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Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with Enfortumab vedotin resistance

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...

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Main Authors: Klümper, Niklas (Author) , Ralser, Damian J. (Author) , Ellinger, Jörg (Author) , Roghmann, Florian (Author) , Albrecht, Julia (Author) , Below, Eduard (Author) , Alajati, Abdullah (Author) , Sikic, Danijel (Author) , Breyer, Johannes (Author) , Bolenz, Christian (Author) , Zengerling, Friedemann (Author) , Erben, Philipp (Author) , Schwamborn, Kristina (Author) , Wirtz, Ralph M. (Author) , Horn, Thomas (Author) , Nagy, Dora (Author) , Toma, Marieta (Author) , Kristiansen, Glen (Author) , Büttner, Thomas (Author) , Hahn, Oliver (Author) , Grünwald, Viktor (Author) , Darr, Christopher (Author) , Erne, Eva (Author) , Rausch, Steffen (Author) , Bedke, Jens (Author) , Schlack, Katrin (Author) , Abbas, Mahmoud (Author) , Zschäbitz, Stefanie (Author) , Schwab, Constantin (Author) , Mustea, Alexander (Author) , Adam, Patrick (Author) , Manseck, Andreas (Author) , Wullich, Bernd (Author) , Ritter, Manuel (Author) , Hartmann, Arndt (Author) , Gschwend, Jürgen (Author) , Weichert, Wilko (Author) , Erlmeier, Franziska (Author) , Hölzel, Michael (Author) , Eckstein, Markus (Author)
Format: Article (Journal)
Language:English
Published: 15 April 2023
In: Clinical cancer research
Year: 2023, Volume: 29, Issue: 8, Pages: 1496-1505
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-22-1764
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-22-1764
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Author Notes:Niklas Klümper, Damian J. Ralser, Jörg Ellinger, Florian Roghmann, Julia Albrecht, Eduard Below, Abdullah Alajati, Danijel Sikic, Johannes Breyer, Christian Bolenz, Friedemann Zengerling, Philipp Erben, Kristina Schwamborn, Ralph M. Wirtz, Thomas Horn, Dora Nagy, Marieta Toma, Glen Kristiansen, Thomas Büttner, Oliver Hahn, Viktor Grünwald, Christopher Darr, Eva Erne, Steffen Rausch, Jens Bedke, Katrin Schlack, Mahmoud Abbas, Stefanie Zschäbitz, Constantin Schwab, Alexander Mustea, Patrick Adam, Andreas Manseck, Bernd Wullich, Manuel Ritter, Arndt Hartmann, Jürgen Gschwend, Wilko Weichert, Franziska Erlmeier, Michael Hölzel, and Markus Eckstein

MARC

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245 1 0 |a Membranous NECTIN-4 expression frequently decreases during metastatic spread of urothelial carcinoma and is associated with Enfortumab vedotin resistance  |c Niklas Klümper, Damian J. Ralser, Jörg Ellinger, Florian Roghmann, Julia Albrecht, Eduard Below, Abdullah Alajati, Danijel Sikic, Johannes Breyer, Christian Bolenz, Friedemann Zengerling, Philipp Erben, Kristina Schwamborn, Ralph M. Wirtz, Thomas Horn, Dora Nagy, Marieta Toma, Glen Kristiansen, Thomas Büttner, Oliver Hahn, Viktor Grünwald, Christopher Darr, Eva Erne, Steffen Rausch, Jens Bedke, Katrin Schlack, Mahmoud Abbas, Stefanie Zschäbitz, Constantin Schwab, Alexander Mustea, Patrick Adam, Andreas Manseck, Bernd Wullich, Manuel Ritter, Arndt Hartmann, Jürgen Gschwend, Wilko Weichert, Franziska Erlmeier, Michael Hölzel, and Markus Eckstein 
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520 |a 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).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.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).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. 
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