Background:
Biliary tract cancers (BTC) are a heterogeneous family of cancers including intrahepatic and extrahepatic cholangiocarcinomas (ICC, ECC) and gallbladder carcinomas (GBC). Treatment options remain limited and prognosis is poor for advanced BTC, underscoring the need for early detection and new therapeutic targets. Next-generation sequencing (NGS) studies have identified mutations associated with homologous recombination deficiency (HRD) in up to 25% of BTC patients, but the proportion with germline (GMut) versus somatic (SMut) mutations has not been established. This retrospective study was designed to determine the prevalence of GMut and HRD-associated SMut in a large BTC convenience sample and their association with key clinical parameters.

Methods:
We retrospectively analyzed de-identified records from 804 BTC patients who received tumor/normal (T/N) matched NGS between 2017-2021 via the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage; full transcriptome RNA-seq). This targeted panel detects single nucleotide variants (SNVs), indels, copy number variants (CNVs), and a selection of rearrangements. Analyses focused on pathogenic/likely pathogenic SMut and CNVs, as well as incidental GMut limited to SNVs and small indels in 50 hereditary cancer genes. HRD-associated GMut and SMut were analyzed across 9 and 18 HRR pathway genes, respectively.

Results:
We identified a cohort of 804 patients with BTC, composed of ICC (n=499), ECC (n=83), and GBC (n=222). The median age was 66 years; 55% were female; and race was White/Black/Asian in 78%/12%/6%. The prevalence of GMut was 4.6% overall. Subgroup analyses showed GMut in 5% of ICC, 4.8% of ECC, and 3.6% of GBC. For patients <50 years of age at diagnosis, pooled prevalence was 6.1% (n=82) vs. 4.5% (n=641) for age ≥50 years (p=0.6). HRD-associated GMut were present in 3.2%. HRD-associated SMut or CNVs were present in 13%, and showed significant variation across subsite (p=0.002) with highest prevalence in GBC (19%, Table). HRD-associated GMut were identified in ATM (n=8), BRCA2 (n=6), and BRCA1 (n=5). Microsatellite instability was present in 1.4% of samples.

Conclusions:
A significant proportion of BTC patients harbors potentially clinically-relevant GMut and SMut associated with HRD. Future studies are warranted to define the role of germline testing and to examine the activity of HRD-targeted therapies in BTC patients.

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