Genomic pathway alterations and their prognostic impact in biliary tract cancer: Insights from a multinational cohort treated with cisplatin, gemcitabine, and durvalumab

Background Biliary tract cancers (BTC) are aggressive malignancies with limited therapeutic options. Recent advances have integrated immunotherapy into the standard of care, yet outcomes remain heterogeneous, emphasizing the need for molecular biomarkers to guide patient selection. This study aimed to assess the prognostic impact of pathway-level genomic alterations in patients with BTC treated with first-line cisplatin, gemcitabine, and durvalumab. Methods This retrospective, multicenter study included 735 patients with advanced BTC, of whom 197 underwent comprehensive genomic profiling using the FoundationOne® CDx assay. Pathways were classified based on the presence of key gene alterations, and their association with overall survival (OS) and progression-free survival (PFS) was assessed through univariate and multivariate analyses. Tumor mutational burden (TMB) was also evaluated as a potential biomarker. Results HRD/BRCAness pathway alterations were associated with significantly improved OS (23.3 vs. 13.8 months, HR 0.51, 95 % CI 0.27–0.93, p = 0.0295) and PFS (13.2 vs. 8.1 months, HR 0.53, 95 % CI 0.32–0.89, p = 0.0153). TGF-β pathway alterations were linked to longer PFS (16.0 vs. 8.1 months, HR 0.53, 95 % CI 0.28–0.99, p = 0.0473) but did not independently predict OS. High TMB (>10 mut/Mb) was associated with improved OS (NR vs. 11.0 months, HR 0.34, 95 % CI 0.14–0.85, p = 0.0206) and PFS (NR vs. 7.6 months, HR 0.40, 95 % CI 0.13–0.96, p = 0.043). However, no single pathway was significantly correlated with early treatment response. Conclusions HRD /BRCA ness and TGF-β pathway alterations, along with high TMB, emerged as potential prognostic biomarkers in patients with BTC treated with chemo-immunotherapy. These findings, if prospectively confirmed and validated, support the integration of molecular profiling into routine clinical practice to improve patient stratification and treatment outcomes in this challenging tumor type.