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Impact of Membranous Nectin-4 on Outcomes of Platinum-Based Chemotherapy in Metastatic Urothelial Carcinoma
1
Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan
2
Department of Pathology, National Taiwan University Hospital, Taipei 100, Taiwan
3
Department of Medical Oncology, National Taiwan University Cancer Center, Taipei 106, Taiwan
4
Department of Urology, National Taiwan University Hospital, Taipei 100, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(3), 433; https://doi.org/10.3390/cancers17030433
Submission received: 9 January 2025
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Revised: 24 January 2025
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Accepted: 26 January 2025
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Published: 27 January 2025
(This article belongs to the Special Issue Clinical Outcomes in Urologic Cancers)
Simple Summary
Metastatic urothelial carcinoma (mUC) is commonly treated with platinum-based chemotherapy (Plt-ChT) as the first-line regimen, but patient responses vary significantly, and predictive biomarkers are lacking. Nectin-4, a cell adhesion molecule and the target of the antibody–drug conjugate enfortumab vedotin, holds potential as a biomarker but has not been thoroughly investigated in the context of chemotherapy. This study evaluated whether membranous nectin-4 expression (mNectin-4) could predict the efficacy of Plt-ChT, including gemcitabine plus cisplatin or carboplatin, in mUC. Analyzing tumor samples from 96 patients revealed that higher mNectin-4 expression was associated with a non-significant trend towards improved outcomes, particularly with gemcitabine and cisplatin therapy. These findings suggest that mNectin-4 may serve as a potential predictive biomarker for refining treatment selection and personalizing therapeutic strategies for mUC. Further validation through larger prospective studies is required to confirm its clinical utility.
Abstract
Background: Platinum-based chemotherapy (Plt-ChT) remains a cornerstone treatment for metastatic urothelial carcinoma (mUC). The nectin-4-targeting antibody–drug conjugate enfortumab vedotin (EV), in combination with immune checkpoint inhibitors, has expanded first-line treatment options. However, biomarkers to guide treatment selection are lacking. Membranous nectin-4 (mNectin-4) expression, a potential marker of EV efficacy, has not been fully explored in the context of Plt-ChT. Methods: We retrospectively analyzed 96 patients with mUC treated with first-line gemcitabine plus cisplatin or carboplatin (GC/GCarbo) and classified mNectin-4 expression using immunohistochemical staining as either high (histochemical score (H-score): 100–300, mNectin-4High) or low (H-score: 0–99, mNectin-4Low). Results: Among these patients, 54.1% exhibited mNectin-4High tumors, which were associated with bladder-origin tumors, a pure urothelial carcinoma histology, de novo presentation, and lymph node-only metastasis. The mNectin-4High subgroup showed a non-significant trend toward better outcomes, including response rate (46.1% vs. 36.3%; p = 0.32), median progression-free survival (7.0 months vs. 4.0 months; adjusted p = 0.06), and median overall survival (20.0 months vs. 8.8 months; adjusted p = 0.06), compared with the mNectin-4Low subgroup. The subgroup analysis revealed that the favorable outcomes for mNectin-4High tumors were predominantly observed in the GC cohort, which was not evident in the GCarbo cohort. Conclusions: Our study suggests a non-significant trend toward improved outcomes with first-line Plt-ChT in patients with mNectin-4High tumors, particularly with the GC regimen. Larger prospective studies are warranted to validate mNectin-4 as a potential predictive biomarker for mUC treatment.
