Annual Review of Medicine

Current Approaches to Germline Cancer Genetic Testing

The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes.

New Therapeutic Options for BRCA Mutant Patients

Pathogenic variants in BRCA1 and BRCA2 are associated with significantly elevated lifetime risks of breast, ovarian, pancreatic, and prostate cancer. These genes are critical in double-strand break repair through homologous recombination. An understanding of the biology of BRCA1 and BRCA2 led to the development of targeted therapeutics, specifically poly(ADP-ribose) polymerase (PARP) inhibitors, which are approved by the US Food and Drug Administration for multiple BRCA1/2 -associated cancers. Here, we discuss the development of PARP inhibitors, mechanisms of resistance, and the potential utility of these drugs beyond canonical BRCA1/2 tumors, and we describe novel agents under study.