Impact of germline RAD51D mutations on breast cancer: Susceptibility to DNA-damaging agents

Germline mutations in homologous recombination-related genes significantly increase the lifetime risk of breast, ovarian, and other cancers; thus, the concept of BRCAness has been extensively studied. In this study, we aimed to investigate the association between germline RAD51D mutations and breast cancer in clinical and experimental settings. Germline pathogenic or likely pathogenic variants in RAD51D were identified through multigene panel testing in the PLEASANT studies. Fourteen cases of breast cancer with germline pathogenic or likely pathogenic variants in RAD51D were identified. Compared to 1,446 wild-type cases of breast cancer, they appeared to be more aggressive. The proportion of patients with triple-negative breast cancer (TNBC) was higher and larger tumors (>2 cm) were more common. RAD51D-deficient tumors showed better pathological complete responses, defined as ypT0 ypN0, to neoadjuvant chemotherapy. Based on clinical findings, we analyzed the impact of RAD51D-deficiency on drug sensitivity in vitro to identify targetable vulnerabilities in RAD51D-deficient tumors. These TNBC cells were significantly more sensitive to cisplatin than wild-type TNBC cells, consistent with our clinical data. In conclusion, RAD51D-deficient tumors were shown to have a phenotype similar to that of BRCA1-deficient tumors, and further investigation of responses to DNA-damaging agents, particularly platinum-based chemotherapy, is warranted.