Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance-Reference-Cited by-同舟云学术

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

Published:2022-12-19 Issue:8 Volume:29 Page:1496-1505
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
Short-container-title:

Author:

Klümper Niklas¹²³⁴^ORCID,Ralser Damian J.²³⁵^ORCID,Ellinger Jörg¹³^ORCID,Roghmann Florian⁴⁶^ORCID,Albrecht Julia¹²³^ORCID,Below Eduard²³^ORCID,Alajati Abdullah¹³^ORCID,Sikic Danijel⁴⁷⁸⁹^ORCID,Breyer Johannes⁴⁹¹⁰^ORCID,Bolenz Christian⁴¹¹^ORCID,Zengerling Friedemann⁴¹¹^ORCID,Erben Philipp⁴¹²^ORCID,Schwamborn Kristina⁹¹³^ORCID,Wirtz Ralph M.⁴¹⁴^ORCID,Horn Thomas⁹¹⁵^ORCID,Nagy Dora³¹⁶^ORCID,Toma Marieta³¹⁶^ORCID,Kristiansen Glen³⁴¹⁶^ORCID,Büttner Thomas¹³^ORCID,Hahn Oliver¹⁷^ORCID,Grünwald Viktor¹⁸^ORCID,Darr Christopher¹⁸^ORCID,Erne Eva¹⁹^ORCID,Rausch Steffen¹⁹^ORCID,Bedke Jens¹⁹^ORCID,Schlack Katrin²⁰^ORCID,Abbas Mahmoud²¹^ORCID,Zschäbitz Stefanie²²^ORCID,Schwab Constantin²³^ORCID,Mustea Alexander³⁵^ORCID,Adam Patrick²⁴^ORCID,Manseck Andreas²⁵^ORCID,Wullich Bernd⁴⁷⁸⁹^ORCID,Ritter Manuel¹³⁴^ORCID,Hartmann Arndt⁴⁷⁹²⁶^ORCID,Gschwend Jürgen⁹¹⁵^ORCID,Weichert Wilko⁹¹³^ORCID,Erlmeier Franziska⁴⁷⁹¹³¹⁹^ORCID,Hölzel Michael²³^ORCID,Eckstein Markus⁴⁷⁹²⁶^ORCID

Affiliation:

1. 1Department of Urology and Pediatric Urology, University Medical Center Bonn (UKB), Bonn, Germany.

2. 2Institute of Experimental Oncology, University Medical Center Bonn (UKB), Bonn, Germany.

3. 3Center for Integrated Oncology Aachen/Bonn/Cologne/Düsseldorf (CIO-ABCD), Germany.

4. 4BRIDGE-Consortium Germany e.V., Mannheim, Germany.

5. 5Department of Gynaecology and Gynaecological Oncology, University Medical Center Bonn (UKB), Bonn, Germany.

6. 6Department of Urology, Marien Hospital, Ruhr-University Bochum, Herne, Germany.

7. 7Comprehensive Cancer Center EMN, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

8. 8Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

9. 9Bavarian Center for Cancer Research (Bayerisches Zentrum für Krebsforschung, BZKF), Erlangen, Germany.

10. 10Department of Urology, University of Regensburg, Caritas St. Josef Hospital, Regensburg, Germany.

11. 11Department of Urology and Pediatric Urology, University Hospital Ulm, University of Ulm, Ulm, Germany.

12. 12Department of Urology and Urosurgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.

13. 13Institute of Pathology, Technical University Munich, Munich, Germany.

14. 14STRATIFYER Molecular Pathology, Cologne, Germany.

15. 15Department of Urology, Technical University Munich, Munich, Germany.

16. 16Institute of Pathology, University Medical Center Bonn (UKB), Bonn, Germany.

17. 17Department of Urology, University Medical Center Göttingen, Göttingen, Germany.

18. 18Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, Interdisciplinary Genitourinary Oncology at the West-German Cancer Center, Essen University Hospital, Essen, Germany.

19. 19Department of Urology, Eberhard Karls University, Tübingen, Germany.

20. 20Department of Urology, University Hospital Münster, Münster, Germany.

21. 21Department of Pathology, University Hospital Münster, Münster, Germany.

22. 22Department of Medical Oncology, National Center for Tumor Disease (NCT), University Hospital, Heidelberg, Germany.

23. 23Institute of Pathology, University of Heidelberg, Heidelberg, Germany.

24. 24Pathologie Ingolstadt, Ingolstadt, Germany.

25. 25Department of Urology, Klinikum Ingolstadt, Ingolstadt, Germany.

26. 26Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Abstract

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

Funder

Else Kröner Fresenius Stiftung

Deutsche Forschungsgemeinschaft

Medical Faculty of the University of Bonn

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-22-1764/3233049/ccr-22-1764.pdf

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