Molecular profile of BRCA-mutated biliary tract cancers

Abstract

IntroductionPrognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA 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 methodsTumour 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.ResultsOverall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. 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 (2.6% for BRCA2 vs 2.1% for BRCA1). 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).ConclusionsBRCA 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 BRCA-mutant BTC.

PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

“…However, germline or somatic BRCAm are being increasingly reported due to the possibility to identify a distinct subgroup of carriers that may benefit from a personalized treatment strategy [ 52 , 53 ]. Curiously, BRCAm in BTC have been observed more frequently as somatic rather than as germline mutations [ 54 ].…”

“…The prevalence of DDR defects in BTC has been described in a range between 28.9% and 63.5%, and unfortunately, this range of frequencies depends on current lack of consensus regarding methods for testing and defining DDR alterations in BTC [ 54 , 55 ]. The recent evolution of sequencing technologies and the use of comprehensive gene sequencing panels has resulted in improved ability to detect variations in DDR genes, beyond BRCA1 / 2 [ 56 ].…”

“…Patients with BRCAm are predisposed for BTC, as BRCA1/2 alterations have been associated with early onset BTC [ 51 , 52 , 53 , 54 ]. More specifically, data from the early 2000s by the Breast Cancer Linkage Consortium (BCLC) suggested that BRCA2- carriers had higher relative risk (RR) of developing BTC than patients affected by infection with liver parasites, hepatitis C virus, and hepatitis B virus (RR 4.97, 95% confidence interval (CI) 1.50–16.52) [ 67 ].…”

“…Interestingly, this study included highly pretreated patients, with 14 out of 25 harboring a germline or somatic BRCA1/2 mutation. More recently, the report by Spizzo and colleagues on 1292 tumor samples of BTC patients suggested a potential association between BRCAm and ICIs response, with tumor mismatch repair, microsatellite instability status, and PD-L1 overexpression associated with BRCAm [ 54 ].…”

The DNA damage repair (DDR) pathway in biliary tract cancer (BTC): a new Pandora’s box?

“…We read with great interest the article 'Molecular profile of BRCA-mutated biliary tract cancers' by Spizzo and colleagues. 1 This study provides substantial evidence of the emerging importance of BRCA 1/2 mutations (BRCAm) identification in biliary tract cancers (BTC), suggesting a potential association between BRCAm and response to immune checkpoint inhibitors (ICIs). The emerging role of these genomic alterations as novel therapeutic target in metastatic solid tumours has led to enhance the concept of patient-focused, personalised medicine, paving the way towards new therapeutic scenarios in poor-prognosis malignancies.…”