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Key Clinical Summary: Understanding the Dual Role of ctDNA

This is a micro-learning module summary of a presentation by Dr. Matthew Galsky which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This program is supported by an independent educational grant from Genentech. This accredited education activity is available to U.S. healthcare professionals only.

Introduction

This summary explores emerging evidence on circulating tumor DNA (ctDNA)‑guided management of muscle‑invasive urothelial carcinoma (MIBC), outlining the evolution of ctDNA as a tool for minimal residual disease (MRD) detection, the distinction between retrospective prognostic analyses and prospective treatment‑guiding applications, and the implications of recent adjuvant immunotherapy trials. It reviews clinical validity data from major randomized studies, and the current evidentiary boundaries that shape how ctDNA can, and cannot yet, inform adjuvant decision‑making.

Evolution of ctDNA and Tumor‑Informed MRD Testing

  • Circulating cell‑free DNA was first identified in 1948, with subsequent decades establishing its association with cancer and the presence of tumor‑specific mutations in plasma.
  • Tumor‑informed assays, such as Signatera, use whole‑exome sequencing of the primary tumor to identify up to 16 patient‑specific variants, enabling highly sensitive detection of MRD.
  • Serial sampling can be performed pre‑operatively, immediately post‑operatively, and during adjuvant therapy, with each time point offering distinct prognostic and potentially therapeutic insights.
  • ctDNA positivity after cystectomy consistently correlates with a markedly increased risk of recurrence, supporting its role as a biomarker of residual micrometastatic disease.

Adjuvant Immunotherapy Trials in MIBC

  • Three major randomized trials have evaluated PD‑1/PD‑L1 blockade after radical cystectomy: IMvigor010 (atezolizumab vs observation), AMBASSADOR (pembrolizumab vs observation), and CheckMate 274 (nivolumab vs placebo).
  • IMvigor010 did not meet its primary endpoint of disease‑free survival (DFS), whereas AMBASSADOR and CheckMate 274 demonstrated significant DFS improvements.
    CheckMate 274 led to regulatory approval of adjuvant nivolumab for high‑risk MIBC.
  • Across trials, a substantial proportion of patients in the control arms experienced durable recurrence‑free survival, highlighting that many are cured by surgery ± neoadjuvant chemotherapy and do not require additional therapy.
  • Conversely, a subset of patients recur despite adjuvant immunotherapy, underscoring the need for biomarkers that distinguish who needs treatment and who benefits from it.

The ‘Double Biomarker Dilemma’

  • In the adjuvant setting, two distinct questions must be answered:
    • Who needs treatment? Identifying patients with residual disease
    • Who benefits from treatment? Predicting therapeutic responsiveness
  • ctDNA primarily addresses the first question by identifying patients with MRD who are at high risk for recurrence.
  • Predicting benefit from specific adjuvant agents remains unresolved, as ctDNA positivity reflects disease biology rather than drug sensitivity.

Retrospective ctDNA Analyses: Clinical Validity

  • Retrospective analyses from IMvigor010 demonstrated:
    • ctDNA‑negative patients had low recurrence risk and did not appear to benefit from adjuvant atezolizumab.
    • ctDNA‑positive patients had high recurrence risk and showed substantial benefit from adjuvant therapy.
  • Similar patterns were observed in CheckMate 274, where ctDNA‑positive patients experienced pronounced separation of DFS and overall survival (OS) curves with nivolumab versus placebo.
  • These findings establish clinical validity: ctDNA reliably stratifies recurrence risk and enriches for populations likely to benefit from adjuvant immunotherapy.
  • However, these analyses were not pre‑specified, were limited by sample availability, and cannot be used to independently guide treatment decisions.

ctDNA as an Intermediate Clinical Endpoint

  • Serial ctDNA dynamics offer a potential real‑time measure of treatment effect, a major advance over traditional time‑to‑event endpoints.
  • In IMvigor010, conversion from detectable to undetectable ctDNA during adjuvant therapy correlated with improved DFS and OS.
  • Despite this promise, ctDNA clearance is not yet a validated surrogate endpoint:
    • Evidence is retrospective and exploratory.
    • It remains unknown whether lack of ctDNA clearance should trigger treatment modification.
    • Prospective trials are required to determine whether ctDNA‑guided escalation or de‑escalation improves outcomes.

Current Clinical Applicability and Limitations

  • ctDNA is a powerful prognostic biomarker for MRD detection after cystectomy.
  • It is not yet a validated tool for:
    • Determining who can safely omit adjuvant therapy.
    • Selecting neoadjuvant therapy.
    • Guiding treatment changes based on serial ctDNA results.
  • Ongoing prospective trials are essential to establish clinical utility, moving from prognostic association to treatment‑guiding actionability.

Conclusions

ctDNA‑based MRD assessment represents one of the most promising advances in precision oncology for MIBC, offering unprecedented ability to identify patients with residual disease who are at high risk for recurrence. Retrospective analyses from major adjuvant immunotherapy trials consistently demonstrate strong prognostic value and enrichment for therapeutic benefit among ctDNA‑positive patients. However, ctDNA has not yet achieved the evidentiary threshold required for treatment‑guiding use, and its role as an intermediate clinical endpoint remains unproven. As prospective ctDNA‑guided trials mature, they will determine whether this biomarker can transition from a powerful prognostic tool to a validated driver of individualized adjuvant therapy decisions.

Content is accurate as of the date of release on 16 March 2026.