Current Treatment Options Guided by Molecular Classification in Endometrial Cancer

In our view, molecular classification should guide, but not independently determine, treatment for endometrial cancer. The four major molecular subtypes-POLE-mutated (POLEmut), mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H), p53-abnormal/copy-number-high (p53abn/CNH), and no specific molecular profile/copy-number-low (NSMP/CNL)-should be interpreted together with histological type, tumor grade, stage, myometrial invasion, lymphovascular space invasion, comorbidities, fertility goals, treatment accessibility, and patient preferences. For advanced or recurrent dMMR/MSI-H disease, we favor immune checkpoint inhibition because this subtype has the clearest predictive evidence, with immunotherapy increasingly incorporated into first-line treatment. For tumors harboring a confirmed pathogenic POLE exonuclease-domain mutation, we support careful consideration of adjuvant treatment de-escalation, while avoiding de-escalation based on non-pathogenic variants, variants of uncertain significance, or molecular classification alone in advanced-stage disease. We regard p53abn/CNH tumors as a high-risk phenotype requiring appropriately intensive multimodality treatment; human epidermal growth factor receptor 2-targeted therapy, DNA damage response-directed strategies, WEE1 G2 checkpoint kinase inhibition, and antibody-drug conjugates should be considered according to tumor biomarkers, treatment setting, and evidence strength. NSMP/CNL should not be managed as a uniform residual category. Secondary stratification using estrogen receptor/progesterone receptor status, L1 cell adhesion molecule expression, catenin beta 1 alterations, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway alterations may identify hormone-sensitive, high-risk, and potentially targetable subgroups. In fertility-sparing management, molecular findings may refine counseling and surveillance but should not replace established eligibility criteria. At recurrence or progression, repeat biopsy and biomarker reassessment should be considered when clinically feasible and likely to alter treatment.