The Role of Biomarkers in the Management of Biliary Tract Cancer

Biomarker analysis plays a crucial role in the management of biliary tract cancers, with comprehensive next-generation sequencing being the standard approach to identify actionable molecular alterations. The most clinically significant biomarkers include IDH1 and IDH2 mutations, FGFR2 fusions or rearrangements, and ERBB2 (HER2) amplifications and mutations. These alterations demonstrate distinct patterns across different biliary tract cancer subtypes, with IDH1 and FGFR2 fusions being predominantly found in intrahepatic cholangiocarcinoma, while KRAS and TP53 mutations are more commonly observed in extrahepatic cholangiocarcinoma. ERBB2 alterations show particular prevalence in gallbladder cancers and extrahepatic cholangiocarcinoma.

Additional actionable alterations include BRAF V600E mutations, NTRK fusions, and DNA damage repair mutations such as BRCA, though these occur with significantly lower frequency. The National Comprehensive Cancer Network (NCCN) guidelines specifically recommend testing for IDH1/2 mutations, FGFR2 fusions, BRAF V600E mutations, and ERBB2 alterations as minimum requirements. Testing also extends to other potentially actionable targets including KRAS, NTRK, microsatellite instability high or mismatch repair deficiency, and BRCA1/2 mutations, particularly in patients with relevant family histories.

Despite comprehensive genomic profiling efforts, the rarity of biliary tract cancers presents unique challenges in treatment access and clinical trial enrollment. When patients harbor alterations for which FDA-approved therapies exist in other disease states but not specifically for biliary tract cancers, clinical trials become essential treatment options. The scarcity of biliary tract cancer–specific clinical trials emphasizes the importance of identifying patients eligible for targeted therapy trials based on their molecular profiles, making biomarker testing not only diagnostically valuable but also critical for accessing experimental treatments that may offer improved outcomes.