Precision Medicine: A New Frontier for Advanced Cholangiocarcinoma - Episode 9

Molecular Testing for CCA


Ghassan Abou-Alfa, MD, MBA: This brings us to a very important point, which Dr Zhu started us with, which is the genetic makeup of the tumor. Andrew, in regard to cholangiocarcinoma, is it haphazard—the mutations that can happen—or is there some kind of map for what mutations can occur in specific patients?

Andrew Zhu, MD, PhD: Collectively over the past few years, we have a very good understanding about the genetic makeup of different subtypes of biliary tract cancers. The major advancement, in my opinion, is how we understand the genetic underpinnings of intrahepatic cholangiocarcinoma. I think from the initial observation, the IDH1 mutation is definitely present in a very well characterized population at a frequency in the neighborhood of 15% to 20%. It has been consistently observed in multiple studies, including at your center and also many other centers around the world. Clearly, the IDH mutation is a well-defined subtype of intrahepatic cholangiocarcinoma, interestingly. This mutation actually occurs much less frequently in extrahepatic cholangiocarcinoma.

Then, we have another very important signature, the so-called FGFR [fibroblast growth factor receptor] fusion signature. Obviously, the frequency is still somewhat debatable, but overall, we probably have at least another 10% to 15% of patients harboring that particular signature. These 2 actually make up as much as 30% of intrahepatic cholangiocarcinoma. Both have very active drug development programs that we’re going to discuss. I think that argues that for patients with cholangiocarcinoma, we should perform the testing relatively routinely, so that we can at least provide options for our patients when they don’t have other treatment options.

Ghassan Abou-Alfa, MD, MBA: Beautifully said, and I like how you delineated it. To go back to Andrea, routinely, are you doing next-generation sequencing on all patients with cholangiocarcinoma? And how do you do it? What’s your pretext to do it?

Andrea Wang-Gilliam, MD, PhD: We’re trying to do it. If we can get tissue, of course, the tissue is preferred at our centers. We use a commercial platform, generally the insurance covers it, so that’s a plus. We have an in-house test form and that we use as well.

The challenge is sometimes the tissue. Sometimes, we’re forced to use a liquid biopsy because we don’t have the tissue. Then you have a sensitivity issue with liquid biopsy in terms of totally capturing what you will see in the tissue. A lot of times, we prefer tissue but we end up with liquid in certain patients. But we routinely do it, and we want to do it at the beginning because we don’t want our patients to start progressing and do it later on. Then they’re not going to have an opportunity to go on trials or try to get a compassionate-use drug if those drugs are not approved because they are in terrible condition. We want to actually test the first time we see them in a metastatic setting.

Ghassan Abou-Alfa, MD, MBA: Teresa, how does it work for you in Europe and Barcelona?

Teresa Macarulla, MD, PhD: It is different than the United States. As you know, we have fewer resources. In our hospital, for example, we can do it because we have clinical trials that we can test, and we perform molecular analysis in all of our biliary tract cancers, especially cholangiocarcinoma, especially in hepatic cholangiocarcinoma. Then outside of these types of hospitals, like our hospital, there’s no opportunity to do it. In the rest of the hospitals, there’s no way to do. We try to convince these oncologists that they have to refer, especially the intrahepatic cholangiocarcinoma, to bigger institutions where they can do it, in order to find these targetable alterations and to include patients in clinical trials. But we have to explain this to the community because it’s different in Europe.

Ghassan Abou-Alfa, MD, MBA: Fair. Martin, as Andrea brought up, and back to the US component of the discussion, how can you justify to get coverage for doing next-generation sequencing for patients with cholangiocarcinoma?

Martin Gutierrez, MD: So, echoing Andrea’s comments, insurance doesn’t cover it. I guess we all have to jump on the bandwagon of the MSI [microsatellite instability]-high….

Ghassan Abou-Alfa, MD, MBA: Yes.

Martin Gutierrez, MD: Getting the results, getting the answer.

Ghassan Abou-Alfa, MD, MBA: That’s a good thought.

Martin Gutierrez, MD: We have all the results together. I have to say, we haven’t really had any pushback yet. Yes, we prefer tissue. Although if I use my other hat that I have, liquid biopsies have actually been very useful as well to detect some of the FGFR fusions.

Ghassan Abou-Alfa, MD, MBA: Sure. That’s very important what we’re hearing. If anything, we know very well that genetic mutations—as. Dr Zhu told us, and he suggested 2 of them—could be very valuable with regard to therapy. Understandably though, and it’s very important to remember, that none of those therapies are yet approved. As such, it could be a challenge to justifying doing the genetic testing, as we heard from Andrea and Teresa.

On the other hand, I think Martin brought up an approach that admittedly we all use, which is under the pretext of looking for MSI-high, which not necessarily will bypass a 5% cholangiocarcinoma, but we still are obligated to test for it. But at the same time, whenever you test for that, along the way you understand and are able to get the details in regard to IDH1, FGFR2, etcetera. So we are finding our way, but both hope and envision that with the advent of new therapies, it will be established care to do next-generation sequencing, as we’re all seeing the necessity. Patients even are asking for it these days.

Transcript Edited for Clarity