Histology-specific ADC target landscapes in ovarian cancer and therapy-associated antigen downshift after ADC exposure

Abstract

Objective. Antibody-drug conjugates (ADCs) are transforming epithelial ovarian cancer therapy, yet the temporal stability of target expression and the impact of therapeutic pressure remain poorly understood. We characterized the longitudinal evolution of seven key ADC targets and evaluated antigen modulation following ADC exposure. Methods. We analyzed 216 specimens from patients with epithelial ovarian cancer (120 HGSC; 38 nonHGSC). Immunohistochemistry (IHC) was performed for TROP2, HER2, B7H3, B7H4, CLDN6, and CDH6. Expression (over-expression: >= 2+) was assessed at diagnosis, interval debulking, and relapse. FOLR1 expression was categorized as low or high using PS2+ criteria. Target dynamics were evaluated in a limited cohort with paired pre- and post-ADC treatment biopsy specimens. Results. ADC target landscapes were markedly histotype-specific. In HGSC, TROP2 overexpression was observed in all cases (100%), while FOLR1-high expression was present in 86.4% at diagnosis and remained prevalent at relapse (72.6%). Non-HGSC subtypes showed distinct profiles: TROP2 was universally overexpressed in endometrioid and clear cell tumors (100%), while mucinous tumors exhibited a unique HER2-rich landscape (70%). In paired analyses, exposure to cognate ADCs tended to be associated with a downward shift in target expression-particularly for FOLR1, HER2, and CDH6-suggesting a possible trend toward therapy-associated antigen reduction. Conclusions. ADC target expression varied substantially by ovarian cancer histotype. In paired specimens, cognate ADC exposure was associated with a directional decrease in target expression, suggesting possible therapyassociated antigen modulation. These preliminary findings support longitudinal biomarker reassessment to guide subsequent ADC selection and trial eligibility. (c) 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar tech