Molecular Classification of Endometrial Cancer: Implications for Surgery and Systemic Treatment

Molecular classification has refined endometrial cancer assessment by distinguishing POLE-mutated, mismatch repair-deficient, p53-abnormal and no-specific-molecular-profile tumors. Evidence was assessed on the biological basis of the molecular classes, diagnostic implementation, surgical staging, adjuvant therapy, advanced disease and fertility preservation. Molecular findings supplement stage, histological type, grade and lymphovascular invasion; they do not replace these variables. Retrospective analyses of randomized trials support clinically meaningful differences in prognosis and treatment response, while contemporary immunotherapy trials establish important benefits in advanced disease, particularly in mismatch repair-deficient tumors. However, biomarker-associated prognosis is distinct from evidence that a treatment can safely be omitted. Sentinel lymph node assessment remains a surgical staging question requiring its own diagnostic evidence. Endocrine and HER2-directed therapies offer options for selected biological contexts, whereas molecularly assigned de-escalation strategies require prospective validation. Hierarchical interpretation of multiple classifiers, appropriate handling of uncertain POLE variants and separation of completed trial results from study protocols.