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.