Universal Molecular Testing for Endometrial Cancers: Institutional Experience and Focus on Phenotypic and Clinical Characterization of POLE-mutated Cases.

Molecular classification of endometrial tumors is now incorporated into the 2023 FIGO staging criteria. The POLE-mutated (POLEmut) subtype is reported to have a favorable prognosis despite aggressive morphologic features. Our institution began universal molecular testing for newly diagnosed endometrial cancers in April 2023. In this study, we describe our institutional experience with this testing and specifically highlight POLEmut endometrial cancers. We aimed to compare the molecular and histopathologic profiles of POLEmut endometrial carcinomas with and without aggressive histopathologic features. A total of 198 endometrial cancer cases were analyzed by a targeted next-generation sequencing panel. We reviewed the results for all cases from April 2023 to December 2024 and for cases with pathogenic POLE exonuclease domain/proofreading mutation, collected relevant molecular, clinical data, immunohistochemical, and resection histopathology if available. Aggressive histopathology was defined as having at least one of the following: FIGO grade 3, ≥ stage pT1b, or lymphovascular invasion. Of 198 tested endometrial cancers, 40.9% (n=81) had no specific molecular profile, 33.8% (n=67) were p53 abnormal, 19.7% (n=39) were MMRd, and 5.6% (n=11) had POLE exonuclease domain/proofreading mutations associated with the ultramutated phenotype. At least one aggressive histopathologic feature was seen in 5/10 POLEmut cases that had resection specimens. TP53 variants were present in 5/11 POLE specimens and were often subclonal. Without sequencing, 4 POLEmut cases would have been misclassified as either p53 abnormal or MMRd. There was no significant difference in biomarker results, molecular variants, or clinical outcomes between cases with aggressive or nonaggressive histopathologic features.