A key resistance mechanism to PARP inhibitors is the development of BRCA1/2 reversion mutations that restore the protein function. Patients with metastatic breast cancer and germline BRCA1/2 mutations were recruited from 14 institutions and treated with olaparib. Targeted next-generation sequencing was performed on circulating tumor DNA (ctDNA) extracted from blood collected at base line and progression on olaparib (Guardant360). The primary objective was to evaluate the frequency of BRCA1/2 reversion mutations in this group. From November 2021 to October 2023, 60 patients were enrolled. The median age was 50.5 years (32–85). Of these, 12 (20.0%) had germline BRCA1 mutation and 48 (80.0%) had germline BRCA2 mutation. The median number of prior chemotherapies was 2 (0–7). Two patients had received platinum. Among patients with tumor progression on olaparib who had available ctDNA results, BRCA1/2 reversion mutations were identified in 25.0% (2/8; 95% CI 3.2–65.1%) with germline BRCA1 mutation and 23.5% (8/34, 95% CI 10.7–41.2%) with germline BRCA2 mutation. In one patient, BRCA2 reversion mutations were found in ctDNA seven months before radiological confirmation of progression on olaparib and again after progression. Among the ten cases with BRCA1/2 reversion mutations, all but one case involved secondary indels on primary indel sites. Reversion mutations were not observed in the C-terminal regions of BRCA1/2. BRCA1/2 reversion mutations were detected in ctDNA as a mechanism of resistance to olaparib. Certain genomic regions and mutation types appeared to be particularly prone to reversion mutations. UMIN000046007.
Sakai et al. (Fri,) studied this question.