Biomarkers For Localized Disease: Are Molecular Predictive Markers Ready For Prime-Time Therapy Decisions?

How to cite: Stewart TF. “Biomarkers For Localized Disease: Are Molecular Predictive Markers Ready For Prime-Time Therapy Decisions?” Grand Rounds in Urology. November 13, 2025. Accessed Feb 2026. https://grandroundsinurology.com/biomarkers-for-localized-disease-are-molecular-predictive-markers-ready-for-prime-time-therapy-decisions/

Summary

Tyler F. Stewart, MD, Associate Clinical Professor of Medicine, University of California, San Diego, San Diego, California, provides a clear, evidence-based assessment of whether molecular predictive biomarkers are ready to guide therapy decisions in localized bladder cancer, with a primary focus on circulating tumor DNA (ctDNA). Dr. Stewart explains that while multiple biomarker platforms are under active investigation, ctDNA currently has the strongest evidence to inform adjuvant decision-making.

He provides a broad overview of biomarker categories relevant to bladder cancer, including blood-, urine-, and pathologic-based, genomic, transcriptomic, proteomic, immunohistochemical, digital pathology, and radiographic approaches. Dr. Stewart emphasizes that ctDNA represents only a fraction of cell-free DNA and that assay methodology continues to evolve rapidly, with digital pathologic complete response, targeted next-generation sequencing, and methylation-based assays all potentially playing roles depending on the clinical context.

The prognostic value of ctDNA is reviewed using early observational data demonstrating that ctDNA positivity at diagnosis, prior to cystectomy, or after surgery is associated with significantly worse outcomes. This concept is expanded through discussion of phase III adjuvant trials. IMvigor010 failed to demonstrate disease-free or overall survival benefit with unselected adjuvant atezolizumab; however, subgroup analyses revealed that ctDNA-positive patients derived meaningful benefit from immunotherapy, while ctDNA-negative patients did not.

Dr. Stewart highlights trials designed around ctDNA as an integral biomarker. IMvigor011 demonstrates that ctDNA-positive patients benefit from adjuvant atezolizumab, with improvements in disease-free and overall survival. Importantly, serial monitoring revealed that approximately 40% of ctDNA-positive patients initially tested negative and converted over time, raising critical questions about the optimal timing of intervention.

Dr. Stewart discusses the MODERN trial, which aims to refine strategies for escalation and de-escalation based on ctDNA status after cystectomy. In contrast, perioperative data from the NIAGARA trial show that baseline ctDNA status is prognostic but does not identify patients who can safely omit perioperative immunotherapy.

Dr. Stewart argues that ctDNA is ready for use in the adjuvant setting but should not yet be used to withhold perioperative therapy or discontinue treatment prematurely. ctDNA also shows promise for tracking disease burden and response in advanced disease, while urinary biomarkers may represent the next major advance.

About the 32nd Annual Perspectives in Urology: Point Counterpoint conference: Presented by Program Chair and Grand Rounds in Urology Editor-in-Chief E. David Crawford, MD, this conference brought together leading experts in urology, medical oncology, and radiation oncology to discuss and debate the latest topics in genitourinary cancers, primarily prostate cancer and bladder cancer. This interactive conference offered topical lectures, pro/con debates, interesting-case presentations, interactive panel discussions, and interactive audience and faculty networking.