Post-Treatment Molecular Biomarker Reassessment in Advanced Endometrial Cancer: An Evidence-Aware Framework for Precision Therapy

Molecular classification has transformed treatment selection in endometrial cancer (EC), but most biomarkers are defined at diagnosis and may not represent the biological state of tumors after therapeutic exposure. In advanced, recurrent, or metastatic EC, treatment can reshape target expression, hormone dependence, immune context, signaling pathways, and DNA damage response (DDR), raising an important clinical question: which treatment-relevant features should be reassessed after progression, and how should the results inform subsequent therapy? This review synthesizes evidence across immune, endocrine, human epidermal growth factor receptor 2 (HER2) and pathway-directed, DDR-directed, and platinum–taxane treatment contexts. We focus on biomarkers that can be evaluated through repeat tissue biopsy, circulating tumor DNA, functional assays, and clinical treatment history, and distinguish biological plausibility from clinical actionability. The evidence is uneven. HER2 evolution and clinical measures of platinum sensitivity have comparatively direct EC-specific human support, whereas hormone receptor dynamics, estrogen receptor 1 (ESR1) evolution, and selected immune features remain clinically emerging, and pathway-rebound and functional DNA repair readouts are largely investigational. We therefore propose an evidence-aware framework for post-treatment biomarker reassessment that prioritizes whether the biological rationale for a previous therapy remains valid, has been weakened, or has been replaced by an alternative dependency. Prospective longitudinal studies are needed to determine when reassessment improves treatment selection and patient outcomes.