Abstract 584P
Background
Neoadjuvant chemotherapy (NAC) followed by interval debulking does not present inferior results to those of primary cytoreduction and offers the opportunity to evaluate chemo-sensitivity in vivo. Chemotherapy response score (CRS) have been shown to correlate with outcome with a complete or near-complete (CRS3) response predicting improved progression-free survival (PFS). Our proposal is to determine the prevalence of BRCA1/2 mutations and to search for other molecular mechanisms of HR inactivation which could explain the great sensitivity to platinum salts.
Methods
Retrospective analysis of data of patients (pts) who experienced a CRS3 response to platinum-based NAC was performed. For pts with no BRCA1⁄2 pathogenic variant (PV), tumoral analysis was performed based on Next Generation Sequencing (NGS) comprising a DNA damage repair (DDR) related panel, mainly associated with HR including noncoding regulatory regions of BRCA1, BRCA2 and RAD51C. In parallel, we performed BRCA1 promoter (Pr) methylation analysis by Droplet digital PCR (ddPCR) for wild-type (WT) samples.
Results
A total of 37 pts were identified. Most had stage III disease (67%) of either serous histology or poorly differentiated adenocarcinoma (70%). The mPFS of the entire cohort was 48 months. The PFS of pts presenting complete response was significantly higher than those presenting near-complete pathological response (24 m x not reached; p=0.0076). No difference in overall survival was observed. To date, germline and/or somatic analyses were available for 27 patients. The prevalence of pathogenic BRCA1/2 variants is higher than expected (11 out of 27 pts; 43%). In addition, among the 16 BRCA1/2 WT pts, alterations were identified in 3 samples (19%): 1 CDK12 PV, 1 CCNE1 amplification, and 1 CHEK2 PV concurrent with a MSH2 PV. Among the 7 wild type samples evaluated for BRCA1 Pr methylation, 4 were methylated (57%) of which 3 are known to be methylated in homozygosity.
Conclusions
HGOC pts presenting CRS3 response to NAC are enriched of BRCA mutations and also BRCA1 promoter hypermethylation. The high rate of BRCA1 Pr methylation among platinum optimal responders highlights its clinical relevance and its importance of being included in tumoral screening when feasible.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Institut Gustave Roussy.
Funding
Has not received any funding.
Disclosure
E. Rouleau: Financial Interests, Institutional, Invited Speaker: AstraZeneca, BMS, GSK. All other authors have declared no conflicts of interest.