Homologous Recombination Deficiency Testing for BRCA-Like Tumors: The Road to Clinical Validation.

Abstract

Simple SummaryOptimal cancer treatment requires the selection of patients based on the characteristics of their tumors. This review explores various strategies to select patients for DNA double strand break-inducing agents, such as PARP inhibitors. Patients with germline BRCA1/2 mutations benefit from these inhibitors. However, patients with a functional defect in the homologous recombination repair pathway without germline BRCA1/2 mutations also show a similar reaction to this treatment. The challenge is to identify the patients with BRCA-like tumors. Here, we review various strategies to select this group of patients and summarize the clinical evidence for their performance.Germline BRCA mutations result in homologous recombination deficiency (HRD) in hereditary breast and ovarian cancer, as well as several types of sporadic tumors. The HRD phenotype makes these tumors sensitive to DNA double strand break-inducing agents, including poly-(ADP-ribose)-polymerase (PARP) inhibitors. Interestingly, a subgroup of cancers without a BRCA mutation also shows an HRD phenotype. Various methods for selecting patients with HRD tumors beyond BRCA-mutations have been explored. These methods are mainly based on DNA sequencing or functional characteristics of the tumor. We here discuss the various tests and the status of their clinical validation.