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<0.05). TP53m tumors had the highest RNA expression of CDH6, B7-H4, CLDN6, ERBB3, ERBB2, FOLR1, NECTIN2, NECTIN3, and TF; NSMP tumors had the highest expression of TROP2 and NECTIN4 relative to other subtypes (Table 1). Compared to all solid tumors, TP53m EC had the highest median RNA expression of B7-H4 and second highest of CLDN6 and FOLR1. Assessing the prognostic effect of ADC targets by subtype, POLEm CLDN6 H tumors had improved OS compared to CLDN6 L (HR 0.39, p=0.003). In MSI-H tumors, TROP2 H , CDH6 H , B7-H4 H , CLDN6 H , ERBB3 H , ERBB2 H , FOLR1 H and NECTIN2-4 H was associated with improved OS (HR 0.57-0.84, p<0.05). In TP53m tumors, TROP2 H , B7-H4 H , FOLR1 H , HER3 H , and NECTIN4 H was associated with improved OS (HR: 0.75-0.80, p<0.05) and NECTIN1 H and B7-H3 H with worse OS (HR: 1.26, p<0.001). In ER- NSMP tumors (n=804), B7-H4 H , ERBB3 H , ERBB2 H and NECTIN4 H had improved OS (HR: 0.62-0.74, p<0.05) and B7-H3 H and NECTIN1 H had worse OS (HR: 1.40, p=0.01). In ER+ NSMP tumors (n=2,896), TROP2 H and TF H had improved OS (HR: 0.73-0.82, p<0.05) and ERBB2 H and CDH6 H had worse OS (HR: 1.24-1.29, p<0.05). Conclusions: Expression of ADC targets differs by molecular subtype with varying associations with OS in EC patients. Focusing future clinical trials on EC subsets with high biomarker expression will be critical to efficiently developing novel targeted therapeutics. RNA expression by subtype (transcripts per million). Subtype B7-H3 B7-H4 CD276 CLDN6 ERBB2 ERBB3 FOLR α NECTIN1 NECTIN2 NECTIN3 NECTIN4 TF TROP2 POLEm 10.0 10.0 24.9 0.38 25.6 52.7 7.6 7.2 14.9 15.0 5.6 0.70 58.2 MSI-H 5.8 12.0 23.2 0.32 23.3 58.9 8.6 7.8 14.7 13.6 9.7 0.84 61.1 TP53m 21.5 15.8 22.0 2.90 32.8 62.4 20.7 6.0 18.6 18.6