Molecular profile of BRCA-mutated biliary tract cancers.

Introduction: Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown.

Material And Methods: Tumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry.

Results: Overall, mutations were detected in 3.6% (n=46) of samples ( 0.6%, 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, mutations (4.0% and 2.7%) were more frequent than (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for vs 2.1% for ). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05).

Conclusions: mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with -mutant BTC.