Precision Medicine: A New Frontier for Advanced Cholangiocarcinoma - Episode 10

Mutual Exclusivity in CCA


Ghassan Abou-Alfa, MD, MBA: I’ll go back to Andrew. We briefly carried out some of that discussion, but we’ll go into more details. Tell us a little bit more about this mutual exclusivity in cholangiocarcinoma of different mutations.

Andrew Zhu, MD, PhD: This is a very interesting concept. Certain tumors probably rely on certain pathways to drive the carcinogenesis. In other words, if you have a very strong oncogenic driver, you do not need an additional mutation. That’s manifested by the mutual exclusivity, as you mentioned.

That’s actually not a very characterized field at this moment, but I think we increasingly have evidence that the IDH mutation and the FGFR2 fusion, they seem to be mutually exclusive. In other words, if you see the IDH mutation in patients, when you do the other additional testing, usually you don’t see the FGFR2 fusion, and vice versa.

But I do think that more detailed work needs to go into this space. Even though these 2 are mutually exclusive, you may actually have additional mutations going either with the IDH mutation or with FGFR2. Those coexisting mutations still will provide very important insight into figuring out the combination treatment in the future.

Ghassan Abou-Alfa, MD, MBA: Fair enough. You are hearing about what, humbly and proudly, we called at Memorial Sloan Kettering Cancer Center at one point, mutual exclusivity of genetic alterations, or MEGA, that was published already. As Dr Zhu just described, we’re not the only one who found the phenomenon. It was described by different groups, including MGH [Massachusetts General Hospital Cancer Center] and MD Anderson Cancer Center, where if a tumor has an IDH1 mutation, it’s unlikely to have an FGR fusion change, and vice versa. However, as Dr Zhu mentioned, there could be some other alterations in between.

By the way, to recite how complex that is, even though we’re focusing on IDH1 and FGFR2, and you’ll understand why, in addition to that we have the EGFR overexpression. We have, the HER2 amplification—maybe it happens more in gallbladder cancer but can happen also in cholangiocarcinoma—BRAF mutations, and of course, ROS1 rearrangement. So it’s important to make sure that we get as much information as possible for having a clinical trial, and hopefully we will have some therapy that we can apply, and as Martin mentioned, since he is an expert in regard to a referral to a phase I new therapy development that could be available for certain patients.

Transcript Edited for Clarity