Proteogenomic profiling defines progression-associated biology in high-risk endometrial cancer

Patients with high-risk endometrial carcinoma (HR-EC) experience substantial mortality despite multimodality therapy, molecular classification and contemporary care. We determined whether proteomic tumor programs capture lethal risk beyond established clinical and genomic classifiers and may inform translational investigations. We performed integrated clinical, genomic, and quantitative proteomic profiling of archival FFPE primary tumors from 274 patients with stage I-III HR-EC treated with curative intent and long-term follow-up. Molecular subtyping, clinical-genomic risk modeling, and proteomic analyses evaluated relationships with endometrial cancer (EC)-specific death and progression. A proteomic risk score for progression was developed and validated in 73 independent HR-EC patients. Among patients with non- POLE tumors, TCGA molecular subtype and TP53 mutation status did not significantly stratify progression or EC-specific mortality. Clinical-genomic classification and regression tree analysis identified distinct risk groups with divergent outcomes. Quantitative proteomic profiling identified reproducible tumor programs independently associated with lethal outcomes after adjustment for clinicopathologic and molecular subtypes. Semi-supervised protein clusters classified high vs. low risk of progression in either serous or grade 3 endometrioid carcinoma. A proteomic risk score stratified progression risk across training, testing, and independent cohorts and recapitulated adverse proteomic biology. Proteomic integration improved prognostic risk stratification and warrants further validation and translational investigation in HR-EC.