The Molecular, Genetic, Pathological Basis and Clinical Perspectives of Endometrial Cancer: A Narrative Review
4 affiliations
- 1Department of Medical Education, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, Taipei 23142, Taiwan
- 2School of Medicine, College of Medicine, MacKay Medical University, New Taipei City 25245, Taiwan
- 3Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, New Taipei City 23142, Taiwan
- 4School of Medicine, Tzu-Chi University, Hualien 97004, Taiwan
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.
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BibTeX
@article{chang2026molecular,
title = {{The Molecular, Genetic, Pathological Basis and Clinical Perspectives of Endometrial Cancer: A Narrative Review}},
author = {Chia-Ling Chang and Jie-Hong Chen and Kuo-Hu Chen},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219511},
url = {https://www.mdpi.com/1422-0067/27/21/9511},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Molecular, Genetic, Pathological Basis and Clinical Perspectives of Endometrial Cancer: A Narrative Review
AU - Chia-Ling Chang
AU - Jie-Hong Chen
AU - Kuo-Hu Chen
PY - 2026
DA - 2026/10/24
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219511
UR - https://www.mdpi.com/1422-0067/27/21/9511
AB - 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.
SN - 1422-0067
ER -