BRCA2 Reversion Mutation Associated With Acquired Resistance to Olaparib in Estrogen Receptor-positive Breast Cancer Detected by Genomic Profiling of Tissue and Liquid Biopsy

Inactivating mutations in BRCA1 or BRCA2 predict response to PARP inhibitors and platinum-based chemotherapeutics. However, acquired secondary reversion mutations in BRCA1/2 that underlie resistance to these therapies have been identified in multiple tumor types. In this case, comprehensive genomic profiling of estrogen receptor-positive breast cancer identified co-occurring ESR1 and BRCA2 mutations. Identification of the BRCA2 mutation provided rational treatment guidance in the resistance setting of ESR1-mutated breast cancer: the patient was treated with olaparib, which led to a positive response and long-term benefit after progression on 7 prior lines of therapy. At disease progression on olaparib, a BRCA2 reversion mutation was detected in both tissue and liquid biopsies, providing a molecular explanation for olaparib resistance. Repeated genomic profiling at disease progression over the course of clinical treatment of metastatic breast cancer captured tumor evolution, uncovering mechanisms of acquired resistance and evolving treatment strategies. (C) 2017 Elsevier Inc. All rights reserved.