NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

被引：37

作者：

Kluemper, Niklas ^{[1
,2
,3
,4
]}

Tran, Ngoc Khanh ^{[1
,2
,3
]}

Zschaebitz, Stefanie ^{[5
]}

Hahn, Oliver ^{[6
]}

Buettner, Thomas ^{[1
,3
]}

Roghmann, Florian ^{[4
,7
]}

Bolenz, Christian ^{[4
,8
]}

Zengerling, Friedemann ^{[4
,8
]}

Schwab, Constantin ^{[9
]}

Nagy, Dora ^{[3
,10
]}

Toma, Marieta ^{[3
,10
]}

Kristiansen, Glen ^{[3
,4
,10
]}

Heers, Hendrik ^{[11
]}

Ivanyi, Philipp ^{[12
]}

Niegisch, Guenter ^{[13
]}

Grunewald, Camilla Marisa ^{[13
]}

Darr, Christopher ^{[14
]}

Farid, Arian ^{[15
]}

Schlack, Katrin ^{[16
]}

Abbas, Mahmoud ^{[17
]}

Aydogdu, Can ^{[18
]}

Casuscelli, Jozefina ^{[18
]}

Mokry, Theresa ^{[19
]}

Mayr, Michael ^{[20
]}

Niedersuess-Beke, Dora ^{[21
]}

Rausch, Steffen ^{[22
]}

Dietrich, Dimo ^{[23
]}

Saal, Jonas ^{[2
,3
,24
]}

Ellinger, Joerg ^{[1
,3
]}

Ritter, Manuel ^{[1
,3
,4
]}

Alajati, Abdullah ^{[1
,3
]}

Kuppe, Christoph ^{[25
,26
]}

Meeks, Joshua ^{[27
]}

Badillo, Francisco E. Vera ^{[28
]}

Nakauma-Gonzalez, J. Alberto ^{[29
]}

Boormans, Joost ^{[29
]}

Junker, Kerstin ^{[30
]}

Hartmann, Arndt ^{[4
,31
,32
,33
]}

Gruenwald, Viktor ^{[34
,35
]}

Hoelzel, Michael ^{[2
,3
]}

Eckstein, Markus ^{[4
,31
,32
,33
]}

机构：

[1] Univ Hosp Bonn, Dept Urol & Pediat Urol, Bonn, Germany

[2] Univ Med Ctr Bonn UKB, Inst Expt Oncol, Bonn, Germany

[3] Ctr Integrated Oncol Aachen Bonn Cologne Dusseldor, Bonn, Germany

[4] BRIDGE Consortium Germany eV, Mannheim, Germany

[5] Univ Hosp, Natl Ctr Tumor Dis NCT, Dept Med Oncol, Heidelberg, Germany

[6] Julius Maximilians Univ, Dept Urol & Pediat Urol, Med Ctr Wurzburg, Wurzburg, Germany

[7] Ruhr Univ Bochum, Marien Hosp, Dept Urol, Herne, Germany

[8] Univ Ulm, Univ Hosp Ulm, Dept Urol & Pediat Urol, Ulm, Germany

[9] Heidelberg Univ, Inst Pathol, Heidelberg, Germany

[10] Univ Hosp Bonn, Inst Pathol, Bonn, Germany

[11] Univ Hosp Marburg, Dept Urol, Marburg, Germany

[12] Hannover Med Sch, Dept Hemostaseol Oncol & Stem Cell Transplantat, Hannover, Germany

[13] Univ Hosp Dusseldorf, Dept Urol, Dusseldorf, Germany

[14] Univ Hosp Essen, Dept Urol, Essen, Germany

[15] Univ Med Ctr Gottingen, Dept Urol, Gottingen, Germany

[16] Univ Hosp Munster, Dept Urol, Munster, Germany

[17] Univ Hosp Munster, Dept Pathol, Munster, Germany

[18] Ludwig Maximilian Univ Munich, Univ Hosp, Dept Urol, Munich, Germany

[19] Heidelberg Univ Hosp, Dept Diagnost & Intervent Radiol, Heidelberg, Germany

[20] Inst Pathol & Microbiol, Clin Ottakring, Vienna, Austria

[21] Wilhelminenspital Stadt Wien, Dept Internal Med 1, Vienna, Austria

[22] Eberhard Karls Univ Tubingen, Dept Urol, Tubingen, Germany

[23] Univ Med Ctr Bonn UKB, Dept Otorhinolaryngol, Bonn, Germany

[24] Univ Med Ctr Bonn UKB, Med Clin Oncol Hematol Immune Oncol & Rheumatol 3, Bonn, Germany

[25] Rhein Westfal TH Aachen, Inst Expt Med & Syst Biol, Aachen, Germany

[26] Rhein Westfal TH Aachen, Div Nephrol, Aachen, Germany

[27] Feinberg Sch Med, Dept Urol, Chicago, IL USA

[28] Queens Univ, Dept Med Oncol, Kingston, ON, Canada

[29] Univ Med Ctr Rotterdam, Erasmus MC Canc Inst, Dept Urol, Rotterdam, Netherlands

[30] Saarland Univ, Dept Urol & Pediat Urol, Homburg, Germany

[31] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Inst Pathol, Erlangen, Germany

[32] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Comprehens Canc Ctr EMN, Erlangen, Germany

[33] Bavarian Ctr Canc Res, BZKF, Erlangen, Germany

[34] Essen Univ Hosp, Interdisciplinary Genitourinary Oncol West German, Clin Internal Med Tumor Res, Essen, Germany

[35] Essen Univ Hosp, Interdisciplinary Genitourinary Oncol West German, Clin Urol, Essen, Germany

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2024年 / 42卷 / 20期

关键词：

RESISTANCE; CARCINOMA; CHEMOTHERAPY; MECHANISMS; HISTOLOGY; SURVIVAL;

D O I：

10.1200/JCO.23.01983

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2446 / 2455

页数：16

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