The Molecular, Genetic, Pathological Basis and Clinical Perspectives of Endometrial Cancer: A Narrative Review

Abstract

Endometrial cancer (EC) is the most common gynecologic malignancy in high-income regions, with a rising global incidence driven by population aging and obesity. Management of EC is undergoing a paradigm shift from traditional histopathological classification (Bokhman Types I and II) to a molecularly integrated model. Key driver alterations include mutations in PTEN, PIK3CA, PIK3R1, ARID1A, KRAS, and TP53, alongside focal amplifications of CCNE1 and ERBB2, all of which drive oncogenesis through dysregulation of the PI3K/AKT/mTOR, Wnt/β-catenin, MAPK/ERK, and p53 signaling cascades. Integrated genomic profiling via The Cancer Genome Atlas (TCGA) and practical surrogates like ProMisE classifies EC into four distinct molecular subgroups: POLE-ultramutated (POLEmut), mismatch repair-deficient (MMRd/MSI-H), copy-number low/non-specific molecular profile (NSMP), and copy-number high/p53-abnormal (p53abn). These subgroups display unique biological features, tumor microenvironments, and prognostic trajectories, and have been formally incorporated into the FIGO 2023 staging system. Crucially, molecular classification directly informs biomarker-driven systemic management. MMRd may predict profound responses to immune checkpoint inhibitors (e.g., pembrolizumab, dostarlimab) in both frontline and recurrent settings. For MMR-proficient disease, combination strategies such as anti-angiogenic/immunotherapy (lenvatinib plus pembrolizumab), hormone/mTOR or CDK4/6 inhibitor combinations, and nuclear export inhibitors (selinexor in TP53 wild-type) seem to offer substantial benefit. Furthermore, novel modalities including HER2-targeted antibody-drug conjugates (trastuzumab deruxtecan), PARP inhibitors, and G2/M checkpoint inhibitors (adavosertib) are actively expanding the therapeutic armamentarium. Integrating multi-omics techniques, artificial intelligence, and novel systemic therapies into clinical workflows emerge to refine risk stratification, avoid over- or undertreatment, and establish a new standard of precision oncology in endometrial cancer.