Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
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Open Access
- 19 December 2022
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 29 (8), 1496-1505
- https://doi.org/10.1158/1078-0432.ccr-22-1764
Abstract
Background: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV has been recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Objective: To determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Main Outcomes and Measures: Membranous NECTIN-4 protein expression was measured (H-score) by immunohistochemistry (IHC) in PRIM and corresponding MET (N=137) and in a multicenter EV-treated cohort (N=47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4 negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs PP<0.001). Conclusion: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/ progressive lesion) before initiation of EV.Keywords
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Funding Information
- Else Kröner Fresenius Stiftung (2020_EKEA.129)
- Deutsche Forschungsgemeinschaft (KL 36381-1)
- Medical Faculty of the University of Bonn (2020-2A-12)
- Medical Faculty of the University of Bonn (2021-1A-14)
- Deutsche Forschungsgemeinschaft (EXC2151–, 390873048)
This publication has 20 references indexed in Scilit:
- Biomarker-Driven Oncology Clinical Trials: Key Design Elements, Types, Features, and Practical ConsiderationsJCO Precision Oncology, 2019
- Antibody–drug conjugates for cancerThe Lancet, 2019
- Antibody-Drug Conjugate-Based Therapeutics: State of the ScienceJNCI Journal of the National Cancer Institute, 2019
- Loss of HER2 after HER2-targeted treatmentBreast Cancer Research and Treatment, 2019
- Receptor Conversion in Distant Breast Cancer Metastases: A Systematic Review and Meta-analysisJNCI Journal of the National Cancer Institute, 2018
- Antibody–drug conjugates for cancer therapyThe Lancet Oncology, 2016
- Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer ModelsCancer Research, 2016
- Preclinical Evaluation of an Anti-Nectin-4 ImmunoPET Reagent in Tumor-Bearing Mice and Biodistribution Studies in Cynomolgus MonkeysMolecular Imaging & Biology, 2016
- OutKnocker: a web tool for rapid and simple genotyping of designer nuclease edited cell linesGenome Research, 2014
- Genome engineering using the CRISPR-Cas9 systemNature Protocols, 2013