780P - Role of BRCA1 promotor methylation in homologous recombination deficiency (HRD) in high-grade ovarian cancer

Background

In high-grade ovarian cancer (OC) TCGA found BRCA1meth inferior to BRCAmut regarding prognosis probably due to lower sensitivity to platinum (Pt⁺⁺)-based chemotherapy.

Methods

In 143 high-grade OCs tested for BRCA mutations, additionally BRCA DNA methylation was determined using MethyLight PCR and genome-wide LOH and Aneuploidy Normalized Telemetric imbalance (ANTI) by means of SNP-Array analysis (GSA-24 v 3.0/Illumina) as surrogates of genome-wide DNA-scarring. For LOH and ANTI a “clinical-threshold” was calculated by Pt⁺⁺-response, determined at the first recurrence. Both were integrated in a common HRD-Score (cut-off: ≥1.912 for HRD positivity).

Results

In the present cohort, BRCA1 DNA methylation (meBRCA1) was detected in 15 (10%) and mostly BRCAwt OCs (n=14, 17%). Only one BRCA1mut OC had concomitant meBRCA1. BRCA2 DNA methylation was not observed. In terms of genomic scars, meBRCAwt and BRCAmut OCs had similar HRD scores, which were higher than those in unmethylated BRCAwt OCs (p<0.003). In BRCAwt OCs, BRCA1 methylation levels (PMR-values) were higher in HRD pos. than in HRD negative OCs (p<0.001). Progression free survival (PFS) of patients with meBRCA1 OCs was noninferior to that of BRCAmut OC patients. Worst PFS and OS was found in the subgroup of unmethylated BRCAwt OCs compared to patients with BRCAmut and meBRCA1 OCs in univariate (p=0.003; p=0.022) and multivariate survival analysis (p=0.006, p=0.018). All but one of the cancers classified as Pt⁺⁺-refractory or -resistant at first relapse (92%) were unmethylated BRCAwt OCs. None of the meBRCA1 cancers were rated Pt⁺⁺-refractory or -resistant, and only one BRCAmut OCs was associated with a Pt⁺⁺-resistant first relapse. 98.6% of the recurrences originating from OCs with genetically or epigenetically altered BRCA genes were Pt⁺⁺-sensitive, of which 77% were considered highly sensitive.

Conclusions

High-grade OCs without genetic or epigenetic BRCA alterations exhibit worst PFS. Based on genome-wide scarring, BRCA1 promotor methylation seems to exert an equivalent detrimental effect on the DNA repair by homologous recombination as pathogenic BRCA mutations.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.