Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).

Abstract

4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.