Assays measuring homologous recombination deficiency (HRD) caused by a broader range of mechanisms than BRCA1/2 loss are the central focus. Now a major clinical challenge is identifying the population of patients with wild-type BRCA1/2 who nonetheless will benefit from PARP inhibition. Germline testing for BRCA1/2 mutations has been available since the 1990s and is used both to assess breast and ovarian cancer risk and to guide use of PARP inhibitors in patients with cancer. 2 The FDA approved the first PARP inhibitor, olaparib (Lynparza), in 2014 for patients with germline BRCA1/2 mutations who have heavily pretreated advanced ovarian cancer, 3 and the agency has since broadened indications for this class of agents in terms of disease settings and biomarker status. Tumors with mutations in BRCA1 and BRCA2, breast cancer susceptibility genes that are quintessential members of the homologous recombination repair (HRR) pathway, are highly sensitive to platinum-based chemotherapy and PARP inhibitors. Homologous recombination, one of the major mechanisms of defective DNA repair, has emerged as a bona fide therapeutic target, yet its optimal use as a biomarker for patient selection remains a clouded scientific question.
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