NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.
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Klümper Niklas, Tran Ngoc Khanh, Zschäbitz Stefanie, Hahn Oliver, Büttner Thomas, Roghmann Florian, Bolenz Christian, Zengerling Friedemann, Schwab Constantin, Nagy Dora, Toma Marieta, Kristiansen Glen, Heers Hendrik, Ivanyi Philipp, Niegisch Günter, Grunewald Camilla Marisa, Darr Christopher, Farid Arian, Schlack Katrin, Abbas Mahmoud, Aydogdu Can, Casuscelli Jozefina, Mokry Theresa, Mayr Michael, Niedersüß-Beke Dora, Rausch Steffen, Dietrich Dimo, Saal Jonas, Ellinger Jörg, Ritter Manuel, Alajati Abdullah, Kuppe Christoph, Meeks Joshua, Vera Badillo Francisco E, Nakauma-González J Alberto, Boormans Joost, Junker Kerstin, Hartmann Arndt, Grünwald Viktor, Hölzel Michael, Eckstein Markus
Аннотация
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.