Kluemper, Niklas and Ralser, Damian J. and Ellinger, Joerg and Roghmann, Florian and Albrecht, Julia and Below, Eduard and Alajati, Abdullah and Sikic, Danijel and Breyer, Johannes and Bolenz, Christian and Zengerling, Friedemann and Erben, Philipp and Schwamborn, Kristina and Wirtz, Ralph M. and Horn, Thomas and Nagy, Dora and Toma, Marieta and Kristiansen, Glen and Buettner, Thomas and Hahn, Oliver and Gruenwald, Viktor and Darr, Christopher and Erne, Eva and Rausch, Steffen and Bedke, Jens and Schlack, Katrin and Abbas, Mahmoud and Zschaebitz, Stefanie and Schwab, Constantin and Mustea, Alexander and Adam, Patrick and Manseck, Andreas and Wullich, Bernd and Ritter, Manuel and Hartmann, Arndt and Gschwend, Jurgen and Weichert, Wilko and Erlmeier, Franziska and Hoelzel, Michael and Eckstein, Markus (2023) Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. CLINICAL CANCER RESEARCH, 29 (8). pp. 1496-1505. ISSN 1078-0432, 1557-3265
Full text not available from this repository. (Request a copy)Abstract
Purpose: The antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prev-alence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).Experimental Design: Membranous NECTIN-4 protein exp-ression was measured (H-score) by 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 establish-ing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts.Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).Conclusions: Membranous NECTIN-4 expression is fre-quently 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AGENT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 14:33 |
| Last Modified: | 30 Jan 2024 14:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60915 |
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