; Roghmann, Florian ; Albrecht, Julia
; Below, Eduard
; Alajati, Abdullah ; Sikic, Danijel ; Breyer, Johannes ; Bolenz, Christian ; Zengerling, Friedemann ; Erben, Philipp ; Schwamborn, Kristina ; Wirtz, Ralph M. ; Horn, Thomas ; Nagy, Dora ; Toma, Marieta ; Kristiansen, Glen ; Büttner, Thomas ; Hahn, Oliver ; Grünwald, Viktor ; Darr, Christopher ; Erne, Eva ; Rausch, Steffen ; Bedke, Jens
; Schlack, Katrin ; Abbas, Mahmoud ; Zschäbitz, Stefanie ; Schwab, Constantin ; Mustea, Alexander ; Adam, Patrick ; Manseck, Andreas ; Wullich, Bernd ; Ritter, Manuel ; Hartmann, Arndt ; Gschwend, Jürgen ; Weichert, Wilko ; Erlmeier, Franziska ; Hölzel, Michael ; Eckstein, Markus 
| Dokumentenart: | Artikel | ||||
|---|---|---|---|---|---|
| Titel eines Journals oder einer Zeitschrift: | Clinical Cancer Research | ||||
| Verlag: | AMER ASSOC CANCER RESEARCH | ||||
| Ort der Veröffentlichung: | PHILADELPHIA | ||||
| Band: | 29 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 8 | ||||
| Seitenbereich: | S. 1496-1505 | ||||
| Datum: | 2022 | ||||
| Institutionen: | Medizin > Lehrstuhl für Urologie | ||||
| Identifikationsnummer: |
| ||||
| Stichwörter / Keywords: | AGENT; | ||||
| Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status: | Veröffentlicht | ||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden: | Ja | ||||
| Dokumenten-ID: | 76263 |
Zusammenfassung
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 ...

Zusammenfassung
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.
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