Genomic characteristics and their clinical significance in a large cohort of biliary tract cancers with more than 4,000 patients.

e16285 Background: Biliary tract cancers (BTCs) are mainly divided into cholangiocarcinoma (CHOL) and gallbladder cancer (GBC). Genomic characteristics of advanced BTCs are still needed to be investigated in large cohorts. The association of genomic alterations with clinical outcome remains elusive in advanced BTCs. Methods: Next Generation Sequencing with targeted panels were conducted for 4350 cases with advanced BTCs. Homologous recombination deficiency (HRD), tumor mutation burden (TMB), microsatellite instability (MSI) and HLA-Ⅰ subtypes were determined. The association of genomic alterations with clinical outcome was investigated in a multi-institutional subset. Results: Compared with historical cohorts which included mainly early stage diseases, the frequencies of KRAS and TP53 mutation in advanced BTCs significantly increased. Compared with GBC, CHOL had significantly more mutations in RTK-RAS pathway but significantly less mutations in other oncogenic pathways such as PI3K, HIPPO, NOTCH, and WNT. The proportion of HRD and TMB in GBC were significantly higher than that in CHOL, but no significant difference was observed for the proportions of MSI and HLA-Ⅰ homozygote subtype. Mutually exclusive or co-occurring mutations (CM) were analyzed. Some CM of TP53 mutations were significantly associated with overall survival (OS). Tumors with such a mutation were defined as the CM subtype of TP53, which had poor prognosis in all patients and in patients treated by immune checkpoint inhibitors (ICIs). Frame_Shift mutations (FM) and Multi_Hit mutations (MM) of TP53 were common in advanced BTCs, which indicated better prognosis in both first-line and second-line immunotherapy. Patients with the FM/MM of TP53 also showed better objective response rate (ORR) than those with the CM of TP53 (80% vs. 0%) in immunotherapy. Therapeutically relevant alterations (TRAs) were further analyzed. The most common TRAs in GBC and CHOL were PI3KCA and KRAS mutations, respectively. GBC had more ERBB2 alterations including amplification and mutations than CHOL (13% vs. 5%; p < 0.001), but FGFR2 fusions were detected almost only in CHOL (34 cases vs. 1 case; p < 0.001). Generally, KRAS mutations and other TRAs in CHOL were mutually exclusive, while the co-occurence of PI3KCA and other TRAs were common in GBC. Compared to the wild-type, IDH1 mutations indicated better immunotherapy prognosis in BTCs. In contrast, ATM, MET, NF1, and NRAS mutations were associated with poor prognosis of immunotherapy. Importantly, patients with PI3KCA mutations cannot benefit from the treatment with ICIs. IDH1/ERBB2 mutations had significantly better ORR than their wild-types (100% vs. 46.4%, p = 0.027). Conclusions: We reported novel findings about genomic heterogeneity between advanced CHOL and GBC in a large cohort. TP53 mutation and several TRAs were biomarkers of prognosis and immunotherapy outcomes.