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Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

Authors: Niklas Klümper, Ngoc Khanh Tran, Stefanie Zschäbitz, Oliver Hahn, Thomas Büttner, Florian Roghmann, Christian Bolenz, Friedemann Zengerling, Constantin Schwab, Dora Nagy, Marieta Toma, Glen Kristiansen, Hendrik Heers, Philipp Ivanyi, Günter Niegisch, Camilla Marisa Grunewald, Christopher Darr, Arian Farid, Katrin Schlack, Mahmoud Abbas, Can Aydogdu, Jozefina Casuscelli, Theresa Mokry, Michael Mayr, Dora Niedersüß-Beke, Steffen Rausch, Dimo Dietrich, Jonas Saal, Jörg Ellinger, Manuel Ritter, Abdullah Alajati, Christoph Kuppe, Joshua Meeks, Francisco E Vera Badillo, J Alberto Nakauma-González, Joost Boormans, Kerstin Junker, Arndt Hartmann, Viktor Grünwald, Michael Hölzel, Markus Eckstein

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. is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate amplifications as a genomic biomarker to predict EV response in patients with mUC.

MATERIALS AND METHODS: We established a -specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of 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 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 CNVs.

RESULTS: 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, 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 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; < .001). In the mUC-non-EV, amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers.

CONCLUSION: amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

PMID: 38657187

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