Abstract 3504: Mutation analysis of ovarian carcinoma patients presenting optimal response to neoadjuvant chemotherapy

Abstract

Abstract 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. Pathological response scores (CRS) have been shown to correlate with outcome with a complete or near-complete CRS (CRS3) predicting improved progression-free survival. Approximately 20% of ovarian cancers present BRCA1/2 mutations, which predict a better response to platinum salts. Our proposal is to determine the prevalence of BRCA mutations or other homologous recombination (HR) alterations among patients with a CRS3 after NAC. Methods: We performed a retrospective analysis of clinical, pathological, and sequencing data of patients who experienced a complete or near-complete response to platinum based NAC. For patients with wild-type (WT) sequencing and with tumor samples available, somatic analysis based on Next Generation Sequencing (NGS) with a large panel of genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CCNE1, CDK12, CHEK2, PALB2,RAD51C, RAD51D, TP53), including specific non-coding regulatory regions of BRCA1, BRCA2 and RAD51C, was also performed. We present preliminary data on the 1st cohort analysed at the time of abstract submission. Results: A total of 33 patients were identified who demonstrated CRS3 post-NAC. Tumors were in majority EC IIIc (57%) and grade II-III serous ovarian carcinoma (90%). Median overall survival (m OS) of the entire cohort was 55 months (IC95% 36-74). To date, germline and/or somatic analyses were available on 23 pts. The prevalence of pathogenic BRCA1/2 variants is higher than expected in this cohort of patients presenting a CRS3. In total, 7 of 23 patients (30%) had a germline (4) or somatic pathogenic (3) BRCA variant. In addition, among the 16 BRCA1/2 WT pts subjected to further HR NGS analysis, the following cases of alterations were identified: one ATM nonsense mutation (c.2465T>G; p.Leu822*), one pathogenic mutation of CDK12 gene (c.3G>A;p.Met1?), one likely pathogenic variant located on BRCT domain of BRCA1 (c.5165C>T p.Ser1722Phe), two 3'UTR BRCA2 variants of uncertain significance (VUS) (c.*14C>T; c.*72A>G), and one BRIP1 VUS (c.2932G>C, p.Gly978Arg). Further, one BRCA WT case presented an unexpected CCNE1 amplification. Conclusion: HGOC patients presenting with a pCR are enriched for BRCA germline and/or somatic BRCA mutations. In addition, among the small subset of BRCA WT pCR tumors, a deleterious ATM and CDK12 mutation were identified. This prevalence can be underestimated in a context of pCR since somatic screening is impossible on the debulking material. Somatic BRCA1/2 and complete HR sequencing on the initial biopsy is recommended to identify additional pts with exclusive somatic mutations. More complete data on this cohort will be presented. Citation Format: Etienne Rouleau, Elizabeth Santana dos Santos, Francilette Maela, Ludovic Lacroix, Aurélie Auguste, Patricia Pautier, Philippe Morice, Catherine Genestie, Alexandra Leary. Mutation analysis of ovarian carcinoma patients presenting optimal response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3504.