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Title:

Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.

Document type:
Editorial; Research Support, Non-U.S. Gov't; Comment
Author(s):
Klümper, Niklas; Ralser, Damian J; Ellinger, Joerg; 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; Must...     »
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 prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). EXPERIMENTAL DESIGN: Membranous NECTIN-4 protein expression 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 establishing 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 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. See related commentary by Aggen et al., p. 1377.
Journal title abbreviation:
Clin Cancer Res
Year:
2023
Journal volume:
29
Journal issue:
8
Pages contribution:
1496-1505
Fulltext / DOI:
doi:10.1158/1078-0432.CCR-22-1764
Pubmed ID:
http://view.ncbi.nlm.nih.gov/pubmed/36534531
Print-ISSN:
1078-0432
TUM Institution:
551; Institut für Allgemeine Pathologie und Pathologische Anatomie (Dr. Mogler komm.); Klinik und Poliklinik für Urologie (Prof. Gschwend)
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