DNA repair and breast cancer: therapeutic opportunities

The discovery and cloning of BRCA1 and BRCA2 was accompanied by optimism that these achievements would usher in a new era of insight into sporadic breast cancer. This optimism was fueled by precedents in other cancer types, where tumor suppressor genes identified in rare hereditary cancer syndromes proved to be involved in some, if not all, of the cases of sporadic cancer of the same type. In sporadic breast cancer, sequencing efforts have failed to show significant numbers of cases of biallelic somatic mutation of either BRCA1 or BRCA2, dashing hopes of simply leveraging the understanding of BRCA1 and BRCA2 into a better understanding of sporadic breast cancer.

Laboratory-based studies of BRCA1 and BRCA2 demonstrated that loss of function of either gene resulted in significantly increased susceptibility to certain forms of chemotherapy, including interstrand DNA cross-linking agents such as the platinum drugs and mitomycin C. More recently, loss of BRCA1 or BRCA2 function has also been shown to increase sensitivity to PARP inhibition, a finding made possible as a result of increased understanding of the DNA repair implications of BRCA1 or BRCA2 loss. To a large extent, these laboratory-based observations have now been verified in clinical trials enrolling patients with hereditary breast cancer. The implications of the discovery of BRCA1 and BRCA2 for treatment options in sporadic breast cancer are more complex. Based on a series of striking phenotypic similarities between the majority of sporadic triple-negative breast cancers and most cancers that arise in BRCA1 heterozygotes, the hypothesis arose that perhaps many of these sporadic cancers might also share a similar lesion in DNA repair (BRCAness) with the BRCA1-related tumors. This notion has now been put to the test in ongoing clinical trials that treat sporadic triple-negative breast cancer patients with platinum agents, PARP inhibitors, or combinations. The current evidence for and against this hypothesis will be discussed.