NECTIN4 amplification is frequent in solid tumors and predicts enfortumab vedotin response in metastatic urothelial cancer
Purpose - The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent f...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
July 10, 2024
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| In: |
Journal of clinical oncology
Year: 2024, Jahrgang: 42, Heft: 20, Pages: 2446-2455 |
| ISSN: | 1527-7755 |
| DOI: | 10.1200/JCO.23.01983 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1200/JCO.23.01983 Verlag, kostenfrei, Volltext: https://ascopubs.org/doi/10.1200/JCO.23.01983 
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| Verfasserangaben: | Niklas Klümper, MD, Ngoc Khanh Tran, Stefanie Zschäbitz, MD, Oliver Hahn, MD, Thomas Büttner, MD, Florian Roghmann, MD, Christian Bolenz, MD, Friedemann Zengerling, MD, Constantin Schwab, MD, Dora Nagy, MD, Marieta Toma, MD, Glen Kristiansen, MD, Hendrik Heers, MD, Philipp Ivanyi, MD, Günter Niegisch, MD, Camilla Marisa Grunewald, MD, Christopher Darr, MD, Arian Farid, MD, Katrin Schlack, MD, Mahmoud Abbas, MD, Can Aydogdu, MD, Jozefina Casuscelli, MD, Theresa Mokry, MD, Michael Mayr, MD, Dora Niedersüß-Beke, MD, Steffen Rausch, MD, Dimo Dietrich, PhD, Jonas Saal, MD, Jörg Ellinger, MD, Manuel Ritter, MD, Abdullah Alajati, PhD, Christoph Kuppe, MD, PhD, Joshua Meeks, MD, PhD, Francisco E. Vera Badillo, MD, J. Alberto Nakauma-González, PhD, Joost Boormans, MD, Kerstin Junker, MD, Arndt Hartmann, MD, Viktor Grünwald, MD, Michael Hölzel, MD, and Markus Eckstein, MD |
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| 245 | 1 | 0 | |a NECTIN4 amplification is frequent in solid tumors and predicts enfortumab vedotin response in metastatic urothelial cancer |c Niklas Klümper, MD, Ngoc Khanh Tran, Stefanie Zschäbitz, MD, Oliver Hahn, MD, Thomas Büttner, MD, Florian Roghmann, MD, Christian Bolenz, MD, Friedemann Zengerling, MD, Constantin Schwab, MD, Dora Nagy, MD, Marieta Toma, MD, Glen Kristiansen, MD, Hendrik Heers, MD, Philipp Ivanyi, MD, Günter Niegisch, MD, Camilla Marisa Grunewald, MD, Christopher Darr, MD, Arian Farid, MD, Katrin Schlack, MD, Mahmoud Abbas, MD, Can Aydogdu, MD, Jozefina Casuscelli, MD, Theresa Mokry, MD, Michael Mayr, MD, Dora Niedersüß-Beke, MD, Steffen Rausch, MD, Dimo Dietrich, PhD, Jonas Saal, MD, Jörg Ellinger, MD, Manuel Ritter, MD, Abdullah Alajati, PhD, Christoph Kuppe, MD, PhD, Joshua Meeks, MD, PhD, Francisco E. Vera Badillo, MD, J. Alberto Nakauma-González, PhD, Joost Boormans, MD, Kerstin Junker, MD, Arndt Hartmann, MD, Viktor Grünwald, MD, Michael Hölzel, MD, and Markus Eckstein, MD |
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| 520 | |a Purpose - The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. - Materials and Methods - We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. - Results - NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. - Conclusion - NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC. | ||
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