Understanding the Genetic Disposition of Cholangiocarcinoma: Panel Discussion

At the 2020 virtual conference of the Cholangiocarcinoma Foundation, a panel of experts focused on the science of cholangiocarcinoma (CCA) addressed the topic of “Genetic Disposition for CCA,” which was moderated by Anna Lleo De Nalda, MD, PhD, Associate Professor, Internal Medicine, Humanitas University, Milan, Italy. The panel members responded to questions from the attendees.

Q: Can we determine through people’s genes if they are at an increased risk for CCA?

Lewis R. Roberts, MB ChB, PhD, Consultant, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, stated that research is just beginning to delve into this question.

He is currently involved in a study titled “Bile Duct Cancer Genome Wide Association Study: Identification of Novel Genetic Loci for Bile Duct Cancer Development,” which aims to identify the proportion of people who are at risk for bile duct cancers, including those who are at risk specifically for CCAs, that can be attributed to genetic (ie, inherited) predispositions in nonprimary sclerosing cholangitis as well as in primary sclerosing cholangitis groups.

This is the first large cohort genome-wide association study in biliary tract cancers that is focused on finding meaningful associations between gene variants and biliary tract cancers in a European population. Dr Roberts noted, however, that “The study is too small, and what we learned is that we need more samples to be able to tell effectively whether we can predict from people’s DNA if they are at high risk for CCA.”

Q: Do you use a follow-up biopsy routinely to determine if tumor mutational changes have occurred after treatment starts?

Eileen M. O’Reilly, MD, Section Head, Hepatopancreaticobiliary and Neuroendocrine Cancers, Memorial Sloan Kettering Cancer Center, New York City, said that there are 2 important aspects to consider about the use of a second biopsy: (1) how a follow-up biopsy applies to clinical care, and (2) where such practice interfaces with research.

Performing follow-up biopsies on tumors helps to define mechanisms of resistance to therapy and the strategies to overcome mechanisms of resistance, Dr O’Reilly said.

One important example, she noted, is the case of patients who are receiving treatment with a targeted therapy for an FGFR2 fusion aberration. Mutations can accumulate as patients are exposed to the therapeutic agent that targets that mutation.

“We are seeing this [development of new mutations] occur more in biliary tract and pancreatic cancers, but we still have a huge amount to learn,” Dr O’Reilly stated.

Q: Can a patient have more than 1 mutation, and if so, how do you manage the treatment?

Dr O’Reilly stated that some mutations may be exclusive, and these are not seen together with other mutations.

“For example,” Dr O’Reilly said, “we do not see targetable IDH and FGFR mutations together in the same tumor. It is a luxury when there are a number of targets in a tumor. It is also rare to see 2 or more pathogenic mutations in the germline.”

Q: Can perihilar and extrahepatic CCA be misclassified, and what may be some of the consequences?

Gregory J. Gores, MD, Reuben R. Eisenberg Endowed Professor in Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, told the attendees that intrahepatic CCA can be misclassified as a perihilar tumor. He noted, however, that more often, perihilar CCA tumors are misclassified as intrahepatic lesions. In addition, true distal CCA tumors can be misclassified based on their anatomy.

The consequences of misclassifying the subtype of CCA tumors are considered from an epidemiologic perspective and a preventive treatment strategy.

“Until we get the coding right, we will never know which subtype of CCA is increasing or decreasing, and which one we should place more focus on for prevention,” Dr Gores said. “That is currently impossible with the data that we have.”

He added that because the pathogenesis of each subtype is different, the treatment of each subtype will also be different.