Abstract 749: Multi-layer molecular characterization of high grade serous ovarian carcinomas
Authors: Hollis Robert L. , Meynert Alison M. , Churchman Michael , Rye Tzyvia , Roxburgh Patricia , Stetson Daniel , Matakidou Athena , Dougherty Brian , Barrett J. Carl , March Ruth E. , Semple Colin A. , Herrington C. Simon , Gourley Charlie 
Published: August 2019

Abstract
High grade serous ovarian carcinomas (HGSOCs) are molecularly and clinically heterogeneous malignancies. Currently, molecular stratification of patient care is limited to tumors rendered homologous recombination deficient (HRD) by BRCA1/2 mutation (BRCAm). Here we explore the overlap, interplay and clinical impact of molecular subgrouping layers in a cohort of 362 FFPE HGSOCs. We overlay genomic subgrouping and tumor-infiltrating lymphocyte (TIL) burden with the three transcriptionally-defined subtypes (Immune, Angio and AngioImmune) we have previously reported as associated with survival and bevacizumab sensitivity.
The BRCAm group, the Immune subtype and those with high CD8+ TIL burden demonstrated prolonged overall survival (OS) as previously reported. The OS benefit of CD8+ TILs was abrogated in the context of gross residual disease following debulking [multivariable hazard ratio (mHR)=0.51 (0.34-0.78) vs 0.93 (0.76-1.52)]. BRCAwild-type patients demonstrating high expression of EMSY, encoding the BRCA2-binding protein EMSY, demonstrated prolonged OS [mHR=0.48 (0.29-0.79)]. BRCA2m and high-EMSY patients displayed greater chemosensitivity (first-line CA125-CR 94.4% and 81.3% vs 48.2%, P&lt;0.001 and P=0.016; CA125-CR at relapse 58.3% and 50.0% vs 14.3%, P=0.002 and P=0.015).
There was significant enrichment and depletion of BRCAm and CCNE1-gain (CCNE1g) in the Immune subtype (28.9% vs 6.3%, P=0.001 and 9.1% vs 17.4%, P=0.050). The Angio subtype harboured far fewer CD8+ TILs compared to the Immune and AngioImmune subtypes (P&lt;0.0001 for both). The frequency of RB1 loss and nonsense TP53 mutation was significantly higher in BRCAm versus BRCA wild-type cases (33.3% vs 13.5%, P=0.020 and 21.4% vs 10.3%, P=0.019).
The clinical impact of CCNE1g was modulated by transcriptomic subtype: in the Immune group, CCNE1g was associated with poor OS [mHR=3.32 (1.49-7.41)], while in the Angio group CCNE1g cases had favourable outcome [PFS mHR=0.26 (0.10-0.68)]. CD8+ TIL burden was not associated with outcome in CCNE1g cases. Missense TP53 mutation was associated with better outcome versus TP53-null mutations in BRCAm patients [PFS mHR=0.43 (0.14-0.82)], but not in the context of HR proficiency [mHR=0.90 (0.67-1.22)].
Integrated classification using the consensus of favourable and unfavourable HR-centric (HRD favourable, HR-proficient unfavourable) and transcriptomic (Immune favourable, Angio/AngioImmune unfavourable) subgrouping yielded three groups with distinct OS [favourable vs unfavourable mHR=0.49 (0.34-0.74); favourable vs no-consensus mHR=0.64 (0.42-0.98); unfavourable vs no-consensus mHR=1.31 (1.00-1.70)].
Together, these data paint a more granular picture of the clinical impact of HGSOC subgroups and demonstrate novel candidate interactions between subgrouping layers. The poorest outcome groups represent those with most to gain from trials of novel treatment regimens.
Citation Format: Robert L. Hollis, Alison M. Meynert, Michael Churchman, Tzyvia Rye, Patricia Roxburgh, Daniel Stetson, Athena Matakidou, Brian Dougherty, J. Carl Barrett, Ruth E. March, Colin A. Semple, C. Simon Herrington, Charlie Gourley. Multi-layer molecular characterization of high grade serous ovarian carcinomas [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 749.