Opportunities for stratification in endometrioid ovarian carcinoma

Edinburgh researchers used unique dataset that combines hormone receptor expression patterns with matched genomic characterisation to identify opportunities for patient stratification in endometrioid ovarian carcinoma: June 2021

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Ovarian cancer remains one of the most lethal malignancies in the developed world. There are over 7000 new ovarian cancer cases in the UK every year.

Endometrioid ovarian carcinoma (EnOC) is a unique ovarian cancer type, with distinct clinical and molecular characteristics. It accounts for approximately 10% of ovarian carcinoma diagnoses. EnOCs are usually characterised as complex nonspecific solid-cystic masses and may be associated with endometriosis. Identiﬁcation of EnOC subtypes with distinct clinical behaviour has the potential to aid patient stratification for therapy and also to identify cases for which new treatment options are needed to improve survival. Molecular characterisation represents an opportunity to identify novel therapeutic vulnerabilities of high-risk and advanced-stage cases to biologically targeted agents, while also highlighting low-risk cases for which de-escalation of chemotherapy may be considered. Unfortunately, early molecular studies characterising the biology of EnOC have been confounded by the inclusion of misclassiﬁed tumours now known to represent variants of high grade serous ovarian carcinoma (HGSOC) – another type of ovarian cancer that can bear morphological resemblance to high grade EnOC but with markedly different clinical prognosis.

To address these shortcomings, CRUK Edinburgh Centre investigators utilised rigorous pathological assessment and refined immunohistochemistry techniques on archived patient-derived tumour samples to review EnOC diagnosis. They subsequently used samples with reconfirmed EnOC diagnosis to characterise hormone receptor expression patterns and performed whole exome sequencing (to obtain the detailed genomic landscape of the tumours analysed), providing extensive molecular characterisation and important insights into EnOC biology. This created a unique and robustly defined EnOC cohort with matched genomic and hormone receptor expression data [Gynecol Oncol. 2019 Nov;155(2):318-323 and Nat Commun. 2020 Oct 5;11(1):4995].

In a recent study titled “Integrated molecular characterisation of endometrioid ovarian carcinoma identiﬁes opportunities for stratiﬁcation” investigators from Edinburgh and Glasgow utilised these unique datasets (linked to the Edinburgh Ovarian Cancer Database) to perform integrated analysis and define the molecular landscape of EnOC with greater granularity.

They found that EnOC patients showing high level of Progesterone Receptor (PR) in their tumours predominantly harboured mutations in CTNNB1 gene (encoding the protein beta catenin which has been implicated in regulation of cell–cell adhesion and gene transcription). Cases with low level of PR displayed higher frequency of mutations in TP53 gene (encoding the protein known as p53 which acts as a tumour suppressor). The study showed that PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features, while in patients with low levels of PR the status of the TP53 gene (mutated or wild type) is important in delineating the outcome. Patients with PR-low and TP53 mutant EnOC have the greatest unmet clinical need, while patients with PR-high tumours experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy. The genomic proﬁle of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT cellular signalling pathways, alongside PARP inhibitors, represent promising candidate agents for improving survival.

The work was published in the journal NPJ Precision Oncology. It was led by investigators from the Nicola Murray Centre for Ovarian Cancer Research within the Cancer Research UK Edinburgh Centre and the Institute of Genetics and Cancer.

Our work shed light on the overlay and interplay of molecular subtyping layers in endometrioid ovarian carcinoma and highlight the distinct clinical and molecular phenotypes displayed by patient groups. It opens novel patient stratification opportunities and should invigorate studies on new treatment options for high risk patients.
Dr Robert L. Hollis, University of Edinburgh
The corresponding author for the published study

Opportunities for stratification in endometrioid ovarian carcinoma

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