Familial Pancreatic Cancer Associated with a Shared BRIP1 Variant: Implications for Homologous Recombination Deficiency and Targeted Therapy

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a subset occurring in the context of hereditary cancer predisposition. BRIP1 is involved in homologous recombination repair, and pathogenic germline variants are established risk factors for ovarian cancer. However, its role in pancreatic cancer susceptibility and treatment response remains poorly defined. We report PDAC in a father and son whose tumors independently harbored the same BRIP1 p.K159E variant of uncertain significance (VUS), with clinical features suggestive of potential homologous recombination deficiency (HRD). A father and son developed PDAC at 70 and 39 years, respectively. Tumor profiling identified the same BRIP1 p.K159E VUS in both, alongside canonical PDAC-associated alterations. Germline testing was not performed. Both patients showed clinically meaningful sensitivity to platinum-based chemotherapy. The father achieved a partial response to FOLFIRINOX for early metastatic recurrence but subsequently deteriorated and died within one year of diagnosis. The son achieved prolonged disease control with platinum-based chemotherapy and multimodal treatment, including surgery and local therapies for oligoprogression, surviving approximately five years. Maintenance olaparib was briefly administered but discontinued because of hematological toxicity and subsequent disease progression. The occurrence of PDAC in two first-degree relatives, including early-onset disease in the son, together with the same BRIP1 p.K159E VUS in both tumors, represents an unusual familial and molecular observation. Although germline status and pathogenicity cannot be established, the shared alteration and platinum sensitivity raise the hypothesis that this BRIP1 variant may warrant further investigation in the context of homologous recombination repair. However, platinum sensitivity alone cannot be considered evidence of homologous recombination deficiency. The uncertain benefit from PARP inhibition further highlights the limitations of inferring therapeutic actionability from an individual HRR gene VUS. Further germline and functional investigation of BRIP1 alterations in PDAC is warranted.