Molecular Classification of Endometrial Cancer in the Era of Precision Oncology: Prognostic Significance, Emerging Biomarkers, and Personalized Therapeutic Strategies-A Systematic Review.

Background/Objectives: Molecular classification has reshaped risk assessment in endometrial cancer (EC), but the strength and clinical applicability of the evidence vary across molecular subgroups, assay platforms, patient populations, and treatment settings. This systematic review critically evaluated the prognostic and predictive value of TCGA-derived classifiers, additional biomarkers, multiple-classifier tumors, and molecularly informed therapeutic strategies. Methods: A protocol was developed a priori but was not prospectively registered. PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched for primary studies published from January 2013 through June 2026. Clinical guidelines were used only to provide clinical context and were not included in the formal evidence set. Because of substantial methodological heterogeneity, findings were synthesized narratively by study design and clinical question. Risk of bias was assessed using QUADAS-2, the Newcastle-Ottawa Scale, and RoB 2. Results: Seventy-four studies involving approximately 42,000 patients were included. POLE-mutated tumors showed the most favorable outcomes in most cohorts, whereas p53-abnormal tumors, defined by abnormal immunohistochemical patterns, generally had the poorest prognosis. Mismatch repair deficiency identified by immunohistochemistry and microsatellite instability-high status identified by PCR- or NGS-based testing were highly related but analytically distinct biomarkers and were not treated as exact synonyms. The NSMP group remained heterogeneous; integrated assessment of estrogen/progesterone receptor expression, CTNNB1, L1CAM, ARID1A, and chromosome 1q alterations may improve risk discrimination, although most of these markers remain investigational. In multiple-classifier tumors, available data support a practical hierarchy in which a pathogenic POLE mutation generally takes precedence, followed by MMR deficiency and then p53 abnormality. Across studies, molecular classification usually added prognostic information to clinicopathologic assessment, but the magnitude of benefit varied, and no overall certainty rating was assigned. Conclusions: Molecular classification is incorporated into contemporary guidelines and can support prognostic assessment and treatment selection when interpreted together with stage, histology, and other clinicopathologic factors. The strongest current clinical utility relates to POLE, MMR/MSI, p53 immunohistochemistry, and HER2 in selected settings; additional NSMP and multi-omics biomarkers require prospective validation, assay standardization, and demonstration of clinical utility before routine adoption.