Combined ER/PR co-positivity enhances prognostic stratification within molecular subtypes of endometrial cancer

OBJECTIVE: To explore the prognostic value of combined estrogen receptor (ER)/progesterone receptor (PR) expression patterns within molecular subtypes of endometrial cancer (EC), particularly in the prognostically heterogeneous no specific molecular profile (NSMP) subtype. METHODS: A retrospective cohort study of 388 EC patients underwent next-generation sequencing-based molecular classification and ER/PR immunohistochemistry. ER/PR status was categorized as co-positive (coP), co-negative, or discordant. Multivariable Cox models and concordance index (C-index) analyses assessed disease-specific survival (DSS) and progression-free survival (PFS). RESULTS: ER/PR co-positivity independently predicted improved DSS overall (hazard ratio [HR]=0.143; 95% confidence interval [CI]=0.065, 0.314; p<0.001) after adjusting for stage and molecular subtype. In NSMP (n=254), coP predicted superior DSS (HR=0.21; 95% CI=0.06, 0.87; p=0.034), while ER positivity predicted better PFS (HR=0.13; 95% CI=0.02, 0.88; p=0.037). Adding coP to staging improved NSMP-DSS prediction (ΔC-index=+0.082; p<0.05). No significant associations were found in non-NSMP subgroups. CONCLUSION: ER/PR co-positivity is a powerful independent predictor of favorable DSS in EC, particularly refining risk stratification for the NSMP subtype when integrated with molecular classification.