Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

• Authors: Britta Weigelt, Memorial Sloan Kettering Cancer Center; Inaki Comino-Mendez, Institute of Cancer Research; Ino de Bruijn, Memorial Sloan Kettering Cancer Center; Lei Tian, University of Pennsylvania; Jane Meisel, Emory University; Isaac Garcia-Murillas, Institute of Cancer Research; Charlotte Fribbens, Institute of Cancer Research; Ros Cutts, Institute of Cancer Research; Luciano G Martelotto, Memorial Sloan Kettering Cancer Center; Charlotte KY Ng, Memorial Sloan Kettering Cancer Center; Raymond S Lim, Memorial Sloan Kettering Cancer Center; Pier Selenica, Memorial Sloan Kettering Cancer Center; Salvatore Piscuoglio, Memorial Sloan Kettering Cancer Center; Carol Aghajanian, Memorial Sloan Kettering Cancer Center; Larry Norton, Memorial Sloan Kettering Cancer Center; Rajmohan Murali, Memorial Sloan Kettering Cancer Center; David M Hyman, Memorial Sloan Kettering Cancer Center; Laetitia Borsu, Memorial Sloan Kettering Cancer Center; Maria E Arcila, Memorial Sloan Kettering Cancer Center; Jason Konner, Memorial Sloan Kettering Cancer Center; Jorge S Reis-Filho, Memorial Sloan Kettering Cancer Center; Roger A Greenberg, University of Pennsylvania; Mark E Robson, Memorial Sloan Kettering Cancer Center; Nicholas C Turner, Institute of Cancer Research
• Journal Title: Clinical Cancer Research
• Volume: Volume 23, Number 21
• Publisher: American Association for Cancer Research | 2017-11-01, Pages 6708-6720
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1158/1078-0432.CCR-17-0544
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; PARP INHIBITORS; POLY(ADP-RIBOSE) POLYMERASE; COPY NUMBER; TUMOR DNA; HETEROGENEITY; REPAIR; LANDSCAPE; CARCINOMA; PATHWAY; ROLES

Abstract

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.