Use of comprehensive multigene panel testing for patients with HBC

June 17, 2022

Hepatobiliary cancer (HBC) comprises a set of malignant tumors that affect the liver and biliary tract, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), gallbladder cancer and cancer of the ampulla of Vater. This form of cancer typically responds poorly to existing systemic therapies and is associated with less favorable survival rates.

Little is known about the degree to which hereditary components and genes are involved in the development of HBC. Identification of an inherited genetic predisposition for these tumors could thus have important implications for prevention, treatment and family counseling.

In an abstract published in the Journal of Clinical Oncology in 2019 and presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, Mayo Clinic researchers reported on the spectrum of pathogenic or likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility of these germline genetic test results. In this retrospective study, the researchers studied a consecutive series of 267 patients referred for germline genetic testing based on a personal history of HBC. Among those patients, 15% had P/LP variants identified in cancer-risk genes.

The researchers concluded that identifying these germline P/LP variants provided information that guided clinical options in a substantial fraction of the patients studied. These options helped identify patients' eligibility for ongoing clinical treatment trials, clinical management recommendations consistent with National Comprehensive Cancer Network guidelines and cascade testing for risk assessment of family members. Lead author Niloy Jewel (Jewel) J. Samadder, M.D., and colleagues concluded that these data demonstrate a need for comprehensive germline multigene panel testing in all patients with HBC. Dr. Samadder is a gastroenterologist and hepatologist specializing in inherited cancers at Mayo Clinic's campus in Arizona.

Building on that knowledge, Dr. Samadder and colleagues sought to determine the prevalence of pathogenic germline variants (PGV) in patients with HBC via a prospective study of germline sequencing. This focus on HBC was part of Mayo Clinic's large, multicenter study of universal testing of patients with cancer known as the Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) trial. The results of the HBC study were published in Cancer Prevention Research in 2022.

Study methods

Researchers used a next-generation sequencing platform consisting of more than 80 genes to analyze samples in 205 prospectively enrolled patients with HBC. Study participants received care at Mayo Clinic Cancer Center between April 1, 2018, and March 31, 2020, and were selected regardless of cancer stage, family cancer history, ethnicity or age. Overall, 64.4% were diagnosed with cholangiocarcinoma, 21.5% with hepatocellular carcinoma, 7.8% with gallbladder cancer, and 4.3% with carcinoma of ampulla of Vater. Family cascade testing was offered at no cost.


Key findings from the INTERCEPT trial data related to HBC include the following:

  • Germline testing results identified PGV in 32 (15.6%) of the 205 participants. And 23 (71.8%) of the PGV involved moderate- and high-penetrance cancer susceptibility genes.
  • Prevalence of PGV was 15.7% in patients with intrahepatic cholangiocarcinoma, 17% in patients with extrahepatic cholangiocarcinoma, 15.9% in patients with hepatocellular cancer and 33% in patients with carcinoma of ampulla of Vater.
  • Of the 34 PGV variants identified, 19 (55%) have approved precision therapy and clinical treatment trials that are recommended or available.
  • Approximately 75% of the patients in whom the researchers identified a PGV would not have been referred for germline testing using currently accepted referral guidelines, and the variant would likely have remained undetected.

According to Dr. Samadder, the INTERCEPT trial is one of the largest prospective multisite studies of universal genetic testing in patients with cancer and offers several significant takeaways.

"Our analysis found that nearly 1 in 6 patients carried a genetic marker that predisposed them to the development of cancer," explains Dr. Samadder. "Importantly, over half of these patients with a genetic mutation would have been eligible for approved precision therapies or clinical treatment trials. Providing germline genetic testing for patients with HBC has the potential to facilitate precision cancer therapy and prevent these deadly cancers through screening and early identification of high-risk, genetically predisposed individuals."

Dr. Samadder notes that larger studies incorporating universal genetic testing of patients with cancer, use of test results to guide cancer therapy selection and longer-term follow-up will help researchers assess if this testing strategy can improve survival rates and patient outcomes.

"At Mayo Clinic Cancer Center, we have genetic assessment clinics linked to all of our oncology practices to allow patients with cancers to have pangenomic assessment to help guide their treatment decisions and cancer journey."

For more information

Samadder J, et al. Landscape of germline mutations in hepatobiliary carcinoma: Unrealized risk, untapped clinical trial opportunities. Journal of Clinical Oncology. 2019;37S:236.

Uson Junior PL, et al. Germline cancer susceptibility gene testing in unselected patients with hepatobiliary cancers: A multi-center prospective study. Cancer Prevention Research. 2022;15:121.

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