Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Precision targeting of known PDAC subtypes may positively affect the outcome of this disease. An important actionable subtype in this cancer is associated with DNA repair dysfunction, including cases with germline BRCA mutations. This subtype can be targeted by inhibitors of poly(ADP-ribose) polymerase (PARP). BRCA mutation–associated PDAC may be the first biomarker-driven subtype in this disease that can be successfully targeted. However, DNA repair defects can extend beyond the narrow spectrum of BRCA1/2 mutations in PDAC and are present in a large proportion of patients with familial PDAC. This review describes the subgroup of patients with PDAC with aberrant DNA repair and discusses diagnostic and therapeutic options.
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