Endometrioid endometrial cancer (EEC) adjuvant therapy decisions rely on risk stratification using histology, grade, stage, and lymphovascular space invasion (LVSI). Recently, molecular classification systems originating from TCGA, evaluated in GOG-210 and PORTEC-3 defined four prognostic subtypes based on POLE, MSI-H/MMR-D, and p53 alterations. Although valuable, this molecular approach still has significant limitations such as applicability to the majority of EEC patients categorized as no-specific molecular profile (NSMP) and the potential need to resolve pathogenic and prognostic heterogeneity within MMR-D, and TP53 subtypes. These unmet needs were key motivators for Tempus to develop a molecular classifier predicting distant recurrence risk in early-stage EEC with a focus on high intermediate-risk (HIR) patients. The RNA-seq-based gene expression profiler (GEP) was trained using a machine-learning pipeline with TCGA data which resulted in a 24 gene signature that classifies EEC patients as molecular risk (MR) high or low (MR-high, MR-low). The GEP MR test was then evaluated on a de-identified cohort of EEC patients (N=1037) from Tempus to test associations with known pathologic or molecular prognostic features. The GEP-MR risk predictor showed significant enrichment of MR high-risk in G3 versus G1/2 histology (p-value < 5e-8). A high correlation was found between the MR score and copy number alteration score (t-test p-value < 1e-5). Next, a clinical evaluation was performed in an early-stage EEC case-control cohort of patients with documented recurrence or no recurrence event at four years (N=109), from Stanford. In the entire cohort, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=4.8, N=109). Next, we performed a subgroup analysis in higher rate of distant recurrence in comparison to the MR-low group (HR=8.0, N=56). Lastly, given the significance of genomic biomarkers in the evolution of EEC FIGO staging, we stratified outcomes by the established TCGA subtypes as a reference standard and performed a subgroup analysis in patients classified as having no specific molecular profile (NSMP). Among patients who were NSMP, the MR-high group showed a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=7.92, N=67). These evaluation studies demonstrate the performance of the GEP MR test in early-stage EEC distant recurrence risk stratification, specifically HIR patients, necessitating further studies to validate the test for clinical use in informing adjuvant clinical management.

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