TY - JOUR
T1 - NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer
AU - Klümper, Niklas
AU - Tran, Ngoc Khanh
AU - Zschäbitz, Stefanie
AU - Hahn, Oliver
AU - Büttner, Thomas
AU - Roghmann, Florian
AU - Bolenz, Christian
AU - Zengerling, Friedemann
AU - Schwab, Constantin
AU - Nagy, Dora
AU - Toma, Marieta
AU - Kristiansen, Glen
AU - Heers, Hendrik
AU - Ivanyi, Philipp
AU - Niegisch, Günter
AU - Grunewald, Camilla Marisa
AU - Darr, Christopher
AU - Farid, Arian
AU - Schlack, Katrin
AU - Abbas, Mahmoud
AU - Aydogdu, Can
AU - Casuscelli, Jozefina
AU - Mokry, Theresa
AU - Mayr, Michael
AU - Niedersüß-Beke, Dora
AU - Rausch, Steffen
AU - Dietrich, Dimo
AU - Saal, Jonas
AU - Ellinger, Jörg
AU - Ritter, Manuel
AU - Alajati, Abdullah
AU - Kuppe, Christoph
AU - Meeks, Joshua
AU - Vera Badillo, Francisco E.
AU - Nakauma-González, J. Alberto
AU - Boormans, Joost
AU - Junker, Kerstin
AU - Hartmann, Arndt
AU - Grünwald, Viktor
AU - Hölzel, Michael
AU - Eckstein, Markus
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2024/7/10
Y1 - 2024/7/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85196284347&partnerID=8YFLogxK
U2 - 10.1200/jco.23.01983
DO - 10.1200/jco.23.01983
M3 - Article
C2 - 38657187
AN - SCOPUS:85196284347
SN - 0732-183X
VL - 42
SP - 2446
EP - 2455
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 20
ER -
