ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 125 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
125 citing papers in PubMed, 2 syntheses or guidelines pooled it, 193 citations in OpenAlex.
- FGFR3 Alterations and Nectin-4 Expression as Therapeutic Biomarkers in Bladder Cancer: A Systematic Review and Single-Arm Meta-Analysis.International journal of molecular sciences · 2026Pooled it
- Nectin-4-Targeted Radiotheranostics for Personalized Cancer Therapy: A Systematic Review.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2026Pooled it
- Prognostic value and diagnostic performance of nectin-4-targeted [European journal of nuclear medicine and molecular imaging · 2026Article
- Spatial, temporal, and molecular heterogeneity of ADC targets in high-grade serous ovarian carcinoma.British journal of cancer · 2026Article
- Article
- Disease stage-dependent expression of ADC-related biomarkers in urothelial carcinoma.Translational andrology and urology · 2026Article
- Review
- Review
- Article
- Evaluation of HER2 and Nectin-4 Expression in Primary Vaginal Cancers.International journal of molecular sciences · 2026Article
- A multi-modal approach for decision making in bladder cancer.Nature reviews. Urology · 2026Review
- Nectin-4 expression in clear cell renal cell carcinoma.Scientific reports · 2026Article
- Nectin-4 Expression in Muscle-Invasive Bladder Cancer Is Associated with Growth-Related and Inflammatory Signaling Pathways.International journal of molecular sciences · 2026Article
- Nectin-4 expression in upper and lower tract urothelial carcinoma: correlation with early-stage disease and prognostic relevance.Virchows Archiv : an international journal of pathology · 2026Article
- ENVELOPE: enfortumab vedotin in patients with advanced small bowel adenocarcinoma refractory or intolerant to platinum-based therapy-phase II investigator-initiated trial (NCCH2412/MK015).ESMO gastrointestinal oncology · 2026Article
- Nectin-4 immunohistochemistry distinguishes urothelial carcinoma in situ from reactive urothelium.Virchows Archiv : an international journal of pathology · 2026Article
- Spatial Multiomics Reveal Insights Into ADC Efficacy.European journal of immunology · 2026Review
- Precision Oncology 2.0: Guiding Magic Bullets With Expression-Based Liquid Biopsy.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2026Article
- Exploring the 89Zr/177Lu Theranostic Pairing with an Extracellular Matrix-Targeted Radiopharmaceutical against Triple-Negative Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Antibody-Drug Conjugates in Oncology: Principles, Clinical Development, and Future Directions.MedComm · 2026Review
65 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Comment on
Authors and funding
40 authors at 15 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeThe antibody-drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). EXPERIMENTAL
designMembranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4-negative/weak (H-score 0-99) versus moderate/strong (H-score 100-300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9-induced polyclonal NECTIN-4 knockouts.
resultsIn our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0-140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).
conclusionsMembranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.