BRAF-mutant melanoma. And then there's no significant other approvals for melanoma for NRAS or KIT, you know, mucosal melanomas tend to have KIT mutations, for example, or uveal melanomas, for that matter, have GNAQ, and there's no targeted therapies. So, what is the actual need of doing a broader testing versus just testing for BRAF? So just trying to understand when you started looking into this question, I'm sure you kind of thought about some of these concepts before you delved into that.

Dr. Dean Regier:
I think that is an excellent question, and it is a question that we asked ourselves: did we really expect any differences in outcomes between the testing strategies? And what did the real-world implementation, physician-guided, physician-led implementation look like? And so, that was kind of one of the other reasons that we really were interested is, why would we go to expanded multigene panel sequencing at all? We didn't really expect or I didn't expect an overall survival a priori. But what we saw in our healthcare system, what happened in our healthcare system was the implementation in 2016 of this multigene panel. And this panel covered advanced melanoma, and this panel cost quite a bit more than what they were doing in terms of the single-gene BRAF testing. And so when you're a healthcare system, you have to ask yourself those questions of what is the additional value associated with that?

And indeed, I think in a healthcare system, we have to be really aware that we do not actually follow to the ideal extent randomized controlled trials or trial settings. And so that's the other thing that we have to keep in mind is when these, whether it's an ICI or a BRAF MEK inhibitor, when these are implemented, they do not look like randomized controlled trials. And so, we really wanted to emulate not just a randomized controlled trial, but a pragmatic randomized controlled trial to really answer those real-world questions around implementation that are so important to decision making.

Dr. Rafeh Naqash:
Sure. And just to understand this a little better: for us in the United States, when we talk about multigene testing, we generally refer to, these days, whole-exome sequencing with whole-transcriptome sequencing, which is like the nuclear option of of the testings, which is not necessarily cheap. So, when you talk about multigene testing in your healthcare system, what does that look like? Is it a 16-gene panel? Is it a 52-gene panel? What is the actual makeup of that platform?

Dr. Dean Regier:
Excellent question. Yeah, so at the time that this study is looking at, it was 2016, when we, as BC Cancer—so British Columbia is a population right now of 5.7 million people, and we have data on all those individuals. We are one healthcare system providing health care to 5.7 million people. In 2016, we had what I call our "home-brew" multigene panel, which was a 53-gene panel that was reimbursed as standard of care across advanced cancers, one of them being advanced melanoma. We have evolved since then. I believe in 2022, we are using one of the Illumina panels, the Focus panel. And so things have changed; it's an evolving landscape. But we're specifically focused on the 53-gene panel. It was called OncoPanel. And that was produced in British Columbia through the Genome Sciences Centre, and it was validated in a single-arm trial mostly around validity, etc.

Dr. Rafeh Naqash:
Thank you for explaining that. So now, onto the actual meat and the science of this project. So, what are some of the metrics from a health economy standpoint that you did look at? And then, methodology-wise, I understand, in the United States, we have a fragmented healthcare system. I have data only from my institution, for that matter. So we have to reach out to outside collaborators and email them to get the data. And that is different for you where you have access to all the data under one umbrella. So could you speak to that a little bit and how that's an advantage for this kind of research especially?

Dr. Dean Regier:
Yeah. In health economics, we look at the comparative incremental costs against the incremental effectiveness. And when we think about incremental costs, we think not just about systemic therapy or whether you see a physician, but also about hospitalizations, about all the healthcare interactions related to oncology or not that a patient might experience during their time or interactions with the healthcare system. You can imagine with oncology, there are multiple interactions over a prolonged time period depending on survival. And so what we try to do is we try to—and the benefit of the single-payer healthcare system is what we do is we link all those resource utilization patterns that each patient encounters, and we know the price of that encounter. And we compare those incremental costs of, in this case, it's the multigene panel versus the single-gene panel. So it's not just the cost of the panel, not just the cost of systemic therapy, but hospitalizations, physician encounters, etc.

And then similarly, we look at, in this case, we looked at overall survival - we can also look at progression-free survival - and ask the simple question, you know, what is the incremental cost per life-year gained? And in that way, we get a metric or an understanding of value for money. And how we evaluate that within a deliberative priority setting context is we look at safety and efficacy first. So a regulatory package that you might get from, in our case, Health Canada or the FDA, so we look at that package, and we deliberate on, okay, is it safe and is it effective? How many patients are affected, etc. And then separately, what is the cost-effectiveness? And at what price, if it's not cost-effective, at what price would it be cost-effective? Okay, so for example, we have this metric called the incremental cost-effectiveness ratio, which is incremental cost in the numerator, and in this case, life-years gained in the denominator. And if it is around $50,000 or $100,000 per life-year gained—so if it's in that range, this ratio—then we might say it's cost-effective. If it's above this range, which is common in oncology, especially when we talk about ICIs, etc., then you might want to negotiate a price. And indeed, when we negotiate that price, we use the economic evaluation, that incremental cost-effectiveness ratio, as a way to understand at what price should we negotiate to in order to get value for money for the healthcare system.

Dr. Rafeh Naqash:
Thank you for explaining those very interesting terminologies. Now, one question I have in the context of what you just mentioned is, you know, like the drug development space, you talked about efficacy and safety, but then on the safety side, we talk about all-grade adverse events or treatment-related adverse events—two different terminologies. From a healthcare utilization perspective, how do you untangle if a patient on a BRAF therapy got admitted for a hypoxic respiratory failure due to COPD, resulting in a hospitalization from the cost, overall cost utilization, or does it not matter?

Dr. Dean Regier:
We try to do as much digging into those questions as possible. And so, this is real-world data, right? Real-world data is not exactly as clean as you'd get from a well-conducted clinical trial. And so what we do is we look at potential adverse event, whether it's hospitalization, and the types of therapies around that hospitalization to try- and then engage with clinicians to try to understand or tease out the different grades of the adverse event. Whether it's successful or not, I think that is a real question that we grapple with in terms of are we accurate in delineating different levels of adverse events? But we try to take the data around the event to try to understand the context in which it happens.

Dr. Rafeh Naqash:
Thank you for explaining that, Dean.

So, again to the results of this manuscript, could you go into the methodology briefly? Believe you had 147 patients, 147 patients in one arm, 147 in the other. How did you split that cohort, and what were some of the characteristics of this cohort?

Dr. Dean Regier:
So, the idea, of course, is that we have selection criteria, study inclusion criteria, which included in our case 364 patients. And these were patients who had advanced melanoma within our study time period. So that was 2016 to 2018. And we had one additional year follow. So we had three total years. And what we did is that we linked our data, our healthcare system data. During this time, because the policy change was in 2016, we had patients both go on the multigene panel and on the single-gene BRAF testing. So, the idea was to emulate a pragmatic randomized controlled trial where we looked at contemporaneous patients who had multigene panel testing versus single-gene BRAF testing.

And then we did a matching procedure—we call it genetic matching. And that is a type of matching that allows us to balance covariates across the patient groups, across the multigene versus BRAF testing cohorts. The idea again is, as you get in a randomized controlled trial, you have these baseline characteristics that look the same. And then the hope is that you address any source selection or confounding biases that prohibit you to have a clean answer to the question: Is it effective or cost-effective? So you address all those biases that may prohibit you to find a signal if indeed a signal is there.

And so, what we did is we created—we did this genetic matching to balance covariates across the two cohorts, and we matched them one-to-one. And so what we were able to do is we were able to find, of those 364 patients in our pool, 147 in the multigene versus 147 in the single-gene BRAF testing that were very, very similar. In fact, we created what's called a directed acyclic graph or a DAG, together with clinicians to say, "Hey, what biases would you expect to have in these two cohorts that might limit our ability to find a signal of effectiveness?" And so we worked with clinicians, with health economists, with epidemiologists to really understand those different biases at play. And the genetic matching was able to match the cohorts on the covariates of interest.

Dr. Rafeh Naqash:
And then could you speak on some of the highlights from the results? I know you did survival analysis, cost-effectiveness, could you explain that in terms of what you found?

Dr. Dean Regier:
We did two analyses. The intention-to-treat analysis is meant to emulate the pragmatic randomized controlled trial. And what that does is it answers the question, for all those eligible for multigene or single-gene testing: What is the cost-effectiveness in terms of incremental life-years gained and incremental cost per life-years gained? And the second one was around a protocol analysis, which really answered the question of: For those patients who were actually treated, what was the incremental effectiveness and cost-effectiveness? Now, they're different in two very important ways. For the intention-to-treat, it's around population questions. If we gave single-gene or multigene to the entire population of advanced melanoma patients, what is the cost-effectiveness? The per-protocol is really around that clinical question of those who actually received treatment, what was the incremental cost and effectiveness? So very different questions in terms of population versus clinical cost and effectiveness.

So, for the intention-to-treat, what we found is that in terms of life-years gained is around 0.22, which is around 2.5 months of additional life that is afforded to patients who went through the multigene panel testing versus the single-gene testing. That was non-statistically significant from zero at the 5% level. But on average, you would expect this additional 2.5 months of life. The incremental costs were again non-statistically significant, but they're around $20,000. And so when we look at incremental cost-effectiveness, we can also look at the uncertainty around that question, meaning what percentage of incremental cost-effectiveness estimates are likely to be cost-effective at different willingness-to-pay thresholds? Okay? So if you are willing to pay $100,000 to get one gain of life-years, around 52.8% of our estimates, in terms of when we looked at the entire uncertainty, would be cost-effective. So actually that meets the threshold of implementation in our healthcare system. So it's quite uncertain, just over 50%. But what we see is that decision-makers actually have a high tolerance for uncertainty around cost-effectiveness. And so, while it is uncertain, we would say that, well, the cost-effectiveness is finely balanced.

Now, when we looked at the population, the per-protocol population, those folks who just got treatment, we actually have a different story. We have all of a sudden around 4.5 or just under 5 months of life gained that is statistically significantly different from zero, meaning that this is a strong signal of benefit in terms of life-years gained. In terms of the changes in costs or the incremental costs, they are larger again, but statistically insignificant. So the question now is, to what extent is it cost-effective? What is the probability of it being cost-effective? And at the $100,000 per life-year gained willingness-to-pay, there was a 73% chance that multigene panel testing versus single-gene testing is cost-effective.

Dr. Rafeh Naqash:
So one of the questions I have here, this is a clarification both for myself and maybe the listeners also. So protocol treatment is basically if you had gene testing and you have a BRAF in the multigene panel, then the patient went on a BRAF treatment. Is that correct?

Dr. Dean Regier:
It's still physician choice. And I think that's important to say that. So typically what we saw in both in our pre- and post-matching data is that we saw around 50% of patients, irrespective of BRAF status, get an ICI, which is appropriate, right? And so the idea here is that you get physician-guided care, but if the patient no longer performs on the ICI, then it gives them a little bit more information on what to do next. Even during that time when we thought it wasn't going to be common to do an ICI, but it was actually quite common.

Dr. Rafeh Naqash:
Now, did you have any patients in this study who had the multigene testing done and had an NRAS or a KIT mutation and then went on to those therapies, which were not captured obviously in the single-gene testing, which would have just tried to look at BRAF?

Dr. Dean Regier:
So I did look at the data this morning because I thought that might come up in terms of my own questions that I had. I couldn't find it, but what we did see is that some patients went on to clinical trials. So, meaning that this multigene panel testing allowed, as you would hope in a learning healthcare system, patients to move on to clinical trials to have a better chance at more appropriate care if a target therapy was available.

Dr. Rafeh Naqash:
And the other question in that context, which is not necessarily related to the gene platform, but more on the variant allele frequency, so if you had a multigene panel that captured something that was present at a high VAF, with suspicion that this could be germline, did you have any of those patients? I'm guessing if you did, probably very low number, but I'm just thinking from a cost-effective standpoint, if you identify somebody with germline, their, you know, first-degree relative gets tested, that ends up, you know, prevention, etc. rather than somebody actually developing cancer subsequently. That's a lot of financial gains to the system if you capture something early. So did you look at that or maybe you're planning to look at that?

Dr. Dean Regier:
We did not look at that, but that is a really important question that typically goes unanswered in economic evaluations. And so, the short answer is yes, that result, if there was a germline finding, would be returned to the patient, and then the family would be able to be eligible for screening in the appropriate context. What we have found in economic evaluations, and we've recently published this research, is that that scope of analysis is rarely incorporated into the economic evaluation. So those downstream costs and those downstream benefits are ignored. And when you- especially also when you think about things like secondary or incidental findings, right? So it could be a germline finding for cancer, but what about all those other findings that we might have if you go with an exome or if you go with a genome, which by the way, we do have in British Columbia—we do whole-genome and transcriptome sequencing through something called the Personalized OncoGenomics program. That scope of evaluation, because it's very hard to get the right types of data, because it requires a decision model over the lifetime of both the patients and potentially their family, it becomes very complicated or complex to model over patients' and families' lifetime. That doesn't mean that we should not do it, however.

Dr. Rafeh Naqash:
So, in summary Dean, could you summarize some of the known and unknowns of what you learned and what you're planning in subsequent steps to this project?

Dr. Dean Regier:
Our North Star, if you will, is to really understand the entire system effect of next-generation sequencing panels, exome sequencing, whole genomes, or whole genomes and transcriptome analysis, which we think should be the future of precision oncology. The next steps in our research is to provide a nice base around multigene panels in terms of multigene versus single-gene testing, whether that be colorectal cancer, lung cancer, melanoma, etc., and to map out the entire system implications of implementing next-generation sequencing panels.

And then we want to answer the questions around, "Well, what if we do exomes for all patients? What if we do whole genomes and transcriptomes for all patients? What are the comparative outcomes for a true tumor-agnostic precision oncology approach, accounting for, as you say, things like return of results with respect to hereditary cancers?" I think the challenge that's going to be encountered is really around the persistent high costs of something like a whole-genome and transcriptome sequencing approach. Although we do see the technology prices going down—the "$1,000 genome" or "$6,000 genome" on whatever Illumina machine you might have—that bioinformatics is continuing to be expensive.

And so, there are pipelines that are automated, of course, and you can create a targeted gene report really rapidly within a reasonable turnaround time. But of course, for secondary or what I call level two analysis, that bioinformatics is going to continue to be expensive. And so, we're just continually asking that question is: In our healthcare system and in other healthcare systems, if you want to take a precision oncology approach, how do you create the pipelines? And what types of technologies really lend themselves to benefits over and above next-generation sequencing or multigene panels, allowing for access to off-label therapies? What does that look like? Does that actually improve patients? I think some of the challenges, of course, is because of heterogeneity, small benefiting populations, finding a signal if a signal is indeed there is really challenging. And so, what we are thinking through is, with respect to real-world evidence methods and emulating randomized controlled trials, what types of evidence methods actually allow us to find those signals if indeed those signals are there in the context of small benefiting populations?

Dr. Rafeh Naqash:
Thank you so much, Dean. Sounds like a very exciting field, especially in the current day and age where cost-effectiveness, financial toxicity is an important aspect of how we improve upon what is existing in oncology. And then lots more to be explored, as you mentioned.

The last minute and a half I want to ask about you as an individual, as a researcher. There's very few people who have expertise in oncology, biomarkers, and health economics. So could you tell us for the sake of our trainees and early career physicians who might be listening, what was your trajectory briefly? How did you end up doing what you're doing? And maybe some advice for people who are interested in the cost of care, the cost of oncology drugs - what would your advice be for them very briefly?

Dr. Dean Regier:
Sure. So I'm an economist by training, and indeed I knew very little about the healthcare system and how it works. But I was recruited at one point to BC Cancer, to British Columbia, to really try to understand some of those questions around costs, and then I learned also around cost-effectiveness. And so, I did training in Scotland to understand patient preferences and patient values around quality of care, not just quantity of life, but also their quality of life and how that care was provided to them. And then after that, I was at Oxford University at the Nuffield Department of Population Health to understand how that can be incorporated into randomized control trials in children. And so, I did a little bit of learning about RCTs. Of course, during the way I picked up some epidemiology with deep understanding of what I call econometrics, what others might call biostatistics or just statistics.

And from there, it was about working with clinicians, working with epidemiologists, working with clinical trialists, working with economists to understand the different approaches or ways of thinking of how to estimate efficacy, effectiveness, safety, and cost-effectiveness. I think this is really important to think through is that we have clinical trialists, we have people with deep understanding of biostatistics, we have genome scientists, we have clinicians, and then you add economists into the mix. What I've really benefited from is that interdisciplinary experience, meaning that when I talk to some of the world's leading genome scientists, I understand where they're coming from, what their hope and vision is. And they start to understand where I'm coming from and some of the tools that I use to understand comparative effectiveness and cost-effectiveness. And then we work together to actually change our methods in order to answer those questions that we're passionate about and curious about better for the benefit of patients.

So, the short answer is it's been actually quite a trajectory between Canada, the UK. I spent some time at the University of Washington looking at the Fred Hutch Cancer Research Center, looking at precision oncology. And along the way, it's been an experience about interdisciplinary research approaches to evaluating comparative outcomes. And also really thinking through not just at one point in time on-off decisions—is this effective? Is it safe? Is it cost-effective?—not those on-off decisions, but those decisions across the lifecycle of a health product. What do those look like at each point in time? Because we gain new evidence, new information at each point in time as patients have more and more experience around it. And so what really is kind of driving our research is really thinking about interdisciplinary approaches to lifecycle evaluation of promising new drugs with the goal of having these promising technologies to patients sooner in a way that is sustainable for the healthcare system.

Dr. Rafeh Naqash:
Awesome. Thank you so much for those insights and also giving us a sneak peek of your very successful career.

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

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

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

In this JCO PO Article Insights episode, host Harold Tan summarizes Low Kynurenine Levels Among Exceptional Responders on Phase Ib Trial of the HDAC Inhibitor Abexinostat with Pazopanib by Tsang et al, published November 07, 2024.

Harold Nathan Tan:

Welcome to JCO Precision Oncology Article Insights, where we explore cutting-edge discoveries in the world of cancer treatment and research. I'm Harold Nathan Tan, your host, and today we're taking a focused look at a compelling phase Ib trial led by Dr. Tsang, which investigates a combination of abexinostat, a histone deacetylase inhibitor, with pazopanib, a VEGF-targeting tyrosine kinase inhibitor, in patients with advanced solid tumors.

VEGF inhibition has long been an established therapeutic strategy across a wide range of tumor types, including colorectal, ovarian, sarcoma, and renal cell carcinoma. These agents function by disrupting tumor angiogenesis, effectively limiting oxygen and nutrient delivery to malignant cells and contributing to improved survival outcomes. However, over time, acquired resistance remains a significant challenge.

A key mechanism implicated in this resistance involves the upregulation of hypoxia-inducible factor 1-alpha, or HIF-1-alpha for short, a master regulator of angiogenesis that restores VEGF signaling under hypoxic conditions. Interestingly, HIF-1-alpha overexpression is mediated by histone deacetylases, especially HDAC2. Preclinical studies suggest that HDAC2 inhibition can suppress tumor cell migration and downregulate HIF-1-alpha activity, effectively disabling a critical escape pathway used by tumors under VEGF pressure. Moreover, combining HDAC inhibition with VEGF blockade has demonstrated synergy in pazopanib-resistant tumor models, forming a compelling rationale for this dual approach.

The phase Ib trial by Tsang et al. was designed to evaluate the safety, tolerability, and preliminary efficacy of this dual-targeted approach in patients with heavily pretreated advanced solid tumors. A dose-expansion cohort focused on individuals with renal cell carcinoma, allowing for more detailed evaluation in this population.

A central component of this study was the incorporation of biomarker analysis, particularly regarding HDAC2 expression levels. The results were noteworthy. Patients with high HDAC2 expression achieved a progression-free survival of 7.7 months compared to only 3.5 months in those with low expression. Even more compelling, overall survival reached 32.3 months for those with a high HDAC2 expression versus just 9.2 months for those with low expression. This suggests the potential role for HDAC2 as a predictive biomarker for response to combination HDAC and VEGF-targeted therapy.

The authors also explored the metabolic landscape of these patients, conducting metabolomic analysis focused on kynurenine, a key tryptophan catabolite known to contribute to the immune suppression in the tumor microenvironment. Its reduction is driven by HIF-1-alpha and inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. What they found was striking. Exceptional responders, defined as patients with treatment responses lasting more than 3 years, had consistently lower levels of kynurenine both before and after treatment. This finding introduces kynurenine as a potential metabolic biomarker. It suggests that patients with lower kynurenine levels may have a less immunosuppressive microenvironment, making them more responsive to the combined effects of HDAC inhibition and VEGF blockade. Of note, VEGF levels themselves did not significantly differ between responders and nonresponders, highlighting that the treatment benefit is not purely VEGF-mediated but likely driven by epigenetic and metabolic modulation.

On the safety front, the combination of abexinostat and pazopanib was generally well tolerated. However, this study did report a correlation between higher plasma concentrations of abexinostat and an increased incidence of thrombocytopenia, a class effect associated with HDAC inhibitors.

This trial introduces several key considerations for future research. First, it calls for validation of HDAC2 as a predictive biomarker. If confirmed in larger cohorts, HDAC2 expression could be used to select patients most likely to benefit from HDAC inhibitor-based regimens, transforming how we approach trial enrollment and treatment planning. Second, the link between low kynurenine and exceptional response supports further investigation into how metabolic pathways can influence treatment response to combined HDAC and VEGF inhibition.

Overall, HDAC inhibitors hold significant promise in precision oncology. Realizing their full therapeutic potential requires a deeper understanding of HDAC biology, refined combination strategies, and thorough preclinical and clinical evaluations tailored to individual patient profiles. This study exemplifies the potential of epigenetic-metabolic crosstalk as a therapeutic vulnerability and underscores the importance of precision stratification in clinical trial design. As research in this space progresses, the integration of molecular, epigenetic, and metabolic profiling will be essential in optimizing the use of HDAC inhibitors and expanding their role within precision oncology.

Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.

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

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

JCO PO author Dr. Timothy Showalter at Artera and University of Virginia shares insights into his JCO PO article, "Digital Pathology–Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase III Trial in Men With Nonmetastatic Castration-Resistant Prostate Cancer" . Host Dr. Rafeh Naqash and Dr. Showalter discuss how multimodal AI as a prognostic marker in nonmetastatic castration-resistant prostate cancer may serve as a predictive biomarker with high-risk patients deriving the greatest benefit from treatment with apalutamide.

TRANSCRIPT 

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

Today, we are excited to be joined by Dr. Timothy Showalter, Chief Medical Officer at Artera and professor of Radiation Oncology at the University of Virginia and author of the JCO Precision Oncology article entitled, "Digital Pathology Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase 3 Trial in Men with Non-Metastatic Castration Resistant Prostate Cancer."

At the time of this recording, our guest's disclosures will be linked in the transcript.

Dr. Showalter, it's a pleasure to have you here today.

Dr. Timothy Showalter: It's a pleasure to be here. Thanks for having me.

Dr. Rafeh Naqash: I think this is going to be a very interesting discussion, not just from a biomarker perspective, but also in terms of how technologies have evolved and how we are trying to stratify patients, trying to escalate or deescalate treatments based on biomarkers. And this article is a good example of that.

One of the things I do want to highlight as part of this article is that Dr. Felix Feng is the first author for this article. Unfortunately, Dr. Felix Feng passed away in December of 2024. He was a luminary in this field of prostate cancer research. He was also the Chair of the NRG GU Committee as well as Board of Directors for RTOG Foundation and has mentored a lot of individuals from what I have heard. I didn't know Dr. Feng but heard a lot about him from my GU colleagues. It's a huge loss for the community, but it was an interesting surprise for me when I saw his name on this article as I was reviewing it. Could you briefly talk about Dr. Feng for a minute and how you knew him and how he's been an asset to the field?

Dr. Timothy Showalter: Yeah. I'm always happy to talk about Felix whenever there's an opportunity. You know, I was fortunate to know Felix Feng for about 20 years as we met during our residency programs through a career development workshop that we both attended and stayed close ever since. And you know, he's someone who made an impact on hundreds of lives of cancer researchers and other radiation oncologists and physicians in addition to the cancer patients he helped, either through direct clinical care or through his innovation. For this project in particular, I first became involved soon after Felix had co-founded Artera, which is, you know the company that developed this. And because Felix was such a prolific researcher, he was actually involved in this and this research project from all different angles, both from the multimodal digital pathology tool to the trial itself and being part of moving the field forward in that way. It's really great to be able to sort of celebrate a great example of Felix's legacy, which is team science, and really moving the field forward in terms of translational projects based on clinical trials. So, it's a great opportunity to highlight some of his work and I'm really happy to talk about it with you.

Dr. Rafeh Naqash: Thanks, Tim. Definitely a huge loss for the scientific community. And I did see a while back that there was an international symposium organized, showcasing his work for him to talk about his journey last year where more than 200, 250 people from around the globe actually attended that. That speaks volumes to the kind of impact he's had as an individual and impact he's had on the scientific side of things as well.

Dr. Timothy Showalter: Yes. And we just had the second annual Feng Symposium the day before ASCO GU this year with, again, a great turnout and some great science highlighted, as well as a real focus on mentorship and team science and collaboration.

Dr. Rafeh Naqash: Thank you so much for telling us all about that. Now going to what you guys published in JCO Precision Oncology, which is this article on using a biomarker approach to stratify non-metastatic prostate cancer using this artificial intelligence based H&E score. Could you tell us the background for what started off this project? And I see there is a clinical trial data set that you guys have used, but there's probably some background to how this score or how this technology came into being. So, could you superficially give us an idea of how that started?

Dr. Timothy Showalter: Sure. So, the multimodal AI score was first published in a peer reviewed journal back in 2022 and the test was originally developed through a collaboration with the Radiation Therapy Oncology Group or Energy Oncology Prostate Cancer Research Team. The original publication describes development and validation of a risk stratification tool designed to predict distant metastasis and prostate cancer specific mortality for men with localized prostate cancer. And the first validation was in men who were treated with definitive radiation therapy. There have been subsequent publications in that context and there's a set of algorithms that have been validated in localized prostate cancer and there's a test that's listed on NCCN guidelines based on that technology.

The genesis for this paper was really looking at extending that risk stratification tool that was developed in localized prostate cancer to see if it could one, validate in a non-metastatic castrate refractory prostate cancer population for patients enrolled on the SPARTAN trial. And two, whether there was a potential role for the test output in terms of predicting benefit from apalutamide for patients with non-metastatic prostate cancer. For patients who are enrolled on the SPARTAN study, almost 40% of them had H&E stain biopsy slide material available and were eligible to be included in this study.

Dr. Rafeh Naqash: Going a step back to how prostate cancer, perhaps on the diagnostic side using the pathology images is different as you guys have Gleason scoring, which to the best of my knowledge is not necessarily something that most other tumor types use. Maybe Ki-67 is somewhat of a comparison in some of the neuroendocrine cancers where high Ki-67 correlates with aggressive biology for prognosis. And similarly high Gleason scores, as we know for some of the trainees, correlates with poor prognosis. So, was the idea behind this based on trying to stratify or sub-stratify Gleason scoring further, where you may not necessarily know what to do with the intermediate high Gleason score individual tumor tissues?

Dr. Timothy Showalter: Well, yeah. I mean, Gleason score is a really powerful risk stratification tool. As you know, our clinical risk groupings are really anchored to Gleason scores as an important driver for that. And while that's a powerful tool, I think, you know, some of the original recognition for applying computer vision AI into this context is that there are likely many other features located in the morphology that can be used to build a prognostic model.

Going back to the genesis of the discovery project for the multimodal AI model, I think Felix Feng would have described it as doing with digital pathology and computer vision AI what can otherwise be done with gene expression testing. You know, he would have approached it from a genomic perspective. That's what the idea was. So, it's along the line of what you're saying, which is to think about assigning a stronger Gleason score. But I think really more broadly, the motivation was to come up with an advanced complementary risk stratification tool that can be used in conjunction with clinical risk factors to help make better therapy recommendations potentially. So that was the motivation behind it.

Dr. Rafeh Naqash: Sure. And one of the, I think, other important teaching points we try to think about, trainees of course, who are listening to this podcast, is trying to differentiate between prognostic and predictive scores. So, highlighting the results that you guys show in relation to the MMAI score, the digital pathology score, and outcomes as far as survival as well as outcomes in general, could you try to help the listeners understand the difference between the prognostic aspect of this test and the predictive aspect of this test?

Dr. Timothy Showalter: So let me recap for the listeners what we found in the study and how it kind of fits into the prognostic and the predictive insights. So, one, you know, as I mentioned before, this is ultimately a model that was developed and validated for localized prostate cancer for risk stratification. So, first, the team looked at whether that same tool developed in localized prostate cancer serves as a prognostic tool in non-metastatic castrate-refractory prostate cancer. So, we applied the tool as it was previously developed and identified that about 2/3 of patients on the SPARTAN trial that had specimens available for analysis qualified as high risk and 1/3 of patients as either intermediate or low risk, which we called in the paper 'non-high risk'. And we're able to show that the multimodal AI score, which ranges from 0 to 1, and risk group, was associated with metastasis free survival time to second progression or PFS 2 and overall survival. And so that shows that it performs as a prognostic tool in this setting. And this paper was the first validation of this tool in non-metastatic castrate-refractory prostate cancer. So, what that means to trainees is basically it helps you understand how aggressive that cancer is or better stratify the risk of progression over time. So that's the prognostic performance.

Dr. Rafeh Naqash: Thank you for trying to explain that. It's always useful to get an example and understand the difference between prognostic and predictive. Now again, going back to the technology, which obviously is way more complicated than the four letter word MMAI, I per se haven't necessarily done research in this space, but I've collaborated with some individuals who've done digital pathology assessments, and one of the projects we worked on was TIL estimation and immune checkpoint related adverse events using some correlation and something that one of my collaborators had sent to me when we were working on this project as part of this H&E slide digitalization, you need color deconvolution, you need segmentation cell profiling. Superficially, is that something that was done as part of development of this MMAI score as well?

Dr. Timothy Showalter

You need a ground truth, right? So, you need to train your model to predict whatever the outcome is. You know, if you're designing an AI algorithm for Ki-67 or something I think you mentioned before, you would need to have a set of Ki-67 scores and train your models to create those scores. In this case, the clinical annotation for how we develop the multimodal AI algorithm is the clinical endpoints. So going back to how this tool was developed, the computer vision AI model is interpreting a set of features on the scan and what it's trying to do is identify high risk features and make a map that would ultimately predict clinical outcomes. So, it's a little bit different than the many digital pathology algorithms where the AI is being trained to predict a particular morphological finding. In this case, the ground truth that the model is trained to predict is the clinical outcome.

Dr. Rafeh Naqash: Sure. And from what you explained earlier, obviously, tumors that had a high MMAI score were the ones that were benefiting the most from the ADT plus the applausive. Is this specific for this androgen receptor inhibitor or is it interchangeable with other inhibitors that are currently approved?

Dr. Timothy Showalter: That's a great question and we don't know yet. So, as you're alluding to, we did find that the MMAI risk score was predictive for benefit from apalutamide and so it met the statistical definition of having a significant interaction p value so we can call it a predictive performance. And so far, we've only looked in this population for apalutamide. I think you're raising a really interesting point, which is the next question is, is this generalizable to other androgen receptor inhibitors? There will be future research looking at that, but I think it's too early to say.

Just for summary, I think I mentioned before, there are about 40% of patients enrolled on the SPARTAN study had specimens available for inclusion in this analysis. So, the SPARTAN study did show in the entire clinical trial set that patients with non-metastatic castrate-refractory prostate cancer benefited from apalutamide. The current study did show that there seems to be a larger magnitude of benefit for those patients who are multimodal AI high risk scores. And I think that's very interesting research and suggests that there's some interaction there. But I certainly would want to emphasize that we have not shown that patients with intermediate or low risk don't benefit from apalutamide. I think we can say that the original study showed that that trial showed a benefit and that we've got this interesting story with multimodal AI as well.

Dr. Rafeh Naqash: Sure. And I think from a similar comparison, ctDNA where ctDNA shows prognostic aspects, I treat people with lung cancer especially, and if you're ctDNA positive at a 3 to 4-month period, likely chances of you having a shorter disease-free interval is higher. Same thing I think for colorectal cancers. And now there are studies that are using ctDNA as an integral biomarker to stratify patients positive/negative and then decide on escalation/de-escalation of treatment. So, using a similar approach, is there something that is being done in the context of the H&E based stratification to de-intensify or intensify treatments based on this approach?

Dr. Timothy Showalter: You're hitting right on the point in the most promising direction. You know, as we pointed out in the manuscript, one of the most exciting areas as a next step for this is to use a tool like this for stratification for prospective trials. The multimodal AI test is not being used currently in clinical trials of non-metastatic castrate-refractory prostate cancer, which is a disease setting for this paper. There are other trials that are in development or currently accruing where multimodal AI stratification approach is being taken, where you see among the high-risk scores, at least in the postoperative setting for a clinical trial that's open right now, high risk score patients are being randomized to basically a treatment intensification question. And then the multimodal AI low risk patients are being randomized to a de-intensification experimental arm where less androgen deprivation therapy is being given. So, I think it's a really promising area to see, and I think what has been shown is that this tool has been validated really across the disease continuum. And so, I think there are opportunities to do that in multiple clinical scenarios.

Dr. Rafeh Naqash: Then moving on to the technological advancements, very fascinating how we've kind of evolved over the last 10 years perhaps, from DNA based biomarkers to RNA expression and now H&E. And when you look at cost savings, if you were to think of H&E as a simpler, easier methodology, perhaps, with the limitations that centers need to digitalize their slides, probably will have more cost savings. But in your experience, as you've tried to navigate this H&E aspect of trying to either develop the model or validate the model, what are some of the logistics that you've experienced can be a challenge? As we evolve in this biomarker space, how can centers try to tackle those challenges early on in terms of digitalizing data, whether it's simple data or slides for that matter?

Dr. Timothy Showalter: I think there's two main areas to cover. One, I think that the push towards digitalization is going to be, I think, really driven by increasing availability and access to augmentative technologies like this multimodal AI technology where it's really adding some sort of a clinical insight beyond what is going to be generated through routine human diagnostic pathology. I think that when you can get these sorts of algorithms for patient care and have them so readily accessible with a fast turnaround time, I think that's really going to drive the field forward. Right now, in the United States, the latest data I've seen is that less than 10% of pathology labs have gone digital. So, we're still at an early stage in that. I hope that this test and similar ones are part of that push to go more digital.

The other, I think, more interesting challenge that's a technical challenge but isn't about necessarily how you collect the data, but it certainly creates data volume challenges, is how do you deal with image robustness and sort of translating these tools into routine real-world settings. And as you can imagine, there's a lot of variation for staining protocols, intensity scanner variations, all these things that can affect the reliability of your test. And at least for this research group that I'm a part of that has developed this multimodal AI tool can tell you that the development is sophisticated, but very data and energy intensive in terms of how to deal with making a tool that can be consistent across a whole range of image parameters. And so that presents its own challenges for dealing with a large amount of compute time and AI cycles to make robust algorithms like that. And practically speaking, I think moving into other diseases and making this widely available, the size of data required and the amount of cloud compute time will be a real challenge.

Dr. Rafeh Naqash: Thank you for summarizing. I can say that definitely, you know, this is maybe a small step in prostate cancer biomarker research, but perhaps a big step in the overall landscape of biomarker research in general. So definitely very interesting.

Now, moving on to the next part of the discussion is more about you as a researcher, as an individual, your career path, if you can summarize that for us. And more interestingly, this intersection between being part of industry as well as academia for perhaps some of the listeners, trainees who might be thinking about what path they want to choose.

Dr. Timothy Showalter: Sure. So, as you may know, I'm a professor at the University of Virginia and I climbed the academic ladder and had a full research grant program and thought I'd be in academia forever. And my story is that along the way, I kind of by accident ended up founding a medical device company that was called Advaray and that was related to NCI SBIR funding. And I found myself as a company founder and ultimately in that process, I started to learn about the opportunity to make an impact by being an innovator within the industry space. And that was really the starting point for me. About four years ago, soon after Felix Feng co-founded Artera, he called me and told me that he needed me to join the company. For those who were lucky to know Felix well, at that very moment, it was inevitable that I was going to join Artera and be a part of this. He was just so persuasive. So, I will say, you know, from my experience of being sort of in between the academic and industry area, it's been a really great opportunity for me to enter a space where there's another way of making an impact within cancer care. I've gotten to work with top notch collaborators, work on great science, and be part of a team that's growing a company that can make technology like this available.

Dr. Rafeh Naqash: Thank you so much, Tim, for sharing some of those thoughts and insights. We really appreciate you discussing this very interesting work with us and also appreciate you submitting this to JCO Precision Oncology and hopefully we'll see more of this as this space evolves and maybe perhaps bigger more better validation studies in the context of this test.

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

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

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

In this JCO Precision Oncology Article Insights episode, Natalie DelRocco summarizes "Digital Pathology–Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase III Trial in Men With Nonmetastatic Castration-Resistant Prostate Cancer" by Felix Y. Feng, et al published January 31, 2025.

Come back for the next episode where JCO Precision Oncology Conversations host, Dr. Rafeh Naqash interviews the author of the JCO PO article discussed, Dr. Tim Showalter.

TRANSCRIPT

Natalie DelRocco: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Natalie Del Rocco. Today, we'll be discussing the article, "Digital Pathology-Based Multimodal Artificial Intelligence Scores and Outcomes in a Randomized Phase III Trial in Men With Nonmetastatic Castration-Resistant Prostate Cancer." We will also be discussing the accompanying editorial, "Leveraging Artificial Intelligence to Improve Risk Stratification in Nonmetastatic Castration-Resistant Prostate Cancer." So, we're going to start by summarizing the original report and then we'll jump into a few of the high-level interpretations that were supplied by the editorial.  

The original report by Feng et. al. describes the application of multimodal artificial intelligence to data collected on a nonmetastatic castration-resistant prostate cancer. We will call this disease moving forward NMCRPC, a Clinical Trial. So, we're looking at data from an NMCRPC clinical trial. The SPARTAN trial was a randomized phase three trial and this study compared metastasis-free survival as the primary endpoint for those treated with traditional androgen deprivation therapy or ADT to those treated with androgen deprivation therapy plus apalutamide. Other secondary endpoints included progression-free survival and overall survival, but the primary endpoint there was metastasis-free survival or MFS. This study found that the addition of apalutamide resulted in a significantly longer median metastasis-free survival compared to androgen deprivation therapy alone. And we should note that this is a double-blind placebo-controlled trial. In the overall study, 1,207 patients participated and over the course of this study histopathology slides were collected and they were digitized for future use. And that future use is what we are going to be discussing today. 

The authors do note that there are currently no good biomarkers for use in NMCRPC. The authors seem to be inspired by the ArteraAI prostate test, which was a recent application of multimodal artificial intelligence models. But in localized prostate cancer as opposed to NMCRPC, the authors constructed a multimodal artificial intelligence model or an MMAI model. They applied this to the SPARTAN trial with the intention of developing a risk score that could be used for risk stratification in NMCRPC. And we should note here that multimodal artificial intelligence or MMAI is a broad class of artificial intelligence models, and they can analyze different types of data at one time, hence the term multimodal. So in this example, the author's primary data source of interest were those digitized histopathology images because histopathology tells you a lot about NMCRPC. The authors though also wanted their model to consider traditional clinical factors that are known to be prognostic such as Gleason score, tumor stage, PSA level, and age. So those two different types of data, those histopathology images and that traditional clinical data are the two different types of data that make this model multimodal. So we should note here importantly, after dropping missing data, 420 patients contribute to this model, the MMAI model. 

The authors generate a risk score from this MMAI model and they categorize that risk score into low, intermediate, and high risk groups using clinical knowledge. The authors found in their results that an increase in this MMAI risk score was associated with an increased hazard of metastasis-free survival event with a hazard ratio from a Cox proportional hazards model of 1.72. To summarize how the authors arrived here, they derived a risk score from this MMAI model which incorporates both imaging and regular data. They plugged this risk score into a Cox proportional hazards mode,l modeling metastasis-free survival and they found that an increase in that MMAI based risk score is associated with increased hazard of metastasis-free event with a hazard ratio of 1.72, which is quite large. Additionally, the risk score seemed to be associated with PFS2 and OS, which were two of the secondary endpoints from the SPARTAN clinical trial, though the effect sizes were more modest. Those are the highlights from the original report, the methods and the results. 

The accompanying editorial notes that both histopathology and Gleason score specifically are very critical to understanding prostate cancer, and Gleason score alone is not sufficient to summarize the complexity of the disease, although it is a well validated prognostic factor for prostate cancer. So this makes MMAI an excellent tool in the setting described by the authors. We have an existing prognostic factor that doesn't describe the entire picture of the disease by itself and so we can use those digitized histopathology slides to help bolster our understanding and provide the model more information. MMAI allows you to do this because it can take in different types of data. So that was the main conclusion of the editorial. 

They also summarize a number of recent validations of MMAI models in prostate cancer research, noting that it will be an important tool for risk stratification and has already been shown to outperform classical techniques. The editorial though does highlight a number of weaknesses of this paper, limitations and I think the most important one to highlight, and we touched on this earlier, is that 420 patients from the SPARTAN clinical trial contributed to the development of this MMAI score. That is a small proportion of the roughly 1200 patients that did participate in the SPARTAN clinical trial. So we have a small subgroup analysis that can be limiting and this model will need to be validated in a broader population in the future.

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

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

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

In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes "Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies." by Dr. Ludmila Papusha et al. published on July 08, 2024.

TRANSCRIPT 

Jiasen He: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Jiasen He, a JCO Journal's Editorial Fellow. Today, I will provide a summary on "Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies." This is an observational study by Dr. Ludmila Papusha and colleagues that investigated the use of target therapies in early childhood with midline low grade glioma.

Low grade glioma located in the hypothalamic chiasmatic region, thalamus and the brain stem are classified as midline low grade gliomas. Due to their unique locations, complete surgical resection is usually not able to be achieved. In young children with low grade glioma, radiation therapy is generally not favored. Traditionally, chemotherapy regimens such as carboplatin and vincristine have been used. However, as Dr. Papusha noted, this population often exhibits poor response to chemotherapy. With a growing understanding of the RAS-RAF-MEK pathways in low grade glioma, targeted therapy has emerged as a promising treatment option for this group. However, limited data is available regarding the mutation status of midline low grade glioma in early childhood and real world evidence on their response to targeted therapy remains scarce.

Dr. Papusha's research aimed to address this critical gap by evaluating the effectiveness of targeted therapy in midline gliomas of early childhood. In this observational study, 40 patients under the age of three with midline low grade glioma were enrolled. Somatic genetic aberrations associated with activation of RAS-RAF signaling pathway were identified in 95% of the cohort with BRAF fusion being the most common aberration followed by the BRAF V600E mutation. These findings confirm the presence of targetable mutations in this specific population and provide a foundation for the use of targeted therapy.

Diencephalic syndrome is a rare neurologic disorder typically affecting infants and young children with tumors located in the diencephalon. In this cohort, 43% of the optic pathway and hypothalamic gliomas manifested diencephalic syndrome. Among 30 patients who received first line chemotherapy, primary carboplatin and vincristine, the two-year and five-year progression-free survival rate were only 24% and 6.4% respectively, indicating that most patients experience disease progression with chemotherapy. Targeted therapy was administered to 27 patients of whom 22 experienced disease progression during or after chemotherapy. A total of 26 patients were available for evaluation. Dr. Papusha reported that all patients benefited from targeted therapy with 12 achieving a partial response, 2 showing a minor response and 12 maintaining stable disease. The median duration of targeted therapy was 16 months. These findings demonstrate the efficacy of targeted therapy in this population.

Regarding toxicity from targeted therapy in this population, the most common adverse event was grade 1 to 2 skin toxicity observed in 52% of patients. Severe toxicity occurred in 36% of patients treated with trametinib including grade 3 skin toxicity, mucositis and hematuria. Additionally, grade 3 gastrointestinal toxicity was reported. Interestingly, all three patients who experienced grade 3 gastrointestinal toxicity had diencephalic syndrome at the time of targeted therapy initiation. The author also noted cases of disease progression during treatment breaks. However, tumor response was restored in all affected patients upon resumption of targeted therapy. The two-year progression-free survival rate was 59%.

In conclusion, Dr. Papusha states the unique characteristics of infantile midline low grade glioma, including the high prevalence of diencephalic syndrome and resistance to chemotherapy. The study contributes valuable information on the targetable mutation profile in this population and provides further evidence supporting the use of targeted therapy while emphasizing the need for low monitoring of severe adverse events. As the author notes, important questions remain regarding the long term side effects of kinase inhibitors in infants and children as well as optimal duration of therapy.

Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

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

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

JCO PO author Dr. Hatim Husain at University of California San Diego, shares insights into his JCO PO article, "Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review", one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Dr. Husain discuss how to utilize real-world and clinical trial data to discern the safety of adagrasib (another KRASG12C inhibitor), following sotorasib discontinuation due to hepatotoxicity.

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center. 

Today, I'm very excited to be joined by Dr. Hatim Hussain, Professor of Medicine at the University of California, San Diego, and author of the JCO Precision Oncology article, "Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review." This was one of the top downloaded articles of 2024. And the other interesting thing is we generally don't do podcasts for case reports or case series, so this is one of the very few that we have selected for the podcast. 

And at the time of the recording, our guest disclosures will be linked in the transcript. 

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

Dr. Hatim Husain: Thank you Dr. Naqash. Such a pleasure to be here and to speak with you all.

Dr. Rafeh Naqash: And for the sake of this podcast, we'll refer to each other using our first names. So again, as I mentioned earlier that this is one of the very few case reports that we have selected for podcasts in JCOPO and the intention was very deliberate because it caters to something that is emerging where we are trying to treat more KRAS mutant patients with different KRAS inhibitors. And you tried to address one very unique aspect of it in this article which pertains to toxicity, especially hepatotoxicity. So for the sake of our listeners who tend to be community oncologists, trainees, academic faculty, can you tell us what are KRAS inhibitors? What is KRAS-G12C? And how do some of these approved KRAS inhibitors try to inhibit KRAS-G12C?

Dr. Hatim Husain: Sure. For a long time actually we've not had a selective way to inhibit mutant KRAS. And over the last several years actually now, we've seen some dramatic advances here, particularly with the FDA approval of some of the selective inhibitors against the G12C variant. So KRAS-G12C is an isoform of KRAS that is most common in lung cancer and in fact actually is a transversion mutation in the KRAS gene that is a product of the carcinogen of tobacco. And in fact, the incidence of KRAS-G12C in lung cancer, it's quite astounding where as many KRAS-G12C patients there are, there can be, as you know, more than EGFR patients in certain populations and cohorts. The medicines sotorasib and adagrasib were rationally designed to be selective KRAS-G12C inhibitors. And the way that they do this is that they lock the KRAS protein in the OFF state. KRAS is a protein that oscillates between an ON and an OFF state and by virtue of locking the protein in an OFF state, it has shown inhibition of downstream signaling and mitigation of tumor growth and, in fact, tumor cell death.

Dr. Rafeh Naqash: I absolutely love the way you describe the ON and OFF state, the oscillation where the ON is bound to the GTP and the OFF is bound to the GDP. The two KRAS inhibitors as currently FDA approved, as you mentioned, are RAS OFF inhibitors and they're emerging KRAS inhibitors that are RAS ON. So now, as we have known from previous data related to immunotherapy and EGFR TKIs such as osimirtinib where toxicity tends to be a compounded effect when you have osimertinib given within a certain timeline of previous checkpoint therapy, we've seen that in the clinic as the data for these KRAS inhibitors is emerging, you talk about some very interesting aspects and data about what has been published so far with regards to prior use of immunotherapy or chemo immunotherapy and the subsequent use of KRAS inhibitors. Could you elaborate upon that?

Dr. Hatim Husain: Sure. So for this population of patients, the first line approved strategy is a strategy that most cases will incorporate immune therapy and chemotherapy. Immune therapy can have some important responses for patients with KRAS-G12C. This may be due to the fact that KRAS-G12C patients may have a higher incidence of prior smoking, perhaps higher mutation burdens in some patients, and perhaps immunogenicity is defined in that context. So the standard of care in the first line currently includes immune therapy or immune therapy and chemotherapy. Where the current FDA approvals for selective G12C inhibitors are are after the first line of therapy. There are a number of trials exploring these medicines in the first line to see if they may be incorporated into a future treatment paradigm.

Dr. Rafeh Naqash: Thank you for that explanation. Now, going to what you published in this manuscript, can you help us understand the context of why you looked at this? Even though the data just comprises a case series of a handful of patients, but the observations are very interesting and these are real world scenarios where we often tend to be in situations where an individual has had toxicity on a certain drug and may have some response to that drug, but at the same time, the toxicity is challenging. And then you try to debate whether another drug in the same class might be beneficial without those toxicities. So you've tried to address that to some extent using this data set. So can you elaborate upon the question, the methodology, what you tried to look at, and important observations that you have?

Dr. Hatim Husain: Yes, our paper was actually inspired by one of my patients. My patient was a patient who had received chemotherapy and immune therapy and actually in the past, even, you know, additional lines of immune therapies, it was really coming to the edge of where standard treatments would exist. It was right at the same time that these selective inhibitors had been approved and the patient had received sotorasib. And what was remarkable was, when given sotorasib, patient had a very high peak and spike in the transaminases. And we would do different trials of strategies around dose, around interruptions. And it was becoming quite difficult, actually, for the patient to proceed with additional therapy. It was around similar times, actually, and I do want to make a note that the patient was progressing, driven in large fact by the fact that we've had to interrupt the medicine. So we feel and believe that the patient had had inadequate dosing because of the level of toxicity that the patient was having with transaminase increase. So it was around the same time that adagrasib was first commercially available that we were at that point, and we did a trial of adagrasib post-sotorasib, largely driven by necessity, without having additional options to provide this patient in our environment. What was remarkable was when the patient received the adagrasib, there were no spikes in transaminases similar to what we had seen before. And that really led us thinking and to say, "Is this adverse event of transaminase increase or hepatotoxicity, is this a class effect with KRAS-G12C inhibitors, or is it more nuanced than that? Are there different, perhaps, mechanisms by which the medicines may work that may more or less differentially contribute to this adverse event?" And so that inspired us to kind of do a larger analysis, kind of really reach out to a larger network of physicians to gather insights and to gather responses in patients who had had a serial approach of sotorasib and then adagrasib. 

What we found in this process was, in fact, actually there were many more cases of patients who resembled my patient, where the sequence of sotorasib going to adagrasib may have demonstrated differential contribution of hepatotoxicity in that context. And that really motivated us to put the publication together to due diligence, and in the publication spend a lot of time to kind of outline each patient case in detail around metrics surrounding time from last immune therapy, the number of days on sotorasib, the best response to sotorasib, the interval between sotorasib and adagrasib, the duration of adagrasib and then the grade of hepatotoxicity seen in each of the contexts, and particularly kind of the adagrasib and patient disease status as well. We were quite inspired by the effort to try to, if we do not have randomized data in comparison of one medicine to another, which we do not at this juncture, we do not have a randomized analysis to really diligently and rigorously compare the rates of AEs across each medicine, and even in sequence, we do not have that with immune therapy. But what we felt was trying to get more analysis of this sequential approach of, if patients had received a medicine, had to be taken off because of toxicity and then actually tried on a new medicine, what were those rates? We felt like that was at least some information to try to get at this question.

Dr. Rafeh Naqash: And you bring forward a very important point, which is, a lot of times in the real world setting we don't have cross trial comparisons that can be fully applicable, or we don't have trials that compare two drugs of the same class with respect to the AE profile or efficacy. And observations like the one that you described that led to this study are extremely critical in trying to help answer these questions. 

From a data standpoint, and you allude to it to some extent in your manuscript, the trials that are trying to address combination of KRAS-G12C with immunotherapy, especially sotorasib or adagrasib, can you elaborate on that data, what has been published so far and summarize it for our listeners?

Dr. Hatim Husain: So there is data from clinical trials looking at patients actually who have received concomitant immune therapy and sotorasib. What was seen in this, in a real world analysis, was that some patients actually who had received sotorasib within a close proximity of immune therapy, as well as a larger study actually which showed in combination there were higher rates of hepatotoxicity in that context. In fact, there were rates of grade 3 hepatotoxicity. And I think built upon that data there's a recognition in the field that we have to be very diligent in terms of even the clinical trial designs in how to understand the pairing between immune therapy and selective G12C inhibitors. There are many trials that are ongoing, one of the studies that is ongoing is known as the KRYSTAL-7 study, which is evaluating adagrasib in combination with pembrolizumab in the first line. And we await more information on that strategy as well. In the context of sotorasib, because of some of the trials that have shown higher rates of hepatotoxicity, there are some additional trials now looking at sotorasib in combination with chemotherapy, and those also have some information that have been reported as well.

Dr. Rafeh Naqash: From a drug development standpoint, as you mentioned, there's always a tendency to combine something with something else. And in my practice, and I'm sure in your practice too, when we do early phase trials, many trials are still focused on choosing the maximum tolerated dose, which may be something that we need to gradually move away from as we try to implement these combinations of multiple antibodies plus some of these target agents from maybe the biological optimal dose rather than the maximal tolerant dose is a better way to look at the drugs, the pharmacokinetic profile, and then see what is likely the safest combination with the most appropriate target engagement. Do you have any thoughts on that or insights on that from a drug development perspective?

Dr. Hatim Husain: It's a wonderful question and I think it is a very insightful question and understanding of where we are in space right now. And I agree with you that historically, cancer drug development was really hinged upon medicines that perhaps required higher doses to see a benefit or to inch out kind of marginal increases upon where we were at. Now, in combination with medicines that have non-overlapping mechanisms of action, the concept is: Can there actually be more synergy across an approach using combinatorial strategies rather than just additive effects? And I think that in some cases this is being studied with immune therapy, in some cases actually even in the context of other novel mechanisms for cancer therapy. I think that in my practice, I will really try to see how a patient at an approved dose will respond. But definitely I'm open to the concept that there may be a dose that doesn't have to be the maximally tolerated dose, but rather the dose that responses can be seen and perhaps actually at a lower dose than what drives many toxicities.

Dr. Rafeh Naqash: I often describe this to my patients as individual patient dose optimization outside of a clinical trial, where I'm sure you've probably done this, where in older adults maybe a lower dose of osimertinib is tolerated better, or a lower dose of sotorasib or adagrasib for that matter, tolerated better with perhaps a similar level of efficacy, since we don't have comparisons between doses and efficacy so far. 

So I think in the bigger picture, as we discussed in a nutshell, what I would really like the listeners to understand is as we try to move towards this field of precision medicine targeting more and more of the undruggable genes, there's bound to be a certain level of toxicity patterns that we'll start observing. So I think these real world scenarios which may not be addressed using clinical trials because it is in the real world setting where you cycle one treatment after another after another, which may or may not be allowed in most trials and the real world setting can inform, in certain cases, subsequent trial designs. So I think the most important message, at least that I took from your manuscript, was that these real world observations can make a huge difference and inform practice, even though the data sets may be small. Of course, you want to validate some of these findings in a bigger, broader setting, but proof of concept is there. And I think next time I see an individual in my clinic where I see better toxicity, I'll definitely try to talk to them about subsequent treatment with another KRAS inhibitor, maybe adagrasib or something else, if and when appropriate. 

Do you have any closing thoughts on some of these things that we discussed?

Dr. Hatim Husain: I just want to leave the audience actually with this concept that sometimes we group targeted therapy side effects as being class effects unanimously. And I do think actually that each inhibitor may have different off target effects on where medicine may act. We don't truly understand the mechanism of hepatotoxicity in the context of selective KRAS-G12C inhibitors. One of the hypotheses may be due to off target cysteine reactivity in the numerous off target binding sites that certain medicines may have over others. And just even qualitatively which off target binding sites there may be, and how that may lead to either immunogenic responses and other organs or such. So I do think that we do need more research to understand the mechanism. But I think where we are at right now in this space is not assuming that all medicines are going to have the exact same toxicity. I think especially when patients may not have other options, this is something to consider as well.

Dr. Rafeh Naqash: Thank you so much. Now, outside of the scientific insights, Hatim, I know you a little bit from before. And knowing the kind of work that you've done in precision medicine, I'm really interested to know about where you started, how you started, how things have been, and what kind of advice you have for junior faculty fellows who are interested in this field of precision medicine that is becoming more and more exciting as we progress in the oncology space.

Dr. Hatim Husain: Thank you, Rafeh. I will say, actually as a medical student, I was actually very interested in oncology, partly because it was then and still remains one disease or a constellation of diseases that just has such a high psychological burden on patients. And through the experiences I've had, I really can understand and relate with that concept. I did my medical school at Northwestern, residency at the University of Southern California, and then my oncology fellowship at Johns Hopkins University. 

And now I've been on faculty at University of California, San Diego, for about 12 years now. It's been a great experience paralleled with the fact that during these last 12 years, I've really seen how the developments in precision oncology, both targeted therapy as well as immune therapy, have really blossomed and unfolded. A large area of my research in my career has kind of focused on cancer genome and integration of novel technologies to really see how they may have clinical application. When I was in my fellowship and as a young faculty, the liquid biopsy was actually coming into development. And this was hinged upon information that had come forward in the prenatal space where some patients actually who were undergoing prenatal testing during pregnancy were found to have complex karyotypes and genomic alterations and then retrospectively found to have cancer. 

And doing my fellowship at Johns Hopkins, some of the pioneers in liquid biopsy were my mentors and really kind of instilled in me that passion for really thinking through how cancer genomics can be integrated through time. And some of the research that I have been doing has been looking at clonal evolution of cancer, how cancer is changing over time, and how we can think through the right surveillance strategies to really understand how that change is occurring. The dynamics of ctDNA in retrospective cohorts have been studied and shown that, you know, there can be associations between progression-free survival and other clinical endpoints. The current paper that we are speaking about parallels that in a certain way where, rather than say, looking at clonal evolution and say, the efficacy answer of sotorasib first and then adagrasib and how frequently can adagrasib salvage patients, this looks at it from a different angle around toxicity. And I think that is a key point because, at my core, I really do enjoy the clinical aspect of complex decision making on behalf of patients weighing efficacy and toxicity that they may have as they try to get the best quality of life through this journey.

Dr. Rafeh Naqash: Thank you again, Hatim, for all those insights, both from the scientific perspective as well as personal perspective. We appreciate that you chose JCOPO as the destination for your work. 

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

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

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

Dr. Hatem Husain Disclosures

Consulting or Advisory Role: AstraZeneca, Foundation Medicine, Janssen, NeoGenomics Laboratories, Mirati

Speakers' Bureau: AstraZeneca, Janssen

Institution Research Funding: Pfizer, Bristol-Myers Squibb, Regeneron, Lilly

Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine