Circulating tumor DNA in urothelial cancer as an intermediate disease state between localized and advanced stages: Moving from risk factors to micrometastatic disease in the perioperative setting.

Urothelial carcinoma, especially muscle-invasive bladder cancer, presents a high risk of recurrence despite curative-intent surgery and perioperative therapies. A major clinical challenge remains the early identification of micrometastatic disease, undetectable with conventional imaging. Circulating tumor DNA (ctDNA), a minimally invasive biomarker, is emerging as a transformative tool for detecting minimal residual disease, allowing for earlier intervention and more tailored and efficacious treatment strategies. This review explores the evolving role of ctDNA in urothelial carcinoma, particularly in the perioperative setting. The negative adjuvant IMvigor010 trial established ctDNA as a prognostic and potentially predictive marker, demonstrating that ctDNA-positive patients postcystectomy were at higher risk of relapse but could benefit from adjuvant immunotherapy. Building on this, IMvigor011 prospectively validated a ctDNA-guided immunotherapy approach, showing that ctDNA clearance correlates with improved disease-free survival. We discuss ctDNA potential to redefine disease staging, introducing an "intermediate" category (M0, ctDNA-positive) between localized and overtly metastatic disease. ctDNA also offers value in surveillance, treatment de-escalation, and monitoring therapeutic response. Advances in tumor-informed assays have enhanced the sensitivity of ctDNA detection, though standardization and accessibility remain key challenges. In summary, ctDNA represents a paradigm shift in urothelial carcinoma management, enabling precision oncology through real-time disease monitoring and personalized treatments. Its integration into clinical practice may improve outcomes by addressing micrometastatic disease before clinical relapse or progression, transforming the way we stratify and treat patients across the urothelial carcinoma continuum.