Molecular Insights into Early-Onset Biliary Tract Cancer

Alok Khorana, MD, Director of the Gastrointestinal Malignancies Program at Cleveland Clinic Cancer Institute, joins the Cancer Advances Podcast to break down the latest research on early-onset biliary tract cancer, diving into the genetic and molecular differences that set it apart. Listen as Dr. Khorana addresses the challenges in diagnosing and treating this cancer and the exciting potential for personalized therapies tailored to these molecular discoveries.

Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Cleveland Clinic Sarcoma Program.

Today I'm happy to be joined by Dr. Alok Khorana, a Professor of Medicine and Director of the Gastrointestinal Malignancies Program here at Cleveland Clinic. He was previously a guest on this podcast to discuss exploring the microbiome in young onset colon cancer patients, and that episode is still available for you to listen to. He's here today to discuss molecular differences with therapeutic implications in patients with early onset compared with average onset biliary tract cancer. So welcome back.

Alok Khorana, MD: Thanks, Dale. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. So remind us a little bit about what you do here at the clinic.

Alok Khorana, MD: I direct the GI cancer program, which as you know, is comprised of not just colorectal cancer, although that's a big illness in this population, but also a lot of pancreatic cancer, milder cancer, gallbladder cancer. And that's why one of the things we're talking about today is biliary tract cancer.

Dale Shepard, MD, PhD: And so, maybe just take a little step back. Previously we talked about young onset colorectal cancer. Now we're going to talk about young onset biliary tract cancer. When we think about definitions, what sort of defines young onset versus average onset?

Alok Khorana, MD: Yeah. There are sort of inconsistent definitions in the literature, but I think there's sort of a consensus building around age 50 as a cutoff. So if you're more than age 50 and you get any of these different types of cancers, you're considered usual onset or average onset. If you're less than 50, that's when you're considered early onset or young onset. The field is sort of plagued by having all these different terminologies. I think young onset to me makes sort of more intuitive sense, but early onset has also taken off, so there's all these terms out there. But typically the cutoff definition is around age 50.

I'm glad you mentioned sort of early onset all cancers, because the last time I was here we talked a lot about early onset colorectal cancer, and that's really what's attracted a bunch of attention. But as we'll see today, it's not just colorectal cancers. A lot of cancers are rising in the younger population, age less than 50, and that does include biliary tract cancers.

Dale Shepard, MD, PhD: Yeah. The American Cancer Society here a couple weeks ago released the statistics, and unfortunately, young patients are the ones who are being most affected at this point.

Alok Khorana, MD: Yeah. And it's not just the US population. There's also a large paper in one of the Lancet journals from a couple of weeks ago showing that early onset cancers are rising across different types of cancers, and then in different countries, I think they named like 27 countries or something like that. So it's definitely a worldwide public health issue. And if you can't sort of figure this out soon, it's sort of doomed to keep going up unless we understand the reasons that's driving it.

Dale Shepard, MD, PhD: Yeah. We're going to specifically talk about biliary tract cancers. A lot of different people might be listening in. Give us a little bit of an idea, what is biliary tract cancers? And again, you've kind of alluded to it, but why it's important to be talking about this when you're here today.

Alok Khorana, MD: Yeah. So biliary tract cancers is sort of a broad grouping of essentially bile duct cancers, but not pancreatic. So it includes intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancers, so all sort of the different cancers that occur in the biliary tree. And as you know, the bile duct sort of comes out and then goes through the pancreas and into the small intestine. Pancreatic cancers typically are treated in a different way, understood in a different way. So they don't belong in this grouping, although there are some overlaps between biliary cancers and pancreatic cancers. But the standard definition includes intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancers.

Dale Shepard, MD, PhD: When we think about this early onset, average onset, one of the big questions is why? And so, things like we're going to talk about today, we're trying to figure this out?

Alok Khorana, MD: Yeah, and that's what's really drove us to investigate this, which is that we know a lot now about early onset colorectal cancer. And our group in particular has studied a lot of the microbiomic profiling, the metabolomic profiling. Other groups have looked at genomic profiling of colorectal cancer. And as we sort of, as GI oncologists, you're not just thinking colorectal cancer all the time, you're thinking some of these other cancers. And we realize we are seeing younger patients with bile duct cancer too.

And so, that has led us to sort of think, "Okay, we've done all this work in colorectal cancer, but there's not a ton of work being done in this particular type of cancer." And so, we decided to investigate. And we're still in the process of looking at pancreatic and other cancers as well, what's driving genomic microbiomic differences in the bile duct and pancreatic cancer population. And so, for this particular paper, we evaluated specifically biliary tract cancers and trying to understand molecular differences, which really is looking at genomics and understanding what are the genomic differences between younger patients and average onset patients with a variety of bile duct cancers.

Dale Shepard, MD, PhD: How did you go about studying this? How many patients? How did you go about trying to answer this question?

Alok Khorana, MD: So thankfully, unlike colorectal cancer where you could find a bunch of younger onset patients in the Cleveland area, in our hospital, biliary tract cancer is not as common. So we had to reach outside of the Cleveland Clinic and work really with a large group of investigators nationally, some from the Cleveland Clinic, some nationally. And we partnered with Caris, which is a very large organization that does next-gen sequencing in people with many different types of cancers. And they were very collaborative in sort of letting us interrogate their data on what are the differences when you look at the biliary tract cancer population by age? And are all these cancers similar genomically or are they different when you look at them by age? And because it's a national data set, we ended up with a lot of patients, about 5,500 patients with biliary tract cancers, of whom about 5,000 had average onset or usual onset biliary tract cancer, and about 500 were younger than age 50. So a big population, especially considering the rarity of this illness.

Dale Shepard, MD, PhD: And when you look at these sort of molecular differences, did you note any findings that you found between the two and any surprises in those?

Alok Khorana, MD: Yeah. One of the big findings that we found was that FGFR2 fusion was much more common in the younger onset population. And this I think if I might use a call for awareness about the importance of genomic testing in the biliary tract cancer population, for many years, and Dale, you've taken care of GI cancer patients so you know this. For many years, these types of cancers were sort of considered an orphan illness, relatively rare, not a lot of understanding of what's driving it, not as much interest in investigating it. But over the past maybe five years, seven years, something like that, it turned out that biliary cancers are a very, what we call a target-rich population. So there's a lot of mutations that seem to occur in patients with biliary tract cancer that are druggable, so that have medications that can target those mutations.

And a good sort of rule of thumb is that somewhere between 30 and 40% of the biliary tract cancer population has something druggable, so FGFR fusions, for instance, IDH mutations, MSI high. And you can sort of go down the list of some are tumor agnostic, so they occur in all different types of cancers, but FGFR and IDH specifically are pretty druggable in the biliary tract cancer population. So those were some of the targets we tried to understand between the younger onset and average onset population.

And we found that FGFR2 fusion was significantly more prevalent in the younger population compared to the usual onset population. And that's really important, because of all the druggable targets in biliary tract cancer, FGFR fusion is probably number one. So there's already a bunch of drugs that target this specific alteration. A couple are approved and a couple more are in trials development and likely to be approved. So this really raises what I want to do, if there's one takeaway from all of this is just make sure you get NGS testing on your biliary tract cancer patients, because you might be missing out on a bunch of therapeutic options if you don't.

Dale Shepard, MD, PhD: Specifically the FGFR2 fusions, when you notice the difference in the younger onset compared to older, I remember having an early phase trial a number of years ago, it was actually hard to accrue to because they had initially done work over, it was more of an Asian population. They brought it here and it was hard to actually find patients, but maybe it was the mix of people we were looking at.

Alok Khorana, MD: Yeah. And this analysis was only in the US population, so I think it's very reflective of the patients we treat. And it's a clinically-based population, because if you're sending your patients' tumor specimen to Caris, you're seeing these patients in the clinic, you're consenting them, you're sending it out, you want to make a clinical decision. So this is very, very generalizable. It's very representative of what you see in the clinic every day.

Dale Shepard, MD, PhD: Was there anything that was noted to be more common in older patients? So the younger onset, you saw more of the FGFR2 fusions. Was there anything characteristic of the older patients?

Alok Khorana, MD: So one of the things when you do this type of analysis is you can also look at pathways. And we did find that certain inflammatory pathways, and there's a couple signatures of these pathways, so the T-cell inflamed signature and then the interferon gamma ifg score. And these are both sort of signaling pathways that are a reflection of the host immune response to tumor cells were higher in the average onset population, which to me was a little bit surprising. Because the expectation generally is younger patients, more active immune systems, you're going to see more pro-inflammatory, pro-immune upregulation in the younger onset population. But in fact, we found the opposite.

It was also surprising because MSI high tumors and high TMB are typically more often seen in the younger population, because a lot of MSI is driven by lynch type hereditary syndrome. And we did see numerically higher MSI high and high TMB in the younger population. But despite seeing that, the immune pathways, interferon gamma and the T-cell inflamed signature, were still higher in the older population. So we need to query that a little bit more and try and understand why exactly that's happening.

Dale Shepard, MD, PhD: Now, the inflammatory sort of signatures as well as the genomic changes, so how do you approach a patient if you do the sequencing? Are you kind of likely to find one or the other to guide therapies, or do you have to sort of choose a therapy in a setting where maybe either pathway is in play?

Alok Khorana, MD: Yeah. At this point, I think the drugs that are approved are driven by the mutational status only. So we're not using these inflammatory pathway signals to utilize drugs. We might in the future, but we're not right now. And so, it's having MSI high, high TMB, those things would dictate sort of use of immunotherapy for specific subgroups in this setting. It is true that overall what's become now the standard regimen in this population is gem-cis-durvalumab. And so, without biomarkers, we are using immunotherapy first line in this setting.

But as with any drug, some people respond and some people don't respond. And I think understanding these pathways might help us figure out who are the ones more likely to respond. Maybe some of these patients need dual immunotherapy like we are seeing in colorectal cancer. And so, much more work to be done, but I think it certainly emphasizes the importance of testing for druggable mutations and the importance of using immune checkpoint immunotherapy in this population.

Dale Shepard, MD, PhD: And I guess as you've said, get the genomics, figure out if there's something actionable. Is the thought that you would do that first line instead of the chemo/immunotherapy as first line, or just having that available as a second line? How are you approaching having the presence of something druggable?

Alok Khorana, MD: That's a great question. So we are a little bit hamstrung in terms of the time it takes to secure the specimen, send it out, get the results back. Things have been sped up, but it still takes a good two, three weeks, Right, in the clinical setting. At this point, gem-cis-durvalumab is still the standard first line treatment, does not require biomarker selection. So what we are doing is sending things out. As soon as we get patient walks in the door, we discuss the diagnosis, we discuss the prognosis, we make a recommendation for first line treatment.

But while everything's cooking, you also want the NGS to be cooking, because you will use that to guide at least second line treatment. And sometimes as a clinician, I think it's easier for me to know what my options are in the second, third line setting. So if somebody has FGF mutation, IDH mutation, lucky enough to have NTRK mutation or something like that, and if they're having a hard time with the chemo/immunotherapy combination or there's some unexpected side effects, I'll be more likely to give that up because I know, "Hey, I have a great option for your second line."

Dale Shepard, MD, PhD: Even if you have to dose-modify and go back to it or something like that.

Alok Khorana, MD: Right. Yeah.

Dale Shepard, MD, PhD: Yeah.

Alok Khorana, MD: So, I think it is important to get this as soon as possible, because it gives you and the patient sort of the full scope of what options are available to you right now.

Dale Shepard, MD, PhD:

What are sort of the thoughts about these kinds of studies identifying these differences in terms of your next steps in looking at other young onset cancers?

Alok Khorana, MD: I think we need more of them, because what we're learning from the colorectal cancer analysis, from this analysis, is that it's not a single homogeneous entity. And the way colorectal cancer is developing in the younger population and possibly the way biliary tract cancers are developing in the younger onset population, the driving mutations may be different, which suggests that the environmental risk factors may be different, which suggests that they may behave differently in the clinic.

We saw in this analysis that even though there wasn't a much higher use of immunotherapy in this population, we still saw better survival in the younger population than the usual onset population. And so, I think with the right selection of treatment, maybe we can extend life in this population more than the older population. So again, we need to think of these as sort of different and related but different entities, and make sure that we are utilizing all the options possible, especially for the younger patients.

Dale Shepard, MD, PhD: We've been talking about biliary tract, not pancreatic, but pancreatic is still the third leading cause of cancer death. It's still, incidence rising, mortality hasn't really been affected much. What's exciting you right now in terms of new therapies, new approaches? I figured while we're here, we'll get some additional info, right?

Alok Khorana, MD: Yeah. So I think broadly speaking in GI cancers, I just came back from ASCO GI, and there's a lot of excitement around sort of two different approaches. One is we are seeing RAS inhibitors finally hit at least the clinical trials. And you do a lot of these early phase trials, Dale, so you know.

Dale Shepard, MD, PhD: Yeah.

Alok Khorana, MD: You know there is some success.

Dale Shepard, MD, PhD: It's a lot of PAN-RAS.

Alok Khorana, MD: A lot of PAN-RAS inhibitors, but we are seeing success with them. And again, very early, very, very early, a lot of these drugs are in the Phase 1 only, so they'll go on to Phase 2, then they'll go on to Phase 3. And we don't fully understand the duration of response, the impact on survival, which obviously is the gold standard here. But the very fact that we are able to find RAS inhibitors that are actually inducing responses, that's a pretty good start. We've been trying that for 20+ years now and have never been able to find a decent RAS inhibitor, and that kind of change with the G12C inhibitors. And now with these PAN-RAS inhibitors, we are seeing what appears to be more success as well.

Dale Shepard, MD, PhD: Yeah, it's encouraging. You used to, if you would find a KRAS mutation, it told you what you couldn't do.

Alok Khorana, MD: Yep. Exactly.

Dale Shepard, MD, PhD: Not necessarily what you could.

Alok Khorana, MD: So, I think that's exciting. And then, we're still struggling for ways to make immune checkpoint inhibitors work in the non-MSS, non-high TMB population. And there's some data with this bot-bal combination that suggests that they might work in an MSS population. There is conflicting data that it might only work in the lung-only metastasis population, but more other studies are showing it might work in liver mets also. So that's also, obviously, a huge chunk of the population is MSS, both in colorectal and non-colorectal GI cancers. And so, can we make immune checkpoint inhibitors work in MSS, low TMB population? That's kind of the holy grail at this point.

Dale Shepard, MD, PhD: Well, it's certainly important that you're doing this work on young onset, early onset. Unfortunately, it's a growing area of concern.

Alok Khorana, MD: Yeah, not something we really wanted to get into.

Dale Shepard, MD, PhD: Yeah.

Alok Khorana, MD: When you see these patients day in and day out in clinic, it just kind of, I think, forces you to say, "Okay, there's something going on here. How do we study this?"

Dale Shepard, MD, PhD: Yeah. So important questions, good work. I appreciate you being here, sharing your insights.

Alok Khorana, MD: Yeah. Thank you, Dale. Thanks for having me.

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