Molecular and Clinical Heterogeneity in Resected Biliary Tract Cancer: A Single-Center Analysis of Treatment Patterns and Oncologic Outcomes

Background/Objectives: Biliary tract cancer (BTC) comprises anatomically and molecularly distinct diseases, yet real-world data integrating molecular testing with clinicopathological characteristics and outcomes after resection remain limited. We evaluated clinical and molecular heterogeneity across the major BTC subtypes in a contemporary surgical cohort. Methods: Consecutive adults undergoing curative-intent resection for intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinoma, or gallbladder cancer (GBC) at a single Vienna center between 2019 and 2025 were analyzed at the patient level using the first qualifying resection as the index procedure. Molecular testing (52-gene Oncomine Focus; 50-gene Precision/Genexus), perioperative and pathological outcomes, recurrence, and overall survival (OS) were assessed. Results: The cohort included 145 patients (73 iCCA, 24 pCCA, 22 dCCA, 26 GBC). Molecular profiling was available in 103 patients (71%). IDH1/2 and FGFR2 alterations were confined to iCCA, whereas KRAS alterations were most frequent in pCCA and dCCA. Major morbidity occurred in 54/145 patients (37%) and was highest in pCCA (16/24, 67%); 17 Grade V events were documented. Median OS was 40.0 months and did not differ significantly across anatomical subtypes (log-rank p = 0.250). Cumulative incidence of recurrence likewise did not differ significantly across subtypes when death without prior recurrence was treated as a competing event (Gray’s test p = 0.163). Conclusions: The principal contribution of this real-world cohort is the integration of routine molecular testing with surgical, pathological, treatment, perioperative, and longitudinal outcome data across resected BTC subtypes. Assay coverage and testing selection must be considered when interpreting molecular findings generated in routine practice.