Comprehensive profiling of antibody-drug conjugate target expression in epithelial ovarian cancer with pre- and post-ADC longitudinal assessment.

Abstract

5594 Background: Antibody–drug conjugates (ADCs) are increasingly used in ovarian cancer, yet target expression may evolve over time and under treatment pressure. We characterized key ADC targets across disease timepoints and assessed paired changes after ADC exposure. Methods: We retrospectively analyzed epithelial ovarian cancer treated at Yonsei Cancer Center (n=158). Serial specimens obtained at diagnosis, interval debulking surgery, and relapse underwent immunohistochemistry for TROP2, HER2, FOLR1, CLDN6, B7H4, B7H3, and CDH6. Targets were scored 0/1+/2+/3+; overexpression was defined as 2+ or 3+. Longitudinal transitions were summarized using Sankey plots, including pre-/post-ADC comparisons. Results: We analyzed 158 epithelial ovarian cancer patients (HGSC n=120; non-HGSC n=38). In HGSC, the most frequent overexpressed targets (2+/3+) were TROP2 (100%) and FOLR1 (91.5%) at diagnosis, remaining high at relapse (TROP2 93.2%, FOLR1 82.2%), while HER2 overexpression was uncommon (20.3% at diagnosis; 6.9% at relapse). In non-HGSC subtypes, TROP2 was most frequently overexpressed in endometrioid (3+ in 100%) and clear cell tumors (2+/3+ in 100%), whereas mucinous tumors showed predominant HER2 overexpression (2+/3+ in 70%). In ADC-exposed paired pre-/post-ADC specimens, expression of the cognate ADC target generally decreased after exposure, including reduced FOLR1 after MIRV/MORAb-202, reduced HER2 after T-DXd, and reduced CDH6 after R-DXd. Conclusions: TROP2 and FOLR1 are broadly and consistently expressed across timepoints. Non-HGSC exhibits distinct histology-specific patterns, with particularly high HER2 expression in mucinous tumors. ADC treatment resulted in a reduced expression profile of its cognate target protein, which may contribute to the development of ADC resistance; however, further investigation is required to elucidate additional underlying mechanisms.