Circulating Tumor DNA in Genitourinary Malignancies: Current Applications and Future Perspectives

Circulating tumor DNA (ctDNA) analysis, a cornerstone of liquid biopsy, is rapidly emerging as a transformative tool in the management of genitourinary (GU) malignancies. This review synthesizes the current evidence-based clinical utility, critical challenges, and future perspectives of ctDNA across the spectrum of major GU cancers—including prostate, urothelial, renal cell, and testicular germ cell tumors. We explore the foundational science and evolving technologies underpinning ctDNA detection and analysis, and detail its diverse clinical applications. These include its role in early detection and diagnosis, risk stratification, prognostication, real-time monitoring of therapeutic response, identification of minimal residual disease (MRD), and the elucidation of resistance mechanisms, comparing its performance with existing standard-of-care biomarkers and imaging. Advanced applications—such as the assessment of tumor mutational burden (TMB), microsatellite instability (MSI), ctDNA methylation patterns, characterization of tumor heterogeneity, and the integration of ctDNA with other liquid biopsy analytes and imaging modalities—are also discussed for their potential to provide deeper biological insights. Despite its promise, the widespread clinical implementation of ctDNA testing faces significant scientific, technical, logistical, and economic hurdles. These include the need for enhanced assay sensitivity, rigorous standardization, comprehensive clinical validation, and strategies for interpreting complex genomic data such as variants of uncertain significance (VUS) and clonal hematopoiesis of indeterminate potential (CHIP)). Furthermore, paramount ethical, legal, and social implications (ELSI) must be proactively addressed. Looking ahead, anticipated technological breakthroughs, the integration of artificial intelligence/machine learning, the development of malignancy-specific ctDNA assays, and innovative clinical trial designs are poised to overcome current limitations. These advancements are expected to unlock the full transformative potential of ctDNA, potentially revolutionizing GU cancer care by enabling more precise, personalized, and effective patient management across the disease continuum. This review provides clinicians and practitioners with a comprehensive overview to navigate the evolving landscape of ctDNA in GU oncology.