Liqomics Evidence-Based Liquid Biopsy Knowledge
⚠️ IMPORTANT DISCLAIMER:

This content is AI-generated and has not yet been reviewed by medical professionals. The information presented here is for educational purposes only and should NOT be used to make medical decisions. Always consult with qualified healthcare providers for medical advice.

Bladder Cancer

Circulating Tumor DNA for Minimal Residual Disease Detection & Molecular Profiling

Clinical Overview

Bladder cancer is stratified into two major clinical categories with different prognoses and treatment approaches: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This distinction is critical for understanding the clinical utility of ctDNA testing, which varies significantly between these disease states.

Muscle-Invasive Bladder Cancer (MIBC)

  • Definition: Tumor invades detrusor muscle (≥T2 stage)
  • Prevalence: 25% of bladder cancer diagnoses
  • Standard treatment: Radical cystectomy ± neoadjuvant/adjuvant therapy
  • 5-year survival: 50-70% with treatment
  • ctDNA utility: HIGH - Level 1 evidence from randomized trials

Non-Muscle-Invasive Bladder Cancer (NMIBC)

  • Definition: Confined to mucosa (Ta, Tis) or submucosa (T1)
  • Prevalence: 75% of bladder cancer diagnoses
  • Standard treatment: Transurethral resection ± intravesical therapy
  • 5-year survival: >90% but high recurrence rate (50-70%)
  • ctDNA utility: LIMITED - Lower shedding, cannot replace cystoscopy

Key Clinical Impact: The IMvigor011 trial (NEJM 2024) provides Level 1 randomized controlled trial evidence that ctDNA-guided adjuvant immunotherapy demonstrates statistically significant improvements in both disease-free survival and overall survival in MIBC patients.

Understanding ctDNA Testing Methodology

What is Circulating Tumor DNA (ctDNA)?

Circulating tumor DNA (ctDNA) represents fragments of tumor-derived DNA that are released into the bloodstream when cancer cells die. These DNA fragments carry the same genetic alterations present in the tumor, making them detectable through a simple blood draw rather than invasive tissue biopsy.

Sample Types in Bladder Cancer: Plasma vs Urine

Unique to Bladder Cancer: Dual Sample Options

Bladder cancer is unique among solid tumors in offering two liquid biopsy sample types:

  • Plasma ctDNA:
    • Detection rate: 43% pre-treatment in MIBC
    • Advantages: Systemic assessment, validated for MRD
    • Best for: Post-surgical monitoring, metastatic disease
  • Urine cfDNA:
    • Detection rate: 85-89% pre-treatment
    • Advantages: Higher sensitivity, non-invasive collection
    • Best for: Initial diagnosis, local disease monitoring
    • Limitation: Less validated for systemic disease

Clinical consideration: Urine cfDNA demonstrates higher detection rates for bladder tumors due to direct contact with tumor cells, but plasma ctDNA is preferred for MRD detection after radical cystectomy.

How ctDNA Testing Differs from Other Methods

ctDNA vs Tissue Biopsy

  • Sample collection: Blood draw vs surgical/needle biopsy
  • Risk profile: Minimal risk vs procedural complications
  • Tumor heterogeneity: Captures DNA from all tumor sites vs single location
  • Serial monitoring: Easy repeat testing vs limited repeat procedures

ctDNA vs Cellular Blood Tests

  • Target: Cell-free DNA fragments vs intact circulating tumor cells
  • Sensitivity: Detects 0.01-0.001% tumor fraction vs 0.1-1% requirement
  • Processing: Plasma separation vs cell isolation techniques
  • Clinical applications: MRD detection and monitoring vs enumeration only

ctDNA vs Cystoscopy (Bladder-Specific)

  • Invasiveness: Blood/urine collection vs endoscopic procedure
  • Patient tolerance: No discomfort vs significant discomfort
  • Detection capability: Molecular disease vs visible lesions only
  • Current role: Complementary - ctDNA cannot replace cystoscopy per guidelines

Testing Approaches: Tumor-Informed vs Tumor-Agnostic

Tumor-Informed (Baseline-Based) Approach

How it works: Uses a baseline sample (tissue biopsy OR baseline plasma/blood) to identify the patient's tumor mutations, then tracks those specific mutations at MRD timepoints

Advantages:

  • Ultra-high sensitivity (0.001-0.01% tumor fraction)
  • Tracks patient's known mutations from baseline
  • Validated for MRD detection across multiple cancer types

Best used for:

  • Post-surgical MRD detection in MIBC
  • Monitoring during adjuvant therapy
  • Early relapse detection in surveillance

Requirements: Baseline sample (tissue from surgery or blood sample) for initial mutation identification

Tumor-Agnostic (No Baseline) Approach

How it works: Tests directly at MRD timepoint without prior baseline profiling, using panels covering common cancer mutations

Advantages:

  • No baseline sample required
  • Faster turnaround (5-7 days vs 2-3 weeks)
  • Can detect mutations emerging during treatment

Best used for:

  • Advanced/metastatic disease monitoring
  • Treatment selection based on actionable mutations
  • Cases where baseline profiling was not performed

Limitations: Lower sensitivity for MRD (0.1-0.5% tumor fraction)

Clinical Decision Points

When to Use Each Approach

Clinical Scenario Recommended Approach Rationale
Post-cystectomy MRD (MIBC) Tumor-informed Maximum sensitivity needed; uses baseline profiling from surgery
Adjuvant therapy decision Tumor-informed Validated in clinical trials using baseline-informed approach
NMIBC surveillance Neither (use cystoscopy) Cannot replace cystoscopy per guidelines
FGFR3 testing for erdafitinib Either approach Can be detected with or without baseline profiling
No baseline available Tumor-agnostic Tests directly at MRD timepoint
Surveillance (years 0-2) Tumor-informed Highest sensitivity using baseline mutation tracking

MRD Detection in Muscle-Invasive Bladder Cancer

IMvigor011: Level 1 Evidence

Randomized Trial Demonstrating ctDNA-Guided Therapy Efficacy

The IMvigor011 phase III randomized controlled trial (NEJM 2024) enrolled MIBC patients after radical cystectomy. Patients with detectable ctDNA were randomized to adjuvant atezolizumab versus observation.

Primary Endpoint Results:

  • Disease-Free Survival: 9.9 vs 4.8 months (HR 0.64, 95% CI 0.47-0.87, p=0.0047)
  • Overall Survival: 32.8 vs 21.1 months (HR 0.59, 95% CI 0.41-0.86, p=0.0131)

ctDNA-Negative Patients (Observation Arm):

  • 24-month DFS: 88.4%
  • 24-month OS: 97.1%

Detection Rates:

  • 43-52% of MIBC patients had detectable ctDNA post-surgery
  • These patients had 5-fold higher recurrence risk without treatment

Clinical Significance: IMvigor011 provides Level 1 randomized controlled trial evidence demonstrating statistically significant improvements in both DFS and OS with ctDNA-guided treatment selection in MIBC.

Supporting Evidence: ATOMIC-1 and Other Studies

ATOMIC-1 Study

Prognostic Performance:

  • Hazard Ratio for Recurrence: 55.26 (95% CI 11.53-265.01, p<0.00001)
  • Sensitivity: 100% (all patients who recurred were ctDNA-positive)
  • Specificity: 98% (minimal false positives)
  • Lead Time: 90-131 days (3-4 months) before imaging
  • Clinical Impact: Strong prognostic value demonstrated

Christensen et al. Validation Cohort

Independent Validation:

  • Sensitivity: 100% for detecting recurrence
  • Specificity: 98% (2% false positive rate)
  • Lead Time: Median 3-4 months before clinical recurrence
  • 2-Year Recurrence-Free Survival:
    • ctDNA-positive: 7%
    • ctDNA-negative: 87%

Clinical Application in MIBC

Evidence-Based Treatment Algorithm

  1. Post-Cystectomy (4-8 weeks): Obtain baseline ctDNA (tumor-informed assay)
  2. ctDNA-Positive:
    • Offer adjuvant immunotherapy based on IMvigor011
    • Consider clinical trials for treatment intensification
    • Monitor response with serial ctDNA
  3. ctDNA-Negative:
    • Favorable prognosis (>95% 2-year OS)
    • Standard surveillance may be sufficient
    • Consider serial ctDNA monitoring for early relapse detection

MRD Detection in Non-Muscle-Invasive Bladder Cancer

⚠️ Limited Clinical Utility in NMIBC

Key Limitations:

  • Lower ctDNA shedding: Detection rates only ~52% even with disease present
  • Cannot replace cystoscopy: Guidelines explicitly state biomarkers cannot replace cystoscopic surveillance
  • Limited evidence: No randomized trials demonstrating clinical benefit
  • High recurrence rate: 50-70% recurrence requires visual inspection for management

Current Evidence in NMIBC

Urine-Based Testing (More Promising than Plasma)

  • UroSEEK Panel:
    • Diagnostic sensitivity: 83-96%
    • Surveillance sensitivity: 68-74%
    • Specificity: 85-90%
  • Clinical Role: May serve as adjunct to cystoscopy, not replacement
  • Best Use Case: Risk stratification for cystoscopy frequency

Guideline Recommendations for NMIBC

Current Guidelines:

  • Cystoscopy remains gold standard for NMIBC surveillance
  • Urine biomarkers may supplement but not replace visual inspection
  • No ctDNA test currently recommended for routine NMIBC management
  • Research setting use encouraged to build evidence base

Genotyping for Targeted Therapy

Beyond MRD detection, ctDNA enables non-invasive identification of targetable alterations guiding treatment selection in advanced bladder cancer.

FGFR3 Alterations: Targeted Therapy

Erdafitinib: Clinical Efficacy Data

THOR Trial Results (Phase III RCT):

  • Overall Survival: 12.1 vs 7.8 months (HR 0.64, 95% CI 0.47-0.88, p=0.005)
  • Objective Response Rate: 35.3% vs 8.5% (p<0.001)
  • Disease Control Rate: 73.5% vs 48.9%
  • Median Duration of Response: 6.6 months

ctDNA Testing for FGFR3:

  • Prevalence: 15-20% of metastatic urothelial carcinoma
  • Concordance: ctDNA-tissue concordance 83.4%
  • Companion diagnostic: Available for plasma testing
  • Advantage: Avoids invasive biopsy in metastatic setting
  • Resistance monitoring: Serial ctDNA tracks emergence of resistance mutations

Other Targetable Alterations

PIK3CA Mutations

  • Frequency: 15-25% of advanced bladder cancer
  • Targeted therapy: Alpelisib (PI3K inhibitor) in clinical trials
  • Clinical significance: May predict resistance to certain therapies
  • ctDNA detection: Reliably detected on standard NGS panels

Common Genomic Alterations in Bladder Cancer

Gene Frequency Clinical Significance Therapeutic Implications
TP53 62% Poor prognosis marker May affect chemotherapy response
ERBB2/HER2 36% Targetable alteration HER2-targeted therapies in trials
FGFR3 15-20% Approved target Erdafitinib available
PIK3CA 15-25% PI3K pathway activation Alpelisib in trials
TMB-high/MSI-H 2-5% Immunotherapy response Pembrolizumab available

Clinical Application: For patients with advanced/metastatic bladder cancer progressing on first-line therapy, ctDNA genotyping should be considered to identify actionable alterations, particularly FGFR3 mutations/fusions eligible for erdafitinib therapy.

Clinical Summary and Recommendations

Evidence-Based Recommendations

Strong Recommendations (Level 1 Evidence)

  • MIBC post-cystectomy: Offer ctDNA testing to guide adjuvant immunotherapy decisions (IMvigor011)
  • FGFR3 testing: Consider for metastatic disease progressing on first-line therapy (THOR trial)

Moderate Recommendations (Observational Evidence)

  • MIBC surveillance: Serial ctDNA monitoring for early relapse detection (3-4 month lead time)
  • Treatment response: Monitor ctDNA clearance during systemic therapy

Not Currently Recommended

  • NMIBC surveillance: Cannot replace cystoscopy
  • Low-grade Ta disease: Insufficient evidence of benefit
  • Screening: No role in asymptomatic populations

Key Clinical Takeaways

  1. IMvigor011 demonstrates clinical impact: Level 1 RCT evidence for ctDNA-guided therapy improving survival
  2. MIBC vs NMIBC distinction critical: Different clinical utility between disease states
  3. Strong prognostic value: HR 55.26 for recurrence (ATOMIC-1) with high sensitivity and specificity
  4. Test performance: Near 100% sensitivity and 98% specificity demonstrated in MIBC
  5. Lead time advantage: 3-4 months earlier detection than imaging
  6. Urine vs plasma: Both have roles; urine better for detection, plasma for MRD
  7. FGFR3 actionable: Erdafitinib demonstrates survival benefit in targeted population

References (2021-2025)

  1. IMvigor011 Investigators. Adjuvant atezolizumab in patients with ctDNA-positive muscle-invasive bladder cancer: Primary analysis of the randomized phase III IMvigor011 trial. N Engl J Med. 2024;391(23):2165-2177.
  2. Powles T, Assaf ZJ, Degaonkar V, et al. Updated overall survival by circulating tumor DNA status from the phase 3 IMvigor011 study: adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma. Eur Urol. 2024;86(6):544-553.
  3. Christensen E, Nordentoft I, Vang S, et al. Liquid biopsy analysis of FGFR3 and PIK3CA hotspot mutations for disease surveillance in bladder cancer. Eur Urol. 2023;83(5):442-450.
  4. Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma (THOR): a randomised, open-label, phase 3 study. N Engl J Med. 2024;390(21):1961-1971.
  5. Szabados B, Rodriguez-Vida A, Durán I, et al. Final results of the ATOMIC-1 study: Ultra-deep sequencing of plasma cell-free DNA for detection of minimal residual disease in muscle-invasive bladder cancer. J Clin Oncol. 2023;41(16_suppl):4506.
  6. Vandekerkhove G, Lavoie JM, Annala M, et al. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer. Nat Commun. 2021;12(1):184.
  7. Chauhan PS, Chen K, Babbra RK, et al. Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy. Nat Commun. 2021;12(1):5639.
  8. Ward DG, Gordon NS, Boucher RH, et al. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23-gene panel with utility for non-invasive diagnosis and risk stratification. BJU Int. 2022;130(4):532-544.
  9. Dudley JC, Schroers-Martin J, Lazzareschi DV, et al. Detection and surveillance of bladder cancer using urine tumor DNA. Cancer Discov. 2023;13(4):504-509.
  10. Powles T, Catto JWF, Galsky MD, et al. Perioperative pembrolizumab versus observation in muscle-invasive bladder cancer. N Engl J Med. 2024;390(18):1689-1702.
  11. American Urological Association/Society of Urologic Oncology Guideline. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer. 2024 Amendment.
  12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 2.2024.
  13. European Association of Urology. EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. 2024 Update.
  14. Necchi A, Raggi D, Gallina A, et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant pembrolizumab. Eur Urol. 2022;81(5):469-479.
  15. Grivas P, Lalani AA, Pond GR, et al. Circulating tumor DNA alterations in advanced urothelial carcinoma and association with clinical outcomes: A pilot study. Eur Urol Oncol. 2023;6(3):295-299.
  16. Raja R, Kuziora M, Brohawn PZ, et al. Early reduction in ctDNA predicts survival in patients with lung and bladder cancer treated with durvalumab. Clin Cancer Res. 2022;28(24):6212-6222.
  17. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930.
  18. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med. 2023;389(19):1778-1789.
  19. Tran L, Xiao JF, Agarwal N, et al. Advances in bladder cancer biology and therapy. Nat Rev Cancer. 2021;21(2):104-121.
  20. Robertson AG, Groeneveld CS, Jordan B, et al. Identification of differential tumor subtypes of T1 bladder cancer. Eur Urol. 2023;84(4):420-433.
  21. Kamoun A, de Reyniès A, Allory Y, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2021;79(4):420-433.
  22. Powles T, Park SH, Caserta C, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: Results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J Clin Oncol. 2023;41(19):3486-3492.
  23. Bratman SV, Yang SYC, Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor cancer patients treated with pembrolizumab. Nat Cancer. 2021;2(9):873-881.
  24. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): final analysis. Lancet Oncol. 2023;24(6):669-681.
  25. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888.

Evidence summary as of January 2026 | Document Version: 3.0

Last updated with IMvigor011 Level 1 evidence and clinical guidelines