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Klümper, Niklas; Ralser, Damian J.; Ellinger, Jörg; 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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance
  • Beteiligte: Klümper, Niklas; Ralser, Damian J.; Ellinger, Jörg; 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; [...]
  • Erschienen: American Association for Cancer Research (AACR), 2023
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-22-1764
  • ISSN: 1078-0432; 1557-3265
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Experimental Design:</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P &amp;lt; 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 &amp;lt; 0.001).</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>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.</jats:p><jats:p>See related commentary by Aggen et al., p. 1377</jats:p></jats:sec>
  • Zugangsstatus: Freier Zugang