POLE mutation

P2, N=35, Recruiting, Sun Yat-sen University | Trial completion date: Jan 2024 --> Dec 2029 | Trial primary completion date: Jan 2024 --> Jan 2028

Selective molecular profiling of newly diagnosed stage III-IVA endometrial cancers using MMR and p53 IHC with reflex to NGS for p53-abnormal tumors improves testing efficiency and reduces unnecessary NGS compared with universal upfront NGS testing.

Despite a relatively low positive predictive value requiring confirmatory sequencing, it effectively enriches candidates needing POLE gene sequencing in resource-limited settings. Future multicenter validation is warranted to assess its clinical utility.

This case provides direct morphologic and molecular evidence of spatial clonal evolution in a multiple-classifier endometrial carcinoma. The clinical implications of this spatial heterogeneity remain uncertain and warrant further investigation.

Molecular classification is prognostically essential in endometrial carcinoma. The integrated FIGO 2023 m system appears to enhance risk stratification relative to FIGO 2009 and non-molecular FIGO 2023. Formal comparison of staging systems is needed to confirm this improvement.

ddPCR demonstrated superior sensitivity and specificity in detecting POLE mutations compared to Sanger sequencing and showed perfect agreement with NGS. With its rapid turnaround, simplicity, and cost-effectiveness, ddPCR is highly suitable for routine clinical use, potentially enhancing patient management and outcomes in EC.

Radiomics and deep-learning models have demonstrated high accuracy in predicting LVSI, DMI, nodal metastasis, and molecular subtypes, offering non-invasive biomarkers aligned with FIGO 2023 prognostic categories. Together, these advances position MRI as a quantitatively enriched, biologically relevant tool that supports precision oncology in endometrial cancer.

Multiple-classifier ECs represent a small but clinically relevant subset encompassing biologically heterogeneous entities. Our findings highlight the limitations of current molecular classification hierarchies and underscore the need for harmonized molecular testing and standardized reporting to improve risk stratification and the management of multiple-classifier ECs.

Importantly, results from all endometrial cancer cases showed complete concordance with NGS analysis for the 11 pathogenic POLE-EDM points tested. This cost-effective and efficient SCF primer qPCR system provides an accessible method for routine molecular classification of endometrial cancer in clinical settings, offering a practical alternative to NGS for detecting pathogenic POLE mutations and supporting clinical decision-making.

Notably, the null pattern appeared exclusively in ECs with pathogenic POLE mutations. These results suggest that ATM IHC staining is an effective screening tool for identifying patients who may benefit from confirmatory POLE sequencing among those lacking MMR deficiency or p53 abnormalities.

Selecting candidates for nonsurgical management of endometrial cancer remains challenging. The association of myometrial invasion to response illustrates the importance of pretreatment imaging. Given non-response in 3 of 4 MMRd and both p53 mutated tumors, molecular testing should be considered in all these patients.

The highest prevalence of L1CAM was found in p53abn endometrial tumors. L1CAM positivity is associated with poor survival outcomes, particularly in MMR-D and NSMP subgroups. These findings highlight the potential of L1CAM as a prognostic biomarker that could refine risk stratification and guide adjuvant management more accurately in endometrial cancer, warranting validation in prospective studies.