Genomic determinants of survival after biliary tract cancer resection.

e16301 Background: Surgical resection is the mainstay for localized, resectable biliary tract cancers (BTCs). Although genomic clusters have been associated with outcomes in BTCs, data linking specific molecular subtypes to post-surgical outcomes remain limited. We aimed to evaluate the prognostic role of tumor genetic signatures in patients with BTC undergoing curative-intent surgery. Methods: We retrospectively analyzed Liver Multi-Disciplinary Clinic (LMDC) patients who underwent curative-intent surgery between 2015 and 2025 with pathology proven BTC. We included patients with detailed pathological records and next generation sequencing (NGS) results. Our endpoints of disease-free survival (DFS) and overall survival (OS) were defined as the time from surgery to their first documented disease recurrence and death from any cause, respectively. Results: There were 97 patients (52.6% male, 47.4% female) in our cohort with a mean age of 65.1 years. Most patients had AJCC Stage II (28.8%) or III disease (27.8%). Median DFS was 20.1 months (CI 16.0–28.7) and median OS was 40.4 months (CI 37.3-52.5). Recurrence occurred in 64.2% of patients, and the median survival post-recurrence was 15.4 months. In gene-level analyses, alterations in SMAD4 and BRAF were significantly associated with shorter DFS (SMAD4: HR 4.2, CI 1.61-11.00, p 0.003; BRAF HR 3.89, CI 1.17-12.92, p 0.03). Mutations in SMAD4 and NTRK1/2/3 were also associated with worse OS (SMAD4: HR 3.53, CI 1.22-10.19, p 0.02; NTRK1/2/3: HR 7.72, CI 2.23 - 26.70, p 0.001), while mutations in FGFR2 significantly improved OS (HR 0.22, CI 0.05-0.92, p 0.03). Subsequently, cluster-based analysis was performed to prevent distortion from low-frequency alterations. Cluster 1 (TP53/KRAS/ATM) and cluster 2 (CDKN2A/2B) were not associated with OS or DFS. In contrast, cluster 3 (ARID1A/PBRM1/IDH1) alterations were associated with decreased OS (HR 2.36, CI 1.23-4.56, p 0.01). Cluster 4 (FGFR2/BAP1) mutations were associated with improved OS (HR 0.33, CI 0.12, 0.92, p 0.03) relative to patients without these alterations. Conclusions: In the post-surgical setting, patients harboring mutations in chromatin remodeling pathways (ARID1A/PBRM1/IDH1), as well as SMAD4 and NTRK1/2/3, experienced worse outcomes, whereas those with BAP1 and FGFR2 alterations demonstrate improved outcomes. Although limited by sample size, our study lays out the foundation for future investigations evaluating the impact of molecular profiling in BTC patients undergoing surgical resection.