Bonn scientists

PD Dr. Niklas Klümper from the Department of Urology and the Institute of Experimental Oncology and Prof. Michael Hölzel from the Institute of Experimental Oncology at the University Hospital Bonn discovered that NECTIN4 amplifications are genomic predictors of long-term survival in patients suffering from metastatic urothelial cancer (mUC). Their findings were published in the latest edition of the “Journal of Clinical Oncology”.

NECTIN4, a cell adhesion molecule belonging to the nectin family, has emerged as an important target molecule in the research of urothelial cancer. In urothelial cancer NECTIN4 expression levels are frequently elevated, suggesting its involvement in the pathogenesis of the disease. Studies indicate that NECTIN4 contributes to various aspects of urothelial cancer progression, including tumor growth, invasion, and metastasis. Its overexpression has been associated with aggressive tumor behavior and poorer clinical outcomes. Hence, there is a growing need to identify novel treatment options against cancer cells expressing NECTIN4.

In recent years, enfortumab vedotin (EV) was developed as an antibody-drug conjugate (ADC) that targets NECTIN4. Clinical trials demonstrated that EV is an effective treatment against mUC as it specifically targets cancer cells overexpressing NECTIN4. In this context, the research team of Dr. Niklas Klümper and Prof. Michael Hölzel analyzed patient data and used NECTIN4 amplifications as biomarkers to predict EV response in patients with mUC: 


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.