1 research outputs found
Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer
Purpose:; Resistance to platinum-based chemotherapy or PARP inhibition in germline; BRCA1; or; BRCA2; mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether; BRCA1/2; reversion mutations could be identified in circulating cell-free DNA (cfDNA) of patients with ovarian or breast cancer previously treated with platinum and/or PARP inhibitors.; Experimental Design:; cfDNA from 24 prospectively accrued patients with germline; BRCA1; or; BRCA2; mutations, including 19 patients with platinum-resistant/refractory ovarian cancer and five patients with platinum and/or PARP inhibitor pretreated metastatic breast cancer, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of; BRCA1; and; BRCA2; Functional studies were performed to assess the impact of the putative; BRCA1/2; reversion mutations on BRCA1/2 function.; Results:; Diverse and often polyclonal putative; BRCA1; or; BRCA2; reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%).; BRCA2; reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a patient with breast cancer who did not respond to treatment and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.; Conclusions:; Putative; BRCA1/2; reversion mutations can be detected by cfDNA sequencing analysis in patients with ovarian and breast cancer. Our findings warrant further investigation of cfDNA sequencing to identify putative; BRCA1/2; reversion mutations and to aid the selection of patients for PARP inhibition therapy.; Clin Cancer Res; 23(21); 6708-20. ©2017 AACR;