JCO PO author Dr. Alok A. Khorana, MD, FASCO, Professor of Medicine, Cleveland Clinic and Case Comprehensive Cancer Center, shares insights into the JCO PO article, "Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers." Host Dr. Rafeh Naqash and Dr. Khorana discuss how multiomic analysis shows higher FGFR2 fusions and immunotherapy marker variations in early-onset biliary cancer. TRANSCRIPT Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO POarticles. 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 joined by Dr. Alok A. Khorana, Professor of Medicine at the Cleveland Clinic and Case Comprehensive Cancer Center, and also the Senior Author of the JCO Precision Oncology article titled, "Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers." At the time of this recording, our guest disclosures will be linked in the transcript. Dr. Khorana, it's an absolute pleasure to have you here today, and welcome to the podcast. Dr. Alok A. Khorana: Thank you. It's an absolute pleasure to be here and thank you for highlighting this article. Dr. Rafeh Naqash: Absolutely. We're going to talk about science, obviously, and a few other things. So to start off, for the sake of our audience, which comprises academicians and community oncologists as well as trainees, can you tell us a little bit about biliary tract cancers, what we have learned over the last decade or so, where the standard of treatment currently lies. And then we can dive into the article that you published. Dr. Alok A. Khorana: As many of you who treat GI cancers know, biliary tract cancers for a long period of time were sort of the orphan cancer in the GI cancer world. They're not nearly as common as, say, pancreatic cancer, and certainly not as common as colorectal cancer. They're sort of also, in this weird 'no man's land' between well known sort of adjuvant therapy trials in pancreatic cancer or colorectal cancer, but because they're not as high in volume, there weren't really large trials done in this population. What's really changed in the past decade, especially, has been the slow but sure realization that biliary tract cancers are in fact a target rich cancer, almost similar to what you would see with lung cancer, and that's only a slight exaggeration. And in some studies, as many as up to 40% of patients with biliary tract cancers can have something that's targetable. And that's really revolutionized the way we think of biliary tract cancers. It also separated this field from pancreatic cancer where formerly the two used to be lumped together, and even within biliary tract cancers, we are now slowly realizing that there are differences between intrahepatic, extrahepatic and gallbladder cancers. Big change is really afoot in this field, particularly with the identification of mutation directed targets. Dr. Rafeh Naqash: Thank you for that explanation. Now, another question I have is, although I don't see any GI cancers, but I have good colleagues of mine at our cancer center who see a lot of GI pancreatic/biliary cancers, and one of the things that comes up in our molecular tumor board often is how certain cancers of unknown primary end up being identified or categorized as biliary tract cancers based on NGS. And again, the uptake for these NGS is perhaps isn't optimal in the field yet, but in your practice, how do you approach situations like that? Do you use NGS in certain cases where the tissue of origin or the patterns of the mutations indicate that this might be biliary tract cancer and then treat the patient accordingly? Dr. Alok A. Khorana: Yeah, that's true. And that's certainly how I approach things, and I would say even in my own personal practice, that has been a change. I was a little bit skeptical about the benefit of sort of tissue of origin type of testing in carcinoma of unknown, primarily, especially if you can sort of narrow it down to one or other area of the GI tract. But with the identification of sort of targeted subpopulations, especially of biliary tract cancer, I think it's become imperative. And I know we're going to get into the paper, but if you want to learn nothing else from this 20, 25 minute podcast, one lesson I just want to make sure everybody gets is that any patient with biliary tract cancer should have NGS done as soon as possible. Dr. Rafeh Naqash: Thank you for highlighting that important aspect. Now, going to the topic at hand, what was the driving factor? I've heard a lot about colorectal cancers, early onset versus later onset. What was the reason that you looked at biliary tract cancers? Is that something that you've seen on a rise as far as early onset biliary tract cancers is concerned? Dr. Alok A. Khorana: Yeah. So we got into this subject also from starting out at colorectal cancer. And as you know, and I'm sure most of your audience knows, there's been a lot of literature out there over the past five, six, seven years suggesting and then documenting and then sort of proving and reproving that colorectal cancer is on the rise, and especially in people younger than age 50. And even in that population, it's on the rise in two different subpopulations, people in their 20s and 30s and then people in their 40s that are close to the screening colonoscopy rates. That's been investigated heavily. We still don't fully understand why that's happening, but it's not restricted to the United States. It's a worldwide phenomenon. You can see it in the United States, in North America. You can see it in western Europe, but you can also see it in many Asian countries with specific sort of subpopulations. For instance, in some countries, men are more likely to have early onset cancers. And then a newer finding that sort of emerged over the past couple of years is that this early onset increase in cancers is not just restricted to colorectal cancer, although that's the one that sticks out the most, but in fact, is widespread across a bunch of different types of cancers. In my own research program, we had gotten into a sort of better understanding of early onset colorectal cancer a couple of years ago, driven primarily by the sort of patients that I saw in my practice. And it's just, as you know, when you have a couple of those heartbreaking cases and they're just impossible to forget, and it sort of just drives your attention, and then you want to do something to help them. And if you can't help them personally, then you want to do something that can change the field so that more of these patients are not coming in your clinic next year or the year after. So a couple years ago, at the Cleveland Clinic where I practice, we created a center for young onset cancers, and at the time it was primarily focused on colorectal cancer. But as we are getting into colorectal cancer, we realize that beyond colorectal cancer, we are also starting to see more younger people with other cancers, including pancreas cancer, including gastric cancer, and including bile duct cancers. And we realized that because so much attention was being focused on colorectal, that maybe we should also be paying a little bit of attention to what was happening in this space. I want to, for your listeners, point out that the problem in bile duct cancers is not to the same degree as you see in colorectal cancer. Just a couple numbers to sort of, to set this in perspective: about 5%, 7% of bile duct cancers are young onset - it's not a huge proportion - 90%+ percent of patients are not young onset. But the impact on society, the impacts on those providing care, is obviously substantial for younger patients. And it is true that even though the proportion of patients is not that high, the incidence is rising. And there's a very nice study done a couple of years ago and published that looked at what the cancers are that are rising at the highest rates. And bile duct cancer and gallbladder cancers were listed amongst the two with the highest rate, so about an 8% rate per year of increase. And so that's really what drove our interest was, as we're seeing early onset bile duct cancers, it's rising year by year, and what is this disease? Is it the same as you see in sort of the average patient with bile duct cancer? Is it different? How do we characterize it? How do we understand it? What are some of the causes precipitating it? And so that's what led us to sort of one of the investigations that we've documented in this paper. Dr. Rafeh Naqash: Excellent. So, talking about this paper, again, can you describe the kind of data that you use to understand the molecular differences and also look at potential immune signatures, etc., differences between the groups? Dr. Alok A. Khorana: Yeah. So the objective in this paper was to look at genomic differences between early onset and usual onset, or average onset biliary tract cancers. And this sort of followed the paradigm that's already been established for early onset colorectal cancer, where you take a bunch of people with early onset disease, a bunch of patients with average onset or usual onset disease, and then look at the profiling of the tumors. And we've done this for genomics, we've done this for microbiomics, we've done it for metabolomics. And the lessons we've learned in colorectal cancer is that, in many ways, the profiles are actually quite substantially different. And you can almost think of them as diseases of the same organ, but caused by different processes, and therefore leading to different genotypes and phenotypes and microbiomes. We had absorbed that lesso
