Mutations associated with homologous recombination deficiency (HRD) have been identified in up to 25% of patients with biliary tract cancers; however, the proportion of patients with germline versus somatic mutations has not been previously defined.
In this retrospective, real-world study, Robin Kate Kelley, MD, University of California, San Francisco, and colleagues sought to determine the prevalence of germline and somatic mutations associated with HRD in a large population of patients with biliary tract cancer, and the association of these mutations with key clinical parameters.
Dr Kelley presented the results at the 2022 ASCO GI Cancers Symposium.
In this retrospective analysis, the investigators identified records of patients with biliary tract cancer who underwent next-generation sequencing between 2017 and 2021.
The analyses focused on pathogenic or likely pathogenic somatic mutations and copy number variants, as well as incidental germline mutations limited to single nucleotide variants and small indels in 50 hereditary cancer genes. HRD-associated germline and somatic mutations were analyzed across 9 and 18 HRR pathway genes, respectively.
A total of 804 patients with biliary tract cancer (median age, 66 years; 55% were female) were included in the analysis; of these, 499 had intrahepatic cholangiocarcinoma (CCA), 83 had extrahepatic CCA, and 222 had gallbladder cancer.
Overall, the prevalence of germline mutations was 4.6%. By subtype, the prevalence of germline mutations was 5% in intrahepatic CCA, 4.8% in extrahepatic CCA, and 3.6% in gallbladder cancer. By age, the prevalence was 6.1% in patients under age 50 years at diagnosis and 4.5% in patients aged ≥50 years.
In all, 3.2% of patients had HRD-associated germline mutations versus 13% of patients with somatic mutations or with copy number variants.
A significant (P = .002) variation in HRD-associated mutations was seen across CCA subtypes, including 19% in gallbladder cancer, 10% in intrahepatic CCA, and 14% in extrahepatic CCA.
By gene alteration, HRD-associated germline mutations included 8 mutations in the ATM gene, 6 mutations in BRCA2, and 5 mutations in BRCA1; microsatellite instability was present in 1.4% of samples.
Based on these real-world data, a significant proportion of patients with biliary tract cancers harbor potentially clinically relevant HRD-associated germline or somatic mutations, according to Dr Kelley and colleagues.
Kelley RK, Ashok A, Mauer E, et al. Prevalence of germline mutations and homologous recombination deficiency (HRD) in a real-world biliary tract cancer (BTC) cohort. Abstract 476.
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