Enhanced Risk Stratification in Early-Stage Endometrial Cancer: Integrating POLE through Droplet Digital PCR and L1CAM

SIMPLE SUMMARY: While a significant number of ECs are successfully treated without recurrence, some cases of EC still result in death even in their early stages. Incorporating molecular classification enhances prognostic accuracy, aiding tailored treatments. This approach has been utilized by the 2021 ESGO/ESTRO/ESP guidelines, the 2022 ESMO guidelines, and the updated 2023 FIGO classification. Our study employed POLE ddPCR, a cost-effective and easy-to-perform test, as an alternative to POLE NGS for molecular classification. This classification was further enriched by the established prognostic marker, L1CAM, resulting in molecular L1CAM classification. The NSMP group was the largest heterogeneous subgroup. Efforts have been made to find additional markers for further subclassification. When we further categorized the NSMP group, which demonstrates an intermediate prognosis between the POLEmut/MMR-D group and the p53abn group, we were able to distinguish the NSMP-L1CAM-positive subgroup, which exhibited a prognosis similar to the p53-mutated subgroup in terms of poorer outcomes. In multivariate analysis, the molecular L1CAM classification showed an independent prognostic factor for recurrence-free survival and overall survival. ABSTRACT: Aim: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). Method: We analyzed archival tumor tissue from 183 early-stage EC patients. POLE pathogenic mutations of P286R, V411L, S297F, A456P, and S459F within exons 9, 13, and 14 were detected using a ddPCR, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI tests. Additionally, we conducted IHC for p53 and L1CAM. Results: The 183 ECs were categorized into four subgroups: POLE-mutated (15.9%), MMR-deficient (29.0%), p53-abnormal (8.7%), and non-specific molecular profile (NSMP, 46.4%). We further subcategorized the NSMP subgroup into NSMP-L1CAMneg (41.5%) and NSMP-L1CAMpos (4.9%), which we refer to as the molecular L1CAM classification. The molecular L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p < 0.001, each). Conclusion: Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS.