Management of BRCA Mutation Carriers With Pancreatic Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. Most patients are diagnosed with advanced disease and median overall survival is limited. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Extensive genomic efforts have been made to subtype PDAC. The DNA damage repair (DDR) deficiency subtype, also known as unstable genome/DSBR (DNA double-strand break repair) subtype, is one of the most clinically relevant biologic abnormalities in PDAC. Increased PDAC risk was found to be associated with inherited syndromes, which are present in approximately 10% of patients with PDAC. Recent updates to the ASCO and NCCN guidelines recommend risk assessment for all individuals with PDAC, irrespective of personal or family history or ethnicity. Germline BRCA mutations associated with DNA repair dysfunction is one of the best illustrations of actionable biologic subtypes in PDAC. This genetic alteration can indeed be targeted by PARP inhibitors (PARPi). Treatment implications for germline BRCA carriers with PDAC include the use of platinum-based therapy and the validation of PARPi administration as a maintenance strategy in platinum-sensitive patients. In the era of precision medicine, this is the first convincing example of targeting identified germline hereditary mutations in PDAC.
Submitted October 12, 2020; accepted for publication February 22, 2021.
Disclosures: Dr. Golan has disclosed receiving grant/research support from AstraZeneca and MSD Merck; receiving consultant fees from Abbvie, AstraZeneca, Teva, Bayer, and MSD Merck; serving on the speakers’ bureau for AbbVie, Bioline, and Roche; and receiving compensation for travel from AstraZeneca and MSD Merck. Dr. Hammel has disclosed receiving grant/research support from AstraZeneca; serving on a speakers’ bureau for AstraZeneca and Bristol Myers Squibb; serving on an advisory board for AstraZeneca; and receiving personal fees and grant support from Celgene, Erythec, Halozyme, Novartis, Pfizer, and Servier.
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