Abstract 4161: Integrated analysis of whole exome sequencing and hormone receptor expression data in endometrioid ovarian cancer
Authors: Robert L. Hollis, John Thomson, Barbara Stanley, Alison M. Meynert, Michael Churchman, Tzyvia Rye, C. Simon Herrington, Charlie Gourley
Journal: Cancer Research (2020)

Abstract Endometrioid ovarian carcinomas (EnOCs) account for 10% of OC diagnoses, representing distinct biological and clinical entities compared to other OC subtypes. We recently reported two molecular subgrouping studies using &amp;gt;100 WT1-negative EnOCs: the first identified molecular subgroups of disease by unsupervised analysis of hormone receptor expression patterns, reporting favorable disease-specific survival (DSS) in the PR-high subgroups (PR+/ER+, PR+/ER- vs PR-/ER+, PR-/ER-). The latter study performed whole exome sequencing, identifying genomic events associated with differential DSS, including TP53 mutation (TP53m) and CTNNB1m. Here, we perform integrated analysis of these data to investigate the overlap between these molecular subgrouping layers. The PR-high subgroups demonstrated low TP53m rate (5% vs 26%, P=0.035) and frequent CTNNB1m (75% vs 26%, P&amp;lt;0.001), with the highest CTNNB1m rate in the PR+/ER+ subgroup (84%, 21/25). Accordingly, TP53m cases demonstrated significantly lower median histoscore (mHS) for PR (3 vs 203, P=0.028) and a trend for lower ER (mHS 66 vs 160, P=0.056), while cases with CTNNB1m demonstrated significantly higher PR and ER expression (mHS 258 vs 40, P&amp;lt;0.001 and 181 vs 75, P=0.002). There was no significant difference in tumor mutational burden, microsatellite instability or tumor heterogeneity as defined by Mutant Allele Tumour Heterogeneity (MATH) score between the hormone-receptor-based subgroups. These groups also demonstrated no significant difference in mutation rate of mismatch repair protein-encoding genes. Multivariable analysis identified only FIGO stage at diagnosis (P=0.002), optimal surgical debulking (P=0.035) and hormone receptor subgroup (P=0.004) as independently associated with DSS. TP53m and CTNNB1m were not independently associated with DSS (P=0.187 and P=0.166), though CTNNB1m demonstrated a trend for association in a corresponding model for relapse-free survival (RFS) (HR=0.26, P=0.064). Within PR-high cases, specific genomic events were not associated with significantly differential survival. Conversely, TP53m was associated with inferior outcome specifically in PR-low cases (P=0.010 for RFS; P=0.066 for DSS). Collectively, these data represent the first depiction of the overlay and interplay between recently identified EnOC subgroups defined by WES and hormone receptor expression patterns. They demonstrate that PR-high cases frequently harbor CTNNB1m, while TP53m is rare in this context. Moreover, they suggest that PR-high cases experience favorable outcome irrespective of genomic profile, while TP53m represents an important marker of prognosis in PR-low EnOC. Moreover, given the high expression of ER and PR in the CTNNB1m population, assessment of the potential efficacy of endocrine therapy in this population may now warrant investigation. Citation Format: Robert L. Hollis, John Thomson, Barbara Stanley, Alison M. Meynert, Michael Churchman, Tzyvia Rye, C. Simon Herrington, Charlie Gourley. Integrated analysis of whole exome sequencing and hormone receptor expression data in endometrioid ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4161.