Post-IMvigor011 Era: CtDNA-Guided Postoperative Adjuvant Treatment Stratification in Muscle-Invasive Bladder Cancer

Jie Sui,1,* Yunfan Chen,2,* Yu Jiang,2 Qiyu He,3 Xiping Guo41Department of Geratology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 3Emergency Department, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 4Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiping Guo, Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, Liaoning, 110001, People’s Republic of China, Email guoxiping_happy@163.comAbstract: Muscle-invasive bladder cancer (MIBC) remains characterized by substantial postoperative heterogeneity after radical cystectomy, and conventional pathology and imaging incompletely identify patients with biologically active residual disease. Circulating tumor DNA (ctDNA) has emerged as the most clinically advanced liquid-biopsy marker of molecular residual disease (MRD) in this setting because it can detect recurrence before radiographic progression and, more importantly, can now inform postoperative treatment selection. The Phase III IMvigor011 trial provided the first prospective randomized evidence that ctDNA-guided adjuvant atezolizumab improves disease-free and overall survival in patients who become ctDNA-positive after cystectomy, thereby establishing molecular relapse as an actionable postoperative state rather than a merely prognostic observation. By contrast, the favorable outcomes observed in persistently ctDNA-negative patients support surveillance-based de-escalation but do not yet constitute randomized proof that adjuvant therapy can be safely omitted. In this review, we examine how the field evolved from early prognostic studies to biomarker-directed intervention, synthesize the distinct clinical logics of escalation and de-escalation, and analyze the remaining barriers to implementation, including assay selection, sampling kinetics, false-negative risk, clonal hematopoiesis of indeterminate potential (CHIP) interference, pre-analytical control, and economic feasibility. We also discuss how emerging data from TOMBOLA, MODERN, and complementary plasma/urine multi-analyte approaches may determine whether ctDNA-guided management matures from selective escalation into a broader risk-adapted postoperative strategy. The central challenge in the post-IMvigor011 era is therefore no longer whether ctDNA is clinically relevant, but how to integrate it rigorously, reproducibly, and contextually into contemporary perioperative MIBC care.Keywords: circulating tumor DNA, minimal residual disease, muscle-invasive bladder cancer, adjuvant immunotherapy, atezolizumab, treatment escalation, treatment de-escalation, molecular residual disease, IMvigor011, liquid biopsy