BRCA1, RAD51C Methylation Linked to Response to PARP Inhibitors

BRCA1 and RAD51C methylation in high-grade ovarian carcinomas are associated with sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors, such as rucaparib, and with high loss of heterozygosity, according to a study presented at the 48^th Annual Meeting of the Society of Gynecologic Oncology.¹

Previous research demonstrated that BRCA1 and RAD51C promoter methylation decreases gene expression in ovarian cancers. For this study, researchers evaluated whether BRCA1 and RAD51C promoter hypermethylation correlates with markers of homologous recombination deficiency (HRD) and with response to rucaparib.

Investigators analyzed pretreatment tumor samples from 165 patients with relapsed, platinum-sensitive, high-grade ovarian carcinoma who received rucaparib in part 1 of the international, phase 2 ARIEL2 trial (ClinicalTrials.gov Identifier: NCT01891344).

Results showed that 12.7% of the evaluable tumor samples were methylated at the BRCA1 promoter; 2.4% were methylated at the RAD51C promoter. Only tumors with mutations in BRCA or other homologous recombination genes had methylation of BRCA1 or RAD51C.

All tumors with RAD51C methylation and about 79% of cases with BRCA1 methylation were associated with high loss of heterozygosity, a genotype driven by homologous recombination deficiency resulting in a BRCA-like phenotype.

More than half of the 21 BRCA1 methylated patients and 75.0% of the 4 RAD51C methylated patients achieved confirmed objective responses.

The findings suggest that methylation of BRCA1 and RAD51C may be a predictor of sensitivity to PARP inhibitors in patients with BRCA mutations or homologous recombination deficiency. Further prospective trials are needed to validate these results.

Reference

1. Swisher EM, Harrell MI, Lin K, et al. BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1. Paper presented at: 48^th Annual Meeting of the Society of Gynecologic Oncology; March 12-15, 2017; National Harbor, MD.