Antibody-drug conjugate (ADC) biomarker targets in endometrial cancer (EC): Molecular characterization and implications for therapeutic decision-making.

5616 Background: Given the evolving landscape of ADCs, we evaluated expression of emerging ADC targets in EC and compared expression patterns across molecular subgroups (POLE mutated [POLEm], MSI-high [MSI-H], TP53-mutated [TP53m] or No Specific Molecular Profile [NSMP]) defined by the Proactive Molecular Risk Classifier for Endometrial Cancer. Methods: Tumors were analyzed by DNA and RNA sequencing and immunohistochemistry (IHC) for select proteins (Caris Life Sciences, Phx, AZ). ER+ defined as % staining ≥ 1%. Statistics were calculated by Mann-Whitney U test and adjusted for multiple comparisons (q < 0.05). Expression was split into top quartile ( H ) and bottom quartile ( L ). Overall survival (OS) was obtained from insurance claims data and calculated from first treatment to last contact. Hazard ratios (HR) were calculated by Cox proportional hazards with p-values by log-rank tests. Results: Of 13,731 EC samples, 2.4% (n=335) were POLEm, 21.6% (n=2,961) MSI-H, 46.8% (n=6,420) TP53m and 29.2% (n=4,015) NSMP. HER2+ by IHC was highest in TP53m tumors compared to POLEm, MSI-H, and NSMP (15.9% vs 1.2% vs 0.8% vs 4.0%; p