Evolving Molecular Classifications and Personalized Therapeutics in Endometrial Cancer: A Narrative Review

Abstract

Endometrial cancer (EC) is the most common gynecological malignancy worldwide and an increasing public health concern. Although most cases are diagnosed at an early stage with favorable outcomes, advanced and high-risk disease remains associated with poor survival, highlighting the need for improved risk stratification. The traditional dualistic Type I/Type II classification inadequately reflects the molecular heterogeneity of EC. The Cancer Genome Atlas (TCGA) introduced a molecular classification defining four prognostically distinct subtypes: POLE ultramutated, microsatellite instability-high (MSI-H), copy-number low, and copy-number high. This framework has been translated into clinically applicable classifiers, including ProMisE and TransPORTEC, which stratify tumors into four clinically relevant molecular subgroups: POLE-mutated (POLEmut), mismatch repair-deficient (MMRd), no specific molecular profile (NSMP), and TP53-abnormal (p53abnormal). This classification has also been incorporated into the 2023 FIGO staging system. POLEmut tumors demonstrate favorable prognosis supporting treatment de-escalation; MSI-H/MMRd tumors show intermediate prognosis and derive benefit from immune checkpoint inhibitors; NSMP tumors are heterogeneous with variable outcomes requiring further molecular refinement; whereas p53abnormal tumors exhibit aggressive behavior and poor prognosis, often necessitating intensified multimodal and targeted therapies. This review highlights the clinical relevance of molecular classification, multiple-classifier tumors, and emerging diagnostic approaches including next-generation sequencing, underscoring a shift toward precision oncology in EC management.