Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer

Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options. Comprehensive molecular profiling can classify tumors according to mutational signatures which may enrich subtypes with therapeutic options. Diagnostic tests to identify HRD phenotypes extend beyond germline and somatic mutations in BRCA1/2 and are evolving to the integration of large volumes of genomic data. The molecular phenotype of HRD is heterogeneous, and our understanding of genetic or epigenetic aberrations in homologous recombination repair (HRR) pathways that contribute to mutagenesis remains incomplete. Resistance mechanisms to DNA damaging agents extend beyond reversion mutations, and include indirect restoration of HRR and protection of stalled replication forks. Combination strategies, including integration of immune-checkpoint inhibitors and trials exploring drug sequencing, may overcome resistance mechanisms.