ENDOESTRO score: Where is the dark side? Evaluation of estrogen receptor expression cutoff in endometrial cancer...

Estrogen receptor (ER) expression has prognostic value in endometrial cancer (EC), also in the context of molecular classification. However, a standardized cutoff to define ER positivity is lacking.

To identify the ER expression cutoff that best correlates with survival outcomes overall and within each molecular subgroup.

We conducted an ambispective study comprising a retrospective phase (Feb 2017-Feb 2022) and a prospective phase (Mar 2022-Jan 2024), including patients with EC who underwent surgery at our institution. In the retrospective cohort, molecular subgroups were defined by immunohistochemistry (IHC): 1) MMRp^IHC: MMR-proficient and wild-type p53 (p53wt); 2) p53abn^IHC: MMRp and abnormal p53; 3) MMRd^IHC: MMR-deficient. In the prospective phase, classification followed current IHC plus NGS standards: POLE-ultramutated (POLEmut), No specific molecular profile (NSMP), p53abn, and MMRd. ER expression was stratified into three groups: ≥ 10 %, < 10 %, and < 1 %.

Among 2084 patients, ER < 10 % was the strongest cutoff for prognosis based on disease-free survival (DFS). Patients with ER < 10 % and < 1 % shared similar unfavorable clinicopathological and molecular features, while ER ≥ 10 % was associated with more favorable profiles. ER < 10 % was an independent adverse prognostic factor in uni- and multivariate analyses for DFS and overall survival, particularly in MMRp^IHC and p53abn^IHC groups. Prospective data confirmed < 10 % as the most reliable cutoff.

ER < 10 % expression is a robust prognostic indicator, associated with worse outcomes and may serve as a clinically meaningful cutoff in endometrial cancer risk stratification. Further prospective validation is warranted.