Diverse <i>BRCA1</i> and <i>BRCA2</i> Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer.
de Bruijn, I
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<b>Purpose:</b> Resistance to platinum-based chemotherapy or PARP inhibition in germline <i>BRCA1</i> or <i>BRCA2</i> mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether <i>BRCA1/2</i> 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.<b>Experimental Design:</b> cfDNA from 24 prospectively accrued patients with germline <i>BRCA1</i> or <i>BRCA2</i> 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 <i>BRCA1</i> and <i>BRCA2</i> Functional studies were performed to assess the impact of the putative <i>BRCA1/2</i> reversion mutations on BRCA1/2 function.<b>Results:</b> Diverse and often polyclonal putative <i>BRCA1</i> or <i>BRCA2</i> reversion mutations were identified in cfDNA from four patients with ovarian cancer (21%) and from two patients with breast cancer (40%). <i>BRCA2</i> 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.<b>Conclusions:</b> Putative <i>BRCA1/2</i> 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 <i>BRCA1/2</i> reversion mutations and to aid the selection of patients for PARP inhibition therapy. <i>Clin Cancer Res; 23(21); 6708-20. ©2017 AACR</i>.
The Institute of Cancer Research (Grant ID: Unspecified)
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Drug Resistance, Neoplasm
Poly(ADP-ribose) Polymerase Inhibitors
Cell-Free Nucleic Acids
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Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (21), pp. 6708 - 6720