Questions and answers on PARP inhibitor use in somatic BRCA-mutated breast cancers.

Abstract

Individuals with pathogenic variants in the BRCA1 or BRCA2 genes have an increased risk of developing breast, ovarian, pancreatic, and prostate cancers. BRCA variants can be of germline origin (ie, inherited) or arise spontaneously during tumor development (ie, somatic). Germline BRCA mutation status is determined by analyzing DNA from nontumor cells in blood or saliva. Tumor BRCA tests detect both germline and somatic BRCA mutations in tumor DNA, and somatic BRCA mutation status is determined when the tumor BRCA test is positive and the germline BRCA test is negative. BRCA1/BRCA2 inactivation results in homologous recombination deficiency, which sensitizes tumor cells with BRCA mutation to poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, timely determination of BRCA status in patients with cancer can help guide optimal disease management. PARP inhibitors are approved across a range of treatment settings for several tumor types, as monotherapy or in combination, as well as in biomarker selected and unselected populations. For patients with human epidermal growth factor receptor 2-negative breast cancer and germline BRCA mutation (United States, European Union, and other markets) or germline or somatic BRCA mutation (Japan), PARP inhibitors are approved in early adjuvant (olaparib) and metastatic (olaparib, talazoparib) settings. Emerging evidence now suggests possible biological similarities in breast tumors with germline BRCA mutation and somatic BRCA mutation, with preclinical and translational data demonstrating that both can result in high levels of biallelic inactivation, homologous recombination deficiency phenotypes, and PARP inhibitor sensitivity. There is also evidence from clinical trials demonstrating the benefit of PARP inhibitor therapy in patients with somatic BRCA-mutated breast cancer, suggesting that the inclusion criteria of more trials should be expanded to include patients with somatic BRCA mutation.