Q and a on PARP inhibitor use in somatic BRCA-mutated breast cancers.

Abstract

Individuals with pathogenic variants in BRCA1 or BRCA2 genes (BRCAm) have an increased risk of developing breast, ovarian, pancreatic, and prostate cancers. BRCAm can be of germline origin (inherited; gBRCAm) or arise spontaneously during tumor development (somatic BRCAm; sBRCAm). gBRCAm status is determined by analyzing DNA from non-tumor cells in blood or saliva. Tumor BRCA tests detect both gBRCAm and sBRCAm in tumor DNA, and sBRCAm status is determined when the tumor BRCAm test is positive and gBRCAm test is negative. BRCA1/BRCA2 inactivation results in homologous recombination deficiency (HRD), which sensitizes tumor cells with BRCAm to poly(ADP-ribose) polymerase (PARP) inhibitors. Thus, timely determination of BRCAm status in patients with cancer can help to 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 gBRCAm (USA, EU, and other markets) or g/sBRCAm (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 gBRCAm and sBRCAm, with preclinical and translational data demonstrating that both can result in high levels of biallelic inactivation, HRD phenotypes, and PARP inhibitor sensitivity. There is also evidence from clinical trials demonstrating the benefit of PARP inhibitor therapy in patients with sBRCAm breast cancer, suggesting that inclusion criteria of more trials should be expanded to include patients with sBRCAm.