ctDNA MRD

  • Circulating tumor DNA (ctDNA) is tumor-derived DNA in plasma cell-free DNA. Molecular residual disease (MRD) is detectable ctDNA after curative-intent surgery in a patient with no radiographic evidence of disease.1,2
  • Tumor-informed assays: sequencing of the resected tumor and matched normal blood identifies patient-specific somatic variants, which are then tracked in plasma by personalized multiplex PCR and deep NGS.3

Biology

  • ctDNA detected after radical cystectomy reflects microscopic residual disease and precedes radiographic relapse; in one cohort, post-cystectomy ctDNA identified metastatic relapse with 100% sensitivity and 98% specificity, a median of 96 days before imaging.2
  • ctDNA status identifies which patients are likely to benefit from adjuvant immunotherapy: in IMvigor010, atezolizumab improved disease-free survival (HR, 0.58) and overall survival (HR, 0.59) only in ctDNA-positive patients, with no difference in ctDNA-negative patients.1

Etiology and Epidemiology

  • 37% (214 of 581) of patients with high-risk muscle-invasive urothelial carcinoma in IMvigor010 were ctDNA-positive at the start of adjuvant therapy; ctDNA positivity carried a 6.3-fold higher risk of recurrence (HR, 6.3; 95% CI, 4.45-8.92) in the observation arm.1
  • IMvigor011: of 761 enrolled patients under serial surveillance, 250 became ctDNA-positive and were randomized; 357 remained persistently ctDNA-negative, with 1-year disease-free survival of 95.4% without adjuvant therapy.4,5

Testing

When to Test:

  • After radical cystectomy for MIBC in patients without radiographic evidence of disease: begin at least 6 weeks after cystectomy, test every 6 weeks for 9 months, with a final test at 1 year. Patients who remain negative continue serial testing until a positive result or completion of the 12-month window.3,6

Testing Methodologies:

  • Signatera CDx (Natera): FDA-approved companion diagnostic (PMA P260004, May 15, 2026), the first approved blood-based MRD companion diagnostic. Whole-exome sequencing of FFPE tumor (at least 20% tumor content) and matched whole blood removes germline and clonal hematopoiesis variants and selects 16 tumor-specific variants; plasma is positive when at least 2 of 16 are detected.3,7
  • Analytical performance: limit of detection 0.043% mean variant allele fraction; 0 of 309 false positives in limit-of-blank testing.3

Guideline Recommendations

  • NCCN (Bladder Cancer, V.2.2026): recommends considering ctDNA MRD testing with an FDA-approved tumor-informed multiplex PCR-NGS assay for risk stratification and to guide adjuvant immunotherapy after cystectomy in patients without prior checkpoint inhibitor therapy; adjuvant atezolizumab for ctDNA MRD-positive status within 1 year of cystectomy is category 1 (other recommended).8

Targeted Therapy

Approved Agents

Atezolizumab (Tecentriq)

FDA-Approved Indication:

  • As a single agent for adjuvant treatment of adults with MIBC after cystectomy who have ctDNA MRD as determined by an FDA-authorized test (May 15, 2026).6

Mechanism of Action:

  • Humanized IgG1 monoclonal antibody that binds PD-L1 and blocks its interaction with PD-1 and B7.1, releasing PD-L1/PD-1-mediated inhibition of the antitumor immune response.6

Drug Information: Learn more about Atezolizumab ›

Patient Resources: https://www.tecentriq.com/

Related Considerations

  • Persistently ctDNA-negative patients had excellent outcomes without adjuvant therapy in IMvigor011, supporting ctDNA-guided de-escalation; earlier unselected atezolizumab trials did not improve outcomes, and atezolizumab's prior metastatic urothelial indications were withdrawn in 2021 and 2022.4,5,6

References

  1. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature. 2021;595(7867):432-437. doi:10.1038/s41586-021-03642-9
  2. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol. 2019;37(18):1547-1557. doi:10.1200/JCO.18.02052
  3. Signatera CDx. Summary of safety and effectiveness data, PMA P260004. US Food and Drug Administration. May 15, 2026.
  4. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. 2025;393(24):2395-2408. doi:10.1056/NEJMoa2511885
  5. Powles T, et al. IMvigor011: a phase 3 trial of ctDNA-guided adjuvant atezolizumab versus placebo in MIBC. Presented at: ESMO Congress 2025; abstract LBA8.
  6. Tecentriq (atezolizumab) injection. Prescribing information. Genentech, Inc; revised 05/2026. Accessed October 2026.
  7. FDA approves atezolizumab for adjuvant treatment of muscle invasive bladder cancer in patients with molecular residual disease. US Food and Drug Administration. May 15, 2026.
  8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.