Molecular Characterization and Clinical Implications of Endometrial Cancer

The classification of endometrial cancer (EC) has diverged from traditional histologic features based on microscopic appearance to objective molecular characterization. Molecular characterization of EC is pivotal to inform prognosis and to guide therapeutic recommendations. First described by the Cancer Genome Atlas, molecular profiling was later revised by the Proactive Molecular Risk Classifier for Endometrial Cancer and TransPORTEC algorithms to create clinically applicable and relatively easy-to-implement molecular classification systems. Since 2020, the World Health Organization recommended molecular classification of EC into four distinct prognostic subtypes: ECs with polymerase ε (POLE) pathogenic mutations assessed by gene sequencing, mismatch repair deficiency determined by immunohistochemistry or microsatellite instability assay, and p53 abnormalities determined by immunohistochemistry or next-generation sequencing. The final molecular subtype without any of these defining features is called "no specific molecular profile" (NSMP). This is further stratified by estrogen receptor (ER) immunohistochemistry status. Patients with cancers identified as POLE pathogenic mutations have the best prognosis with almost no recurrence or death events, followed by those with strong ER-positive NSMP cancers. Mismatch repair deficiency ECs have intermediate prognosis, whereas p53 abnormalities and ER-negative NSMP have the worst prognosis. Other molecular and pathologic biomarkers of interest include tumor mutational burden, human epidermal growth factor receptor 2, L1 cell adhesion molecule, β-catenin ( CTNNB1 ), and lymph vascular space invasion, which may have prognostic and predictive implications. The current guidelines will continue to evolve; however, at minimum, it is recommended that all patients undergo testing for mismatch repair, p53, and ER, and POLE testing may be prioritized in select circumstances. Molecular classification provides the critical framework to deliver effective, personalized, high-quality care and informs clinical trial design. Molecular assessment ensures consistent diagnosis and provides prognostic information and predictive data to guide appropriate management.