Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers

Purpose: BRAF mutations are rare in Biliary Tract Cancers (BTC), but of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF Class I, II and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. Experimental design: We analyzed two, non-overlapping cohorts. We examined the genomic landscape of BRAF mutated iCCA in a 'genomic cohort' [187 Class I, 82 Class II, 113 Class III BRAF-mutants and 8,026 wildtype (WT)]. We also analyzed median progression free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional 'clinical cohort' of BTC (including intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer) patients (41 Class I, 32 Class II+III BRAF-mutants and 1,042 WT). Results: In the entire BTC clinical cohort, the median PFS was shorter for class I [hazard ratio (HR) 2.11 (p<0.001)] and class II+III [HR 1.72 (p=0.007)] as compared with BRAF WT. OS was also shorter in Class I [HR 2.04 (p=0.011)] and Class II+III [HR 1.86 (p=0.002)] as compared with BRAF WT. In the iCCA subgroup, Class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2 and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. Conclusions: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.