Clinicopathological and Molecular Characterization of High Grade Endometrial Carcinomas of No Specific Molecular Profile (NSMP) Stratified by ER Status

This study represents a omprehensive characterization of high-grade endometrial carcinoma (EC) of no specific molecular profile (NSMP) to improve our understanding of their poor clinical outcome. A previously molecularly classified cohort of 412 high-grade EC from the Danish Cancer Registry was extensively reviewed by 2 expert pathologists blinded for associated clinical and molecular data. Immunohistochemistry (IHC) was performed to determine ER, PR, and L1CAM status and a 10% cut-off value was applied for positivity. Shallow whole-genomic sequencing (sWGS) and next-generation sequencing (NGS) was performed to describe the molecular landscape. Survival analysis was performed using the Kaplan-Meier method, and survival difference was tested using the log-rank test. Of the 57 high-grade NSMP tumors, ER negativity was found in 30 (53%). All clear cell NSMP EC (n=12, 21%) were ER negative. L1CAM overexpression was found in 29 high-grade NSMP EC (53%) and showed overlap (n=20, 69%) with ER negativity. A high frequency of copy number (CN) events and fraction genome altered (FGA) was observed, with the median number of CN events clustering by ER status (28 vs. 43, P <0.05). Overall, the cohort showed a 52% (CI: 31.6%, 72.4%) 5-yr overall survival (OS) and 61% (CI: 42.6%, 79.4%) 5-yr disease-specific survival (DSS). No significant additional prognostic refinement was found when stratifying for ER status (5-yr OS: 46% vs. 65%, P =0.068). High-grade NSMP ECs are a heterogenous group of tumors with high prevalence of loss of ER, L1CAM overexpression, and substantial copy number alterations. Within this group, no prognostic effect of ER was identified, providing support for grouping these tumors into one risk group. This work adds to the growing body of evidence that both high-grade and/or loss of ER expression can be used to identify NSMP EC patients with a poor clinical outcome.