Background Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement.

Methods Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n=424), and a Dutch prospective clinical cohort called MST (n=256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox’s proportional hazard models were used for survival analysis.

Results In total, 649 HR-EC were included. No independent prognostic value of ER, PR, L1CAM and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75).

Conclusions ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. ER-positive NSMP EC may be regarded as a novel fifth molecular subgroup. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.

The authors have declared no competing interest.

The translational study and the PORTEC-3 randomized clinical trial were supported by the Dutch Cancer Society (TB, 31843, UL2006-4168/CKTO 2006-04). EJC is supported by a National Institute for Health Research (NIHR) Advanced Fellowship (NIHR300650) and the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Committee of Medical Ethics (CME) of Leiden Den Haag Delft gave ethical approval for the work on PORTEC-3 randomized clinical trial. Committee of Medical Ethics (CME) of Leiden Den Haag Delft waived ethical approval for the work on the prospective cohort study MST.

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