Details

Autor(en) / 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
• 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

Titel

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

Ist Teil von

• Clinical cancer research, 2023-04, Vol.29 (8), p.1496-1505

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2023

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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. See related commentary by Aggen et al., p. 1377.