Impact of Molecular Alterations on Survival in Biliary Tract Cancers: A Retrospective Belgian Cohort Study.

Biliary tract cancers (BTCs) are aggressive malignancies associated with a poor prognosis. Although molecular profiling is recommended to guide therapeutic decision-making, real-practice data on the prevalence and prognostic significance of genomic alterations in European BTC cohorts remain limited. This retrospective cohort study characterized the molecular landscape of BTCs in a Belgian real-practice setting and evaluated its prognostic relevance. Patients with BTC who underwent informative molecular testing as part of routine diagnostics at Antwerp University Hospital between 2016 and 2024 were included. Demographic, clinical, and molecular data were extracted from electronic health records. Survival outcomes were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. Among 224 included patients, genomic alterations were identified in 59.4% of tumors, with clear subtype-specific patterns. IDH1 mutations (17.3%) and FGFR2 fusions (13.9%) were exclusively observed in intrahepatic cholangiocarcinoma, KRAS mutations were most prevalent in extrahepatic cholangiocarcinoma (42.9%), and ERBB2 amplification was enriched in gallbladder cancer (16.7%). Co-occurring alterations were present in 7.8% of cases. KRAS mutation was the most frequent alteration overall (20.4%) and remained significantly associated with worse overall survival in multivariate analysis adjusted for tumor subtype and tumor stage (HR = 1.54, 95% CI: 1.03-2.31, p = 0.04). Although 32.6% of tumors harbored a potentially actionable alteration, only 31.6% of eligible patients received matched targeted therapy. These findings underscore the clinical value of routine molecular profiling in BTC and highlight its importance for identifying therapeutic opportunities in clinical practice.