Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Robb Hollis, Barbara Stanley, John P. Thomson, Michael Churchman, Ian Croy, Tzyvia Rye, Clare Bartos, Fiona Nussey, Melanie J Mackean, Alison M Meynert, Colin A Semple, Charlie Gourley, C Simon Herrington

Research output: Contribution to journalArticlepeer-review

Abstract

Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and estrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathology assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR+/ER+, PR+/ER-) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P<0.001), while PR-low (PR-/ER+, PR-/ER-) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P=0.001), greater genomic complexity (P=0.007) and more frequent copy number alterations (P=0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR=0.16, 95% CI 0.04-0.71). TP53 mutation further delineates the outcome of patients with PR-low tumors (HR=2.56, 95% CI 1.14-5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumors – which are typically CTNNB1-mutant and TP53 wild-type – experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.
Original languageEnglish
Journalnpj Precision Oncology
Early online date2 Jun 2021
DOIs
Publication statusE-pub ahead of print - 2 Jun 2021

Keywords

  • ovarian cancer
  • endometrioid
  • genomics
  • progesterone receptor
  • estrogen receptor
  • stratification

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