FGFR3 Alterations and Nectin-4 Expression as Therapeutic Biomarkers in Bladder Cancer: A Systematic Review and...

Bladder cancer is a molecularly heterogeneous malignancy in which biomarker-driven therapies increasingly shape clinical management. Fibroblast growth factor receptor 3 (FGFR3) alterations and nectin-4 expression are key therapeutic targets, yet their integrated biological and clinical relevance remains unclear. A systematic search of PubMed, Scopus, and Cochrane Central was conducted from database inception to 22 February 2026 (PROSPERO: CRD420261309413). Studies reporting the prevalence of FGFR3 alterations and/or nectin-4 expression in bladder cancer were included. Proportions were pooled using a random-effects model with restricted maximum likelihood and Freeman-Tukey transformation. Heterogeneity was assessed with I² and Cochran's Q. Fourteen studies (three randomized and 11 observational), including 3955 patients (mean age: 67.34 years), were analyzed. The pooled prevalence of FGFR3 alterations was 52% (95% CI: 23.33-80.12; I² = 99%), while that of nectin-4 expression was 78% (95% CI: 64.23-89.81; I² = 91%). FGFR3 prevalence varied significantly by disease stage, study design, and region, with higher rates in advanced/metastatic disease and randomized trials (p < 0.05). Nectin-4 expression was generally high across included studies, although interpretation was limited by the small number of studies and assay variability. Sensitivity analyses showed the stability of estimates; however, interpretation is limited by substantial heterogeneity. The observed prevalence estimates are strongly influenced by study design, biomarker selection, and assay variability, limiting their interpretation as true biological prevalence. These results should, therefore, be interpreted cautiously and viewed as descriptive rather than definitive estimates. Separate analyses of biomarker-enriched trials and unselected cohorts are necessary to obtain clinically meaningful estimates.