Detection and therapeutic implications of homologous recombination repair deficiency in pancreatic cancer: a narrative review

BACKGROUND AND OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. A major recent advance has been the identification of a subset of patients with PDAC who harbor inherited or somatic genetic alterations that result in homologous recombination deficiency (HRD) in tumor cells. These patients often respond favorably to drugs that can exploit this vulnerability. This review outlines the biomarkers that have been developed to predict HRD and their performance related specifically to PDAC, as well as novel HRD-targeted therapies for PDAC. METHODS: We conducted a narrative review of the HRD in PDAC based on PubMed, Google Scholar, website and citation searches. KEY CONTENT AND FINDINGS: Germline mutations in BRCA1 and BRCA2 remains the only validated biomarker for the HRD state but various platforms are now available to define HRD beyond BRCA1/2 alterations. Currently, the available evidence supports the use of platinum-based chemotherapy as well as PARP inhibitors, and there is also emerging data that immune checkpoint inhibitors can produce some durable responses in these patients. CONCLUSIONS: Consistently detecting clinically significant the HRD status in PDAC has remained challenging with current commercially available platforms. Multiple novel HRD-targeted therapies for PDAC are currently in development and clinical trials, offering new opportunities for these patients.