Introduction
The protein-encoded BRCA is involved in homologous recombination repair and plays an important role in DNA double-strand break repair. PARP plays a vital role in DNA single-strand break repair.1 Therefore, olaparib, a PARP inhibitor, is effective for tumors with a germline BRCA mutation owing to its synthetic lethality.2 The OlympiAD trial demonstrated the efficacy of olaparib in patients with human epidermal growth factor receptor type2 (HER2)-negative metastatic breast cancer with a germlineBRCA mutation.2 The median progression-free survival was significantly longer in the olaparib group than in chemotherapy of the physician’s choice group (7.0 vs. 4.2 months; P < 0.001).2
In recent years, several mechanisms of resistance to PARP inhibitors have been proposed,3 including protein alteration in the homologous recombination pathway, altered expression of a protein in the DNA replication fork protection pathway,4 epigenetic modifications, restoration of ADP-ribosylation, and pharmacological alterations.3 Importantly, reversion mutation has been recently reported as a mechanism of resistance to the PARP inhibitor olaparib.5,6
Herein, we describe a case of a patient with breast cancer with aBRCA2 pathogenic variant that was resistant to olaparib and was suspected to be a reversion mutation based on cancer genomic profiling.