Integrated Molecular Classification of Endometrial Cancer: Impact on Diagnosis, Prognosis, and Clinical Management—A Systematic Review

Objective: To systematically review the literature on the impact of integrated molecular classification of endometrial cancer on diagnosis, prognostic stratification, and clinical management. Methods: A systematic search was conducted in PubMed/MEDLINE, Web of Science, Scopus, and Cochrane Library (January 2013–December 2025), following PRISMA 2020 guidelines. We included original studies, systematic reviews, clinical guidelines, and cost-effectiveness analyses applying TCGA molecular classification or its surrogate classifiers (ProMisE, TransPORTEC). Data were extracted on subtype distribution, survival outcomes, hazard ratios, stage migration, and therapeutic implications. Results: Fifty studies were included. Of these, 13 provided data on molecular subtype distribution (comprising 3527 patients), 8 reported survival outcomes, and 7 reported hazard ratios. The weighted subtype distribution from the 13 studies was as follows: POLEmut 8.9%, MMRd 25.8%, p53abn 16.7%, and NSMP 48.2%. POLEmut was associated with an excellent prognosis (5-year overall survival >95%, hazard ratio <0.5), while p53abn represented the poorest prognosis group (5-year disease-free survival 33–58%, hazard ratio >2.0). p53abn was the only independent risk factor for peritoneal (odds ratio 8.54) and vaginal (odds ratio 6.51) recurrence. Molecular classification modified risk group assignment in 6–33% of patients and improved prognostic discrimination of the 2023 FIGO staging system. Therapeutic implications include treatment de-escalation in POLEmut, immunotherapy in MMRd, and intensive chemotherapy in p53abn. Barriers to implementation include access to POLE sequencing and cost-effectiveness. Conclusions: Integrated molecular classification is an essential tool for prognostic stratification and treatment personalization in endometrial cancer. Molecular subtypes demonstrate clearly differentiated prognostic profiles and recurrence patterns, justifying their systematic incorporation into clinical practice and international guidelines.