Beyond Molecular Classification: The Incremental Value of Prognostic Biomarkers in Endometrial Cancer

Molecular classification underpins prognostic assessment in endometrial carcinoma, but heterogeneity persists within molecular classes. This narrative review examines whether tissue-based, circulating and emerging biomarkers add prognostic information beyond molecular class and clinicopathological factors. We distinguish four evidentiary levels: prognostic association, independence after adjustment for molecular class, within-class stratification and incremental predictive performance. Clinical utility is considered separately. Estrogen receptor (ER) status now contributes to risk stratification of no specific molecular profile (NSMP) tumors in the 2025 European guidelines, primarily on within-class prognostic evidence. Its incremental predictive performance has been demonstrated only in high-risk disease, with internal validation. Clinical utility remains unproven, and findings within mismatch repair-deficient disease are discordant. CTNNB1 mutation has shown inconsistent associations with recurrence, mainly in early-stage disease. Chromosome 1q32.1 amplification was associated with recurrence within NSMP in two cohorts. Neither marker has been formally assessed for incremental predictive performance. Where model comparisons were performed, gains in discrimination were generally modest. Larger gains arose from small samples or models without external validation, and external validation remained uncommon. No individual biomarker examined has demonstrated prospective clinical utility on its own.