The impact of molecular alterations in patients with advanced biliary tract cancer receiving cisplatin, gemcitabine and durvalumab: a large real-life worldwide population

Background & aims: Cisplatin, gemcitabine, and durvalumab (CGD) combination is a standard first-line treatment for advanced biliary tract cancer (BTC). This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced BTC treated with CGD in real-world clinical practice. Methods: Patients with unresectable, locally advanced, or metastatic BTC treated with CGD across 39 centers in 11 countries (Europe, United States, and Asia) were included in this analysis. Results: The cohort included 513 patients with advanced BTC. The five most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (HR 0.49, p = .018) and overall survival (OS) (HR 0.11, p = .023), while TP53 mutations were linked to worse PFS (HR 1.62, p = .0047) and TERT mutations to worse OS (HR 8.92, p = .0012). No other genomic alterations were significantly associated with outcomes.Subgroup analysis showed that TP53 mutations negatively impacted PFS and OS in intrahepatic cholangiocarcinoma (iCCA), while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma (eCCA). No gene alterations were linked to outcomes in gallbladder cancer. Conclusions: This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and OS and highlights the negative prognostic roles of TP53 (PFS) and TERT (OS) mutations, providing valuable insights for personalized treatment strategies in BTC.