Genomic Profiling of Biliary Tract Cancers: Comprehensive Assessment of Anatomic and Geographic Heterogeneity, Co-Alterations and Outcomes.

BACKGROUND

Biliary tract cancers (BTCs) represent distinct biological and genomic entities. Anatomic and geographic heterogeneity in genomic profiling of BTC subtypes, genomic co-alterations, and their impact on long-term outcomes are not well defined.

METHODS

Genomic data to characterize alterations among patients with BTCs were derived from the AACR GENIE registry (v15.1) and other genomic data sets. Patterns of mutational co-occurrence, frequency of co-alterations, and their impact on long-term outcomes among BTC patients were examined.

RESULTS

Alterations in IDH1 and FGFR2 genes were mostly noted among intrahepatic cholangiocarcinoma (iCCA) samples, TP53, ERBB2/HER2, and SMAD4 mutations were more frequent among gallbladder cancer (GBC) samples while extrahepatic cholangiocarcinoma (eCCA) more commonly harbored KRAS mutations (all Q < 0.001). Alterations in IDH1 and FGFR2 genes were more frequent among iCCA samples from Western vs. Eastern populations, while KRAS, SMAD4, and ERBB2 mutations were more commonly observed among Eastern populations(all Q < 0.05). FGFR2 gene was frequently co-mutated with BAP1 (log2OR: 1.55, Q < 0.001), while IDH1 gene was commonly co-mutated with PBRM1 (log2OR: 1.09, Q < 0.001). Co-alteration rate among patients with IDH1-mutant iCCAs, FGFR2-rearranged iCCAs, KRAS-mutant eCCA, and HER2-mutant GBCs were 80.8%, 85.2%, 76.7%, and 100%, respectively. Among patients with iCCA and FGFR2 fusions/rearrangements, harboring co-alterations in the TP53 pathway or PI3K pathway correlated with worse overall survival (OS), while patients with IDH1-mutant iCCA had worse OS when harboring co-alterations in the cell cycle pathway.

CONCLUSIONS

Marked genomic heterogeneity exists among patients with BTCs based on anatomic and geographic location. The overwhelming majority of BTC patients with clinically significant mutations had concurrent genomic co-alterations. The current study highlights the molecular complexity of BTCs with multiple alterations that commonly co-exist and could potentially be targeted to treat BTCs.