BRCA-Mutated Pancreatic Cancer: From Discovery to Novel Treatment Paradigms

Simple Summary Approximately 10-20% of pancreatic cancer patients will have a mutation in their DNA, passed on in families, that contributes to the development of their pancreatic cancer. These mutations are important in that they effect the biology of the disease as well as contribute to sensitivity to specific treatments. We describe the critical role that these genes play in various cellular processes in the body that contribute to their role in cancer development and normal cellular function. In this review, we aim to describe the role of certain genes (BRCA1 and BRCA2) in the development of pancreatic cancer and the current and future research efforts underway to treat this subtype of disease. The discovery of BRCA1 and BRCA2 in the 1990s revolutionized the way we research and treat breast, ovarian, and pancreatic cancers. In the case of pancreatic cancers, germline mutations occur in about 10-20% of patients, with mutations in BRCA1 and BRCA2 being the most common. BRCA genes are critical in DNA repair pathways, particularly in homologous recombination, which has a serious impact on genomic stability and can contribute to cancerous cell proliferation. However, BRCA1 also plays a fundamental role in cell cycle checkpoint control, ubiquitination, control of gene expression, and chromatin remodeling, while BRCA2 also plays a role in transcription and immune system response. Therefore, mutations in these genes lead to multiple defects in cells that may be utilized when treating cancer. BRCA mutations seem to confer a prognostic benefit with an improved overall survival due to differing underlying biology. These mutations also appear to be a predictive marker, with patients showing increased sensitivity to certain treatments, such as platinum chemotherapy and PARP inhibitors. Olaparib is currently indicated for maintenance therapy in metastatic PDAC after induction with platinum-based chemotherapy. Resistance has been found to these therapies, and with a 10.8% five-year OS, novel therapies are desperately needed.