BioBladder – a national longitudinal sampling study providing a comprehensive framework to precision oncology in urothelial cancer

Background Urothelial cancer (UC) represents a major global health burden with more than 600,000 new cases and over 220,000 deaths annually. Although many tumors present at superficial stages, patients remain at lifelong risk of progression to muscle-invasive bladder cancer (MIBC) and metastatic urothelial cancer (mUC). Despite therapeutic advances, including perioperative immune-checkpoint inhibitors, antibody–drug conjugates, targeted FGFR inhibitors, and novel combination regimens, response rates remain limited, relapse is common, and long-term survival in advanced disease is poor. Substantial variability in treatment response underscores the need to identify mechanisms of resistance and develop robust prognostic and predictive biomarkers to support individualized therapy. Methods BioBladder is a national, prospective, longitudinal, observational study including patients treated in routine clinical practice, designed to accelerate translational biomarker research in UC. The protocol systematically integrates longitudinal liquid biopsies and tumor tissue sampling across predefined cohorts spanning the entire disease spectrum: from early-stage primary tumors (T1) to MIBC and mUC across all systemic therapy lines. Sampling schedules are aligned with routine clinical visits to minimize patient burden. In parallel, the study captures extensive clinical data through a dedicated electronic case report form using standardized vocabularies and a common data model, including demographic, pathological, treatment, imaging, and outcome variables. Standardized processing of fresh and formalin-fixed paraffin-embedded tumors and serial plasma samples enable multi-omics analyses, including circulating tumor DNA (ctDNA), transcriptomics, proteomics, and spatial tissue profiling. BioBladder enables exploratory longitudinal biomarker development, associations with response rate, duration of response, progression-free survival, overall survival, and toxicity thereby providing a framework for future interventional studies. Discussion This nationwide real-world platform provides an unprecedented resource for biomarker discovery, for studying tumor evolution and treatment resistance over time under treatment pressure across all stages of UC and therapeutic modalities. Integration of serial biospecimens with detailed clinical annotation, enables advanced molecular analyses including ctDNA-based minimal residual disease assessment, spatial multi-omics, and functional drug testing. In summary, BioBladder establishes a comprehensive infrastructure to bridge clinical and molecular research, foster national and international collaboration, and generate biological insights for the design of future biomarker-driven interventional trials aimed at improving precision medicine for patients with UC.