Abstract IA12: Determinants of resistance and response in high-grade serous ovarian cancer.

Abstract

Abstract In contrast to other solid cancers, overall survival for patients with high-grade serous ovarian cancer (HGSC) is little changed over the last 30 years and it has been difficult to advance beyond platinum-based combination chemotherapy. As HGSC are driven by genomic copy number change rather than recurrent point mutation, we undertook whole genome sequence (WGS) analysis of a large HGSC cohort in order to survey structural variation at high resolution. Utilizing 114 tumors from 92 patients, we performed transcriptome, methylation, and miRNA expression analyses to support the WGS data, and compared resistant, refractory, and sensitive primary disease. We evaluated tumor and normal DNA samples from patients with primary refractory, primary resistant or primary sensitive disease to better understand the drivers of these clinical phenotypes. We also characterized paired pre-treatment chemosensitive and post-resistance samples, and end-stage HGSC obtained from patients who underwent a research autopsy. We found that gene breakage involving tumor suppressors such as NF1 and RB1 is a common form of inactivation in HGSC and in other circumstances contributes to acquired chemotherapy resistance in some patients. We found evidence of a chemotherapy footprint in the genome of recurrent tumor samples. We observed a striking degree of diversity of other mechanisms of acquired resistance, including multiple independent germline BRCA1 or BRCA2 reversion events in individual patients, loss of BRCA1 promoter methylation, a shift in molecular subtype to a desmoplastic phenotype, and a recurrent promoter fusion associated with overexpression of a driver of drug resistance, validated in an independent dataset. Collectively these findings underscore the plasticity of the HGSC genome and indicate that pre-empting resistance by modifying current first line therapy or countering it when it emerges will require a diversity of approaches. Citation Format: David D. L. Bowtell. Determinants of resistance and response in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA12.