Reply to Editorial Comment: Identification of a Highly Sensitive Combination of Urinary Protein Biomarkers for the Detection of High-Grade Bladder Cancer

We appreciate the thoughtful Editorial Comment by Dr Harmon and Dr Svatek regarding our study on a 4-protein urinary panel for high-grade bladder cancer detection.1 Their summary accurately highlights both the strengths of our proteomics-based approach and the challenges that remain in transitioning urinary biomarkers toward routine clinical use.2 We agree that the modest sample size and retrospective design position our study as an initial step rather than a definitive clinical tool. To address this, we are currently completing a prospective cohort of approximately 1000 patients in Sherbrooke, designed specifically to capture the full spectrum of presentations—hematuria, benign urologic conditions, and surveillance populations. In parallel, a 1200-patient multicentric study across Canada, France, Germany, and Bangladesh is underway to rigorously validate the assay's performance in diverse populations and healthcare environments. These efforts directly respond to the concern raised about reproducibility and generalizability and will allow us to benchmark the panel against commercially available urinary tests under real-world conditions. We also acknowledge the need for improved specificity in patients with prior bladder cancer, a limitation shared by many urinary protein-based assays.3,4 The expanded cohorts will enable stratified analyses within surveillance populations, including assessments by risk category, recurrence history, and treatment exposures. Ultimately, as noted by the authors, defining true clinical utility will require prospective trials measuring meaningful outcomes such as reduced cystoscopy burden, earlier detection of recurrences, improved quality of life, or cost benefit. Our ongoing and planned studies are being structured with these downstream trial designs in mind. We thank Dr Harmon and Dr Svatek for their constructive review and for highlighting key considerations that will guide the next phase of our biomarker development program.