Abstract 5082: Determinants of clinical outcome in high grade serous ovarian cancer

Abstract

Abstract Five-year survival for patients with high-grade serous ovarian cancer (HGSC) is between 35-40% and is strongly influenced by the extent of disease at presentation (stage) and the extent of residual tumor following primary debulking surgery. Among HGSC patients matched for stage and debulking status considerable variation in outcome exists, suggesting other determinants of survival are at play. We have made substantial progress in identifying the multiple molecular factors that influence patient outcome in HGSC. Molecular subtype: Our previous gene expression profiling of HGSC identified four molecular subtypes (Tothill et al Clin Can Res 2008). In a meta-analysis of four gene expression datasets involving over 900 HGSC samples we see a consistent pattern of clinical outcome in women with different subtypes. Amplification and over expression of MYCN, and a downstream pathway involving LIN28B, LET7 and HMGA2 is specifically associated with the C5 subtype, consistent with the notion that the subtypes reflect distinct patterns of pathway disruption that influence clinical outcome. Germline status: We recently completed a comprehensive analysis of the frequency of BRCA1/2 germline mutations in 1000 women with invasive ovarian cancer, ascertained through a population-based cohort with very detailed clinical follow up data. Mutation was essentially restricted to women with HGSC, where the rate was 16.7%. Approximately 40% of germline carriers lacked a family history. Mutation status strongly influenced response to first and subsequent lines of chemotherapy, with implications for the delivery of platinum-based therapy in carriers. A spread of outcomes was seen in women with identical germline mutations, even when correcting for debulking status, pointing to other factors controlling response. Non-carriers who consistently responded to multiple cycles of platinum based therapy were enriched for somatic BRCA1/2 mutations. A subset of patients with advanced bulky disease was characterised with exceptional responses to chemotherapy (>3.5y PFS). CCNE1: Amplification of CCNE1 (cyclinE1) locus is the dominant amplicon associated with primary chemotherapy failure in HGSC. Recent findings suggest that the poor outcome in women with CCNE1 amplification is associated with a lower frequency of BRCA1/2 germline mutations (TCGA Consortium, Nature 2011). We find that HGSC tumour cells have a pronounced amplicon-dependent oncogene addiction to cyclinE1 and its protein partner cdk2, as evidenced by increased apoptosis, reduced cellular proliferation and induced G1 arrest, validating cyclinE1 as a key druggable target in HGSC. The substantial frequency of CCNE1 amplification in non-carriers is an important finding because it provides an avenue for targeting patients who have intact homologous recombination repair pathways, and are therefore less likely to benefit from platinum-based therapy or PARP inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5082. doi:1538-7445.AM2012-5082