BRCA1/2 are the most famous two genes in the homologous recombination DNA repair system. DNA-damaging therapies, including platinum chemotherapy and PARP inhibitors, are known with anti-tumor activity in BRCA1/2 tumors. The reversion of BRCA1/2 mutation had been identified in PARP inhibitor-resistant ovarian cancer. However, the resistance mechanism is still unknown in breast cancer patients who received DNA-damaging therapies. Eight breast cancer patients with germline BRCA1/2 mutation resistant to platinum chemotherapy or PARP inhibitors were enrolled in this study. Whole exome sequencing was performed on the pre- and post-resistance tumor samples and cell-free DNA. The RAD51 focus formation (a biomarker for homologous recombination status) was also examined in tumor samples. The sequencing results of post-resistance samples showed that four patients had somatic BRCA1/2 reversion. Two patients had mutations that may increase DNA end resection and restore homologous recombination, one with loss TP53BP1 and the other one with amplification of MRE11A. The RAD51 focus formation testing results revealed restore homologous recombination in post-resistance tumor samples of all eight patients. These results indicated that both reversion and nonreversion mechanisms in BRCA1/2 will cause drug resistance, and RAD51 may be a good biomarker for treatment selection.
Waks AG. et al. Annals of Oncology. 2020