Liquid biopsy in genitourinary cancers: circulating tumor DNA as a predictive biomarker for treatment selection and resistance monitoring
TL;DR
CTDNA functions primarily as a prognostic and treatment-monitoring biomarker across GU malignancies, with predictive utility for treatment selection well established in muscle-invasive bladder cancer (MIBC) and still maturing elsewhere, and limited capacity, outside MIBC, to guide treatment selection.
Abstract
Background: Genitourinary (GU) cancers—prostate, urothelial, and renal cell carcinomas (RCCs)—are a leading source of oncologic morbidity and mortality. Tumor heterogeneity and evolving resistance limit static tissue biopsies, requiring real-time, non-invasive biomarkers. Circulating tumor DNA (ctDNA) captures the tumor’s mutational landscape in real time and has emerged as a candidate biomarker for treatment selection and resistance monitoring in GU malignancies. Methods: An integrative review was conducted by two independent reviewers following the Whittemore and Knafl integrative review framework, informed by PRISMA 2020 conventions. Searches covered PubMed/MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Web of Science (January 2020–April 2026). Screening and extraction were performed independently by both reviewers, with disagreements resolved by consensus. After deduplication, 118 records were screened, 39 assessed in full text, and 15 studies met inclusion criteria, stratified by cancer site. Results: ctDNA functions primarily as a prognostic and treatment-monitoring biomarker across GU malignancies, with predictive utility for treatment selection well established in muscle-invasive bladder cancer (MIBC) and still maturing elsewhere. In castration-resistant prostate cancer (CRPC), ctDNA tumor fraction (TF) at enzalutamide cycle 3 independently predicts progression-free and overall survival (OS; median OS 16.0 vs. 22.1 months, ctDNA-detected vs. -undetected with discordant prostate-specific antigen). In MIBC, post-cystectomy ctDNA identifies relapse with 94% sensitivity and 98% specificity, and a ctDNA-stratified IMvigor010 analysis reveals an OS benefit from adjuvant atezolizumab [hazard ratio (HR) 0.59] in ctDNA-positive patients only. In RCC, the least mature stratum, cfDNA quantity, TP53 mutation, TF, and BAP1 status are associated with survival on systemic therapy. In upper tract urothelial carcinoma (UTUC), perioperative ctDNA fraction predicts recurrence-free survival, with clonal haematopoiesis accounting for a notable share of false positives. Conclusion: ctDNA is a molecularly grounded biomarker with the strongest evidence in metastatic CRPC (mCRPC) and MIBC, an expanding but preliminary base in RCC, and limited capacity, outside MIBC, to guide treatment selection.