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 lesson from colorectal cancer, and we wanted to replicate it in this type of cancer.

But as we discussed earlier, this is a relatively rare cancer, not that many cases per year. For colorectal, we could do a single institution or two institution studies. But for this, we realized we needed to reach out to a source of data that would have access to large national data sets. We were happy to collaborate with Caris Life Sciences. Caris, many of you might know, is a provider of genomics data, like many other companies, and they house this data, and they had the age categorization of patients less than 50, more than 50. And so we collaborated with investigators at Caris to look at all the specimens that had come in of bile duct cancers, identified some that were young onset and some that were older onset. It was roughly about 450 patients with the early onset or young onset, and about 5000 patients with usual onset cases. And then we looked at the genomics profiling of these patients. We looked at NGS, whole exome sequencing, whole transcriptome sequencing, and some immunohistochemistry for usual, like PDL-1 and MSI High and things like that. And the purpose was to say, are there differences in molecular profiling of the younger patient versus the older patient? And the short answer is yes, we did find substantial differences, and very crucial for providers treating these patients is that we found a much higher prevalence of FGFR2 fusion. And that's important because, as I'm sure you've heard, there's a ton of new drugs coming out that are targeting specifically FGFR fusion in this and other populations. And hence my statement at the outset saying you’ve got to get NGS on everybody, because especially younger patients seem to have higher rates of some of these mutations.

Dr. Rafeh Naqash: Excellent. You also looked at the transcriptome, and from what I recollect, you identified that later onset tumors had perhaps more immune favorable tumor microenvironment than the early onset. But on the contrary, you did find that FGFR2 early onset had better survival. So how do you connect the two? Is there an FGFR link, or is there an immune signature link within the FGFR cohort for early onset that could explain the differences?

Dr. Alok A. Khorana: Yeah, that's a great question. So, to kind of summarize a couple of these things you talked about. So, one is we looked at these genomic alterations, and, yes, FGFR2 fusion was much more prevalent. It's close to 16% of young onset patients, as opposed to roughly 6% of average onset patients. So almost a threefold increase in FGFR fusion. And because there's so many drugs that are targeting FGFR fusion, and because the population included a period of time when these drugs had already been approved, we think some of the benefit or the improvement in median survival associated with being younger is likely driven by having more FGFR fusion and therefore having more drugs available to treat FGFR fusion related tract cancer with corresponding increase and increase in survival. And that was part of it.

There was one other alteration, NIPBL fusion, that's been sort of known to be associated with a certain subtype of cholangiocarcinoma, but it doesn't really have a drug that targets it, so it's not sort of very useful from a clinical perspective.

The other two things you talked about, so transcriptome and immuno oncology markers, we found a couple different results on this. So one is that we found in younger people, angiogenesis was enriched, and why this is so we don't quite have a good answer for that. The other was inflammatory responses. So there's a couple of gamma interferon pathways and a couple other types of pathways that you can sort of do pathway analysis, and we found that those were enriched in the older patients or the average onset patients. But the benefit for immunotherapy was similar across the two groups. So even though we saw these differences in signaling in terms of which pathways are upregulated or downregulated, it didn't seem to translate into the current generation of immune checkpoint inhibitors that we're using in terms of benefit for patients. But we did see those differences.

Dr. Rafeh Naqash: I completely agree, Doctor Khorana. As you mentioned, that one size fits all approach does not necessarily work towards a better, optimal, personalized treatment stratification. So, as we do more and more sequencing and testing for individuals, whether it's early onset cancers or later onset cancers, figuring out what is enriched and which subtype, I think, makes the most sense.

Now, going to the FGFR2 story, as you and most listeners probably already know, FGFR is an approved target, and there are a band of FGFR inhibitors, and there's some interest towards developing specific FGFR2, 3 fusion inhibitors. What has your experience with FGFR inhibitors in the clinic been so far? And what are you personally excited about from an FGFR standpoint, in the drug development space for GI cancers?

Dr. Alok A. Khorana: Yeah, I think the whole FGFR fusion story sort of actually deserves more excitement than it's gotten, and it may be because, as I mentioned earlier, biliary tract cancers are a relatively low volume type of cancer. But the results that we are seeing in the clinic are very impressive. And the results that we are anticipating, based on some ongoing phase two and phase three trials, appear to be even more impressive for the very specific inhibitors that are about to hopefully come out soon.

Also, the possibility of using successive lines of FGFR inhibitors - if one fails, you try a second one; if the second one fails, you try a third one because the mechanisms are subtly different - I think it will take a little while to figure out the exact sequencing and also the sort of the rates of response in people who might previously have been exposed to an FGFR inhibitor. So that data may not be readily available, because right now most patients are going in for longer trials. But having that type of possibility, I think, kind of reminds me of the excitement around CML back when imatinib suddenly became not the only drug and a bunch of other drugs came out, and it's kind of like that. I think again, it's not a very common cancer, but it's really wonderful to see so many options and more options along the way for our patients.

Dr. Rafeh Naqash: Thank you. Now, going to your personal story, which is the second part of this conversation, which I think personally, for me, is always very exciting when I try to ask people about their personal journeys. For the sake of the listeners, I can say that when I was a trainee, I used to hear about Dr. Khorana’s course, I always thought that Dr. Alok Khorana was a hematologist. My friends corrected me a few years back and said that you’re a GI oncologist. Can you tell us about your love for GI oncology and the intersection with hematology thrombosis, which you have had a successful career in also? Can you explain how that came about a little bit?

Dr. Alok A. Khorana: Yeah, sure. So it is a common, I guess I shouldn't say misperception, but it's certainly a common perception that I'm a hematologist. But I'll sort of state for the record that I never boarded in hematology. I did do a combined hem-onc fellowship, but only boarded in oncology. So I'm actually not even boarded in hematology. My interest in thrombosis came about- it's one of those things that sort of happen when you're starting out in your career, and things align together in ways that you don't sort of fully understand at the time. And then suddenly, 10 years later, you have sort of a career in this.

But it actually came about because of the intersection of, at the time, angiogenesis and coagulation. And this is the late ‘90s, early two ‘00s, there was a lot of buzz around the fact that many of the factors that are important for coagulation are also pro angiogenic and many factors that are coagulation inhibitors. These are naturally occurring molecules in your body, and can be anticoagulant and anti angiogenic. A great example of this is tissue factor, which is, as you'll remember from the coagulation pathways, the number one molecule that starts off the whole process. But less widely appreciated is the fact that nearly every malignancy expresses tissue factor on its cell surface. This includes breast cancer, it includes leukemia cells, it includes pancreatic cancer. In some cancers, like pancreatic cancer, we've even shown that you can detect it in the blood circulation. And so for me, as a GI oncologist who was seeing a lot of patients get blood clots, it was particularly fascinating to sort of see this intersection and try and understand what is this interaction between the coagulation and angiogenic cascades that's so vital for cancers. Why is coagulation always upregulated in cancer patients? Not all of them get blood clots, but subclinical activation of coagulation always exists. So I would say I was fascinated by it as an intellectual question and really approached it from an oncology perspective and not a hematology perspective.

But then as I got deeper into it, I realized not everybody's getting blood clots, and how can I better predict which patients will get blood clots. And so I had both a hematology mentor, Charlie Francis, and an oncology mentor, Gary Lyman. And using sort of both their expertise, I drafted a K23 career development award specifically to identify predictors of blood clots in cancer patients. And that's the multivariate model that later became known as the Khorana Score. So again, I approach it from an oncology perspective, not a hematology perspective, but really a fascinating and still, I would say an understudied subject is why are cancer patients having so many clotting problems? And what does it say about the way cancer develops biologically that requires activation of the coagulation system across all of these different cancers? And I think we still don't fully understand the breadth of that.

Dr. Rafeh Naqash: Very intriguing how you connected two and two and made it a unique success story. And I completely agree with you on the tissue factor. Now there's ADCs antibody drug conjugates that target tissue factor, both a prude as well as upcoming.

Now, the second part of my question is on your personal journey, and I know you've talked about it on social media previously, at least I've seen it on social media, about your interactions with your uncle, Dr. Har Gobind Khorana, who was a Nobel Prize winner in medicine and physiology for his work on DNA. Could you tell us about how that perhaps shaped some of your personal journey and then how you continued, and then also some personal advice for junior faculty trainees as they proceed towards a successful career of their own?

Dr. Alok A. Khorana: Yeah, thank you for bringing that up. So very briefly, this is about my uncle. He's actually my great uncle. So he's my grandfather's youngest brother. And I grew up in India in the ‘70s and ‘80s, and at the time, I ran away from this association as fast as I could, because growing up in India in the 70s and ‘80s, it was a socialist economy. There wasn't a lot going on. There was certainly none of the IT industry and all of everything that you see right now. And so there were very few icons, and my great uncle was definitely one of those few icons. As soon as you mentioned your last name, that would sort of be the first question people would ask. But he did serve as a role model, I think, both to my father, who was also a physician scientist and a professor of medicine, and then to myself in sort of making me realize, one, that you can't really separate medicine from science. I think those are really integrated, and we want to ask questions and answer questions in a scientific manner. He chose to do it in a basic science world. My father did it in a clinical science world, and I have done it in a clinical and a translational science world. Again, sort of using science as the underpinning for sort of understanding diseases, I think, is key. And so that was certainly a massive inspiration to me.

And then after I immigrated to the US in the late ‘90s, I met him on a regular basis. He was certainly very inspirational in his successes, and I realized the breadth of what he had done, which I did not realize in my youth growing up. But this is a person who came to the US. This was before Asian immigration was even legal. So he got here and they had to pass a special bill in Congress to let him be a citizen that was based on the sort of work that he had done in Canada and in the UK before he came here. And then he sets up shop in the University of Wisconsin in Madison and hires tons of these postdocs and essentially converted his lab into this massive factory, trying to figure out the genetic code. Really just the type of dedication that that needs and the amount of work that that needs and the ability to do that in a setting far removed from where he grew up, I think it's just really quite mind boggling.

And then he didn't stop there. He got the Nobel for that, but I have these letters that he wrote after he got the Nobel Prize, and he was just completely obsessed with the possibility that getting the Nobel would make him sort of lose his mojo and he wouldn't be as focused on the next aspects of science. And he was just really dedicated to synthesizing DNA in the lab, so creating artificial DNA, which he ended up doing. And the offshoot of that work, so not just the genetic code, but PCR essentially was developed by his lab before it became sort of what we now know as PCR. And then ditches all of that in the ‘80s and ‘90s and moves to understanding the retina and just focuses on retinal disorders. And then signal transduction, essentially trying to figure out when a single photon of light hits your eye, what happens biologically. It's a completely different field. And just took that on and spent the next 20,30 years of his life doing that. So the ability to sort of change fields, I thought that was very inspirational as well, that you don't have to just stick to one question. You can get into one question, answer it as much as possible, and then find something else that's really interesting to you and that really grabs your attention, and then stick with that for the next couple of decades. So lots to learn there.

Dr. Rafeh Naqash: Thank you. Thank you. And then, based on some of your personal lessons, what's your advice for junior faculty and trainees as you've progressed in your career?

Dr. Alok A. Khorana: I think, number one, and I can't emphasize this enough, and sometimes it actually causes a little bit of anxiety, but it is finding the right mentor. And for me, certainly that was key, because my mentor, who was Charlie Francis, was not an oncologist who was a hematologist, but was like me, sort of supported this idea of trying to understand, hey, why does coagulation interact with cancer? And so he approached it from a hematology perspective, I approached it from a cancer perspective, but he sort of gave me the freedom to ask those questions in his lab and then later on in the clinical setting and clinical translational setting, and then got me access to other people who are experts in the field and introducing you and then getting you on committees and making sure you sort of get into clinical trials and so on. And so having a mentor who sort of supports you but doesn't stifle you, and that's really key because you don't want to just ask the question that the mentor is interested in. And as a mentor now, I don't want to have my mentee ask the question that I'm interested in, but also a question that the mentee is interested in. And so there's a little bit of a chemistry there that's not always replicable, and it can go wrong in sort of five different ways, but when it goes right, it's really vital. And I mentioned it causes anxiety because, of course, not every day is great with your mentor or with your mentee, but over a period of time, has this person done sort of their best to get your career off to a start? And have you served that mentor well by doing the things that are– there's responsibilities on both sides, on both on the mentor and on the mentee. And if you can find that relationship where there's a little bit of chemistry there and both of you are effectively discharging both your responsibilities and satisfying your intellectual curiosity, I think that can't be beat, honestly. To me, sort of number one is that and everything else follows from that. So, the networking, making sure your time is sort of allocated appropriately, fighting with sort of the higher ups to make sure that you're not having to do too much, things that are sort of away from your research interests, all of that sort of flows from having the right person.

Dr. Rafeh Naqash: Couldn't agree with you more, Dr. Khorana, thank you so much. It was an absolute pleasure. Thank you for sharing with us the science, the personal as well as the professional journey that you had. And hopefully, when you have the next Khorana Score, Khorana score 2.0, JCO Precision Oncology will become the home for that paper and we'll try to have you again maybe in the near future.

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 so much.

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Disclosures:

Dr. Khorana - Honoraria Company: Pfizer, Bayer, Anthos, Sanofi, BMS, WebMD/Medscape
Consulting or Advisory Role Company: Janssen, Bayer, Anthos, Pfizer, Sanofi, BMS
Research Funding Company: Anthos, Bristol-Myers, Squibb
Travel, Accommodations, Expenses Company: Janssen, Bayer, Bristol-Myers Squibb

Molecular Characteristics of Early-Onset Biliary Tract Cancer

JCO Precision Oncology Conversations