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Published on: July 25, 2020
Histology-specific ADC target landscapes in ovarian cancer and therapy-associated antigen downshift after ADC
Yong Jae Lee1, Junsik Park2, Yoo-Na Kim2
1Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, Republic of Korea.
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 non-HGSC). 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 therapy-associated antigen modulation. These preliminary findings support longitudinal biomarker reassessment to guide subsequent ADC selection and trial eligibility.
Insights
Antibody-drug conjugates (ADCs) show varied target expression in ovarian cancer histotypes. ADC treatment may decrease target expression, suggesting antigen modulation and the need for biomarker reassessment.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Antibody-drug conjugates (ADCs) represent a promising therapeutic strategy for epithelial ovarian cancer.
- Understanding the stability of ADC targets and antigen modulation under therapeutic pressure is crucial for optimizing treatment efficacy.
Purpose of the Study:
- To characterize the longitudinal expression of seven key ADC targets in epithelial ovarian cancer.
- To evaluate antigen modulation in response to ADC therapy.
Main Methods:
- Analysis of 216 epithelial ovarian cancer specimens (including HGSC and non-HGSC subtypes) at different disease stages.
- Immunohistochemistry (IHC) for TROP2, HER2, B7H3, B7H4, CLDN6, CDH6, and FOLR1 expression.
- Paired analysis of pre- and post-ADC treatment biopsies to assess target dynamics.
Main Results:
- ADC target expression profiles were histotype-specific across different ovarian cancer subtypes.
- In high-grade serous ovarian cancer (HGSC), TROP2 was universally overexpressed (100%), and FOLR1-high expression remained prevalent from diagnosis to relapse.
- Paired analyses indicated a trend towards decreased target expression (FOLR1, HER2, CDH6) following ADC exposure, suggesting antigen modulation.
Conclusions:
- Ovarian cancer histotype significantly influences ADC target expression patterns.
- ADC therapy may induce antigen modulation, leading to decreased target expression.
- Longitudinal biomarker assessment is recommended to guide ADC selection and clinical trial eligibility.
