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  • Mini Review
  • OPEN ACCESS

The Role of Liquid Biopsy in the Detection, Risk Stratification, and Surveillance of Non-muscle-invasive Bladder Cancer: A Mini Review

  • Yun-Mao Gao1,#,
  • Tian-Xiang Chen1,#,
  • Hai-Tao Liang2,3,# and
  • Yun-Lin Ye1,2,3,* 
 Author information 

Abstract

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high recurrence rate and a substantial long-term surveillance burden. However, current detection and surveillance strategies rely largely on invasive cystoscopy and urine cytology, which are limited by patient discomfort, suboptimal adherence, and insufficient sensitivity, particularly for low-grade disease. This mini review examines the role of liquid biopsy in the detection, risk stratification, and surveillance of NMIBC. It summarizes current evidence on circulating tumor DNA, circulating tumor cells, exosomes and extracellular vesicles, urinary tumor DNA, and DNA methylation and protein biomarkers in blood or urine. For detection, urine-based molecular assays complement cystoscopy and cytology in the noninvasive assessment of patients with suspected bladder cancer. For risk stratification, molecular detection of residual disease and longitudinal biomarker changes help identify patients at increased risk of recurrence or progression. During surveillance, urine-based assays support earlier recurrence detection and, in selected settings, help reduce the frequency of cystoscopy. Overall, liquid biopsy is a promising minimally invasive complement to conventional NMIBC management although technical standardization and prospective clinical validation are required before routine implementation.

Keywords

Non-muscle-invasive bladder cancer, Liquid biopsy, Circulating tumor DNA, Methylation, Minimal residual disease, Urinary tumor DNA

Introduction

Bladder cancer is the tenth most common cancer worldwide, with approximately 75% of patients presenting with non-muscle-invasive bladder cancer (NMIBC; stages Ta, T1, and carcinoma in situ). Although transurethral resection of bladder tumor (TURBT) plus adjuvant intravesical therapy can control local disease, NMIBC has a 5-year recurrence rate of 50–70% and a 10–20% risk of disease progression.1-3 For high-risk disease, repeat TURBT is recommended to reduce understaging and adverse oncological outcomes. Consequently, prolonged surveillance is required, with cystoscopy and urine cytology typically scheduled every 3 months during the first 2 postoperative years.

Cystoscopy with histopathological confirmation remains the diagnostic gold standard for bladder cancer, but its limitations include invasiveness, cost, patient discomfort, and the risk of urinary tract infection. Urine cytology has good sensitivity for high-grade tumors, but its sensitivity falls below 40% for low-grade lesions.4,5 Over the past two decades, multiple noninvasive modalities, including urinary tumor protein assays and fluorescence in situ hybridization (FISH), have been developed to provide accurate, high-throughput, patient-friendly diagnostic tools for bladder cancer.6,7 More recently, advances in next-generation sequencing (NGS) have facilitated the development of liquid biopsy, a minimally invasive molecular testing strategy, as a potential adjunct across several stages of NMIBC management.8-10

Circulating tumor DNA (ctDNA) has been validated as a predictive biomarker for guiding adjuvant immunotherapy in muscle-invasive bladder cancer (MIBC), but its role in NMIBC remains incompletely defined. Notably, urine is in direct contact with urothelial lesions and can be collected less invasively than blood.11,12 This mini review examines the applications of liquid biopsy in NMIBC detection, risk stratification, and surveillance and discusses how molecular testing may inform future clinical decision-making (Fig. 1).

Potential adjunctive roles of liquid biopsy in NMIBC management.
Fig. 1  Potential adjunctive roles of liquid biopsy in NMIBC management.

The dark blue refers standard clinicopathological and guideline-based clinical decision, and bright orange refers investigational adjunct based on liquid biopsy, which cannot independently guide treatment decisions. MRD, minimal residual disease; NMIBC, non-muscle-invasive bladder cancer; TURBT, transurethral resection of bladder tumor.

Technical platforms and core biomarkers of liquid biopsy for NMIBC

Unlike blood samples, which primarily reflect systemic tumor invasion or metastatic potential, urine is a particularly relevant specimen for NMIBC liquid biopsy because it is in direct contact with bladder tumors. Major liquid biopsy biomarkers evaluated in NMIBC research include the following:

FISH: Identifies aneuploidy of chromosomes 3, 7, and 17 and loss of the 9p21 locus.

Tumor-associated proteins: Classic urinary markers include NMP22 and BLCA-1/4 but have suboptimal diagnostic specificity.

Circulating tumor cells (CTCs): Have low detection rates in localized NMIBC but may be associated with the risk of tumor progression.

DNA methylation markers: Aberrant hypermethylation of genes such as GDF15, VIM, and ZNF582 has been reported in NMIBC tissues and paired urine specimens.

Exosomes/extracellular vesicles: Contain tumor-derived RNA, proteins, lipids, and DNA and may enable dynamic monitoring of tumor-associated molecular changes.

Plasma ctDNA: Captures tumor-specific somatic mutations (e.g., FGFR3, TERT, and PIK3CA) that characterize the genomic landscape of urothelial carcinoma.

Urinary tumor DNA (utDNA): May more sensitively reflect the genomic profile and tumor burden of localized bladder lesions than blood-derived circulating nucleic acids.

These platforms have distinct technical strengths and potential clinical applications, as summarized in Table 1.

Table 1

BiomarkerTechnical platformAdvantagesLimitationsApplicable scenarios
DNA mutation markersNext-generation sequencing (NGS)Directly assesses tumor-associated driver alterations and may provide high specificityLow tumor DNA fraction in NMIBC may result in false-negative findingsPostoperative surveillance
DNA methylation markersBisulfite conversion, methylation-sensitive restriction enzymes, or other methylation-specific amplification or sequencing methodsHigh tissue specificity and greater stability than mutation detectionProvides epigenetic information only; may require integration with mutation data for comprehensive screening and surveillanceEvaluation of patients with hematuria; postoperative surveillance
ctDNATumor-informed patient-specific panels based on tumor profiling or fixed tumor-naïve panels for plasma analysisCaptures tumor-specific somatic alterations and may provide high specificityPrimarily reflects systemic tumor burden and has low sensitivity for low-burden NMIBCPostoperative recurrence and progression surveillance
utDNATumor-informed or fixed panels for analysis of tumor-derived DNA in urineRelatively simple, noninvasive urine samplingReflects intravesical tumor burden and shows interindividual variability in detection performanceInitial diagnostic evaluation and postoperative surveillance
CTCsEnrichment and detection of tumor cells from whole blood based on size, morphology, or surface markersMay reflect invasive and metastatic potentialLow detection rate and variable sensitivity in NMIBCAssessment of tumor progression risk
EV-related markersDetection of DNA, mRNA, miRNA, proteins, and lipids derived from extracellular vesiclesProvides multi-omic tumor information and may reflect tumor biology and the microenvironmentLack of standardized detection and analytical workflowsEmerging research for comprehensive tumor evaluation
Protein markersEnzyme-linked immunosorbent assay (ELISA)Simple, rapid, and low-cost detectionLimited diagnostic specificity and susceptibility to interference from urinary inflammationInitial diagnostic evaluation and surveillance
FISHDetection of aneuploidy of chromosomes 3, 7, and 17 and loss of 9p21 in urinary exfoliated cellsEstablished adjunctive assay with available clinical evidenceLow sensitivity for low-grade tumors and dependence on adequate numbers of intact exfoliated cells or nucleiAdjunctive diagnostic evaluation and surveillance

ctDNA, circulating tumor DNA; CTCs, circulating tumor cells; EVs, extracellular vesicles; FISH, fluorescence in situ hybridization; mRNA, messenger RNA; miRNA, microRNA; NMIBC, non-muscle-invasive bladder cancer; utDNA, urinary tumor DNA.

Clinical application of liquid biopsy in bladder cancer detection and primary diagnosis

Early detection and diagnostic evaluation

Although cystoscopy is the diagnostic gold standard for bladder cancer, the procedure is invasive, costly, and time-consuming and may limit acceptability as an initial diagnostic assessment in some patients. An ideal noninvasive biomarker should reliably distinguish bladder cancer from benign causes of hematuria and other urinary tract conditions with minimal patient burden.

Urinary methylation profiling is among the most mature translational approaches in this field. A prospective cohort of 254 patients (146 with newly diagnosed bladder cancer) compared the diagnostic performance of Bladder EpiCheck, a panel of 15 methylation biomarkers, with routine urine cytology.13 Bladder EpiCheck yielded a sensitivity of 73% and a specificity of 99%, substantially outperforming conventional cytology. The UriFind assay detects ONECUT2 and VIM methylation; in a prospective trial of 175 participants (109 with confirmed bladder cancer), it achieved 91.7% sensitivity and 77.3% specificity, suggesting potential as a screening assay.14

AssureMDx integrates mutations in several genes (FGFR3, TERT, OTX1, etc.) and epigenetic alterations and has reported a negative predictive value (NPV) of up to 93% for ruling out bladder cancer in patients with hematuria. A separate multitarget urine DNA study reported an NPV of 93.33%, which may help reduce unnecessary cystoscopy referrals.15,16 The Xpert Bladder Cancer Monitor measures five messenger RNA (mRNA) targets (ABL1, CRH, IGF2, UPK1B, and ANXA10) and was evaluated in a cohort of 828 patients with hematuria, with diagnostic performance benchmarked against cystoscopy and histopathology as well as cytology and UroVysion FISH.17 Xpert achieved an overall sensitivity of 78%, an NPV of 98%, and a specificity of 84%, supporting its potential to identify low-risk patients who might be candidates for reduced cystoscopy after further validation. Despite the promising diagnostic performance of several commercial urine assays, standardized operating procedures and clinical interpretation thresholds remain lacking for routine use.

By contrast, protein biomarkers and CTCs generally have lower sensitivity for early bladder cancer detection. Urinary NMP22 and bladder tumor antigen assays have reported sensitivities of 50–65% for bladder cancer diagnosis. The CellSearch platform has reported 71.4% sensitivity for metastatic urothelial carcinoma but detects CTCs in only 20% of localized NMIBC cases.6,18-20 FISH has moderate sensitivity, ranging from 59.4% to 72.0%.21 The multiplex urinary protein assay Oncuria-Detect has shown encouraging preliminary diagnostic performance.22 Among 292 patients with microscopic hematuria (22 with confirmed bladder malignancies), Oncuria-Detect achieved 82.0% sensitivity and a 97.5% NPV, compared with BladderChek (NMP22; 9.3% sensitivity and 95.4% NPV) and urine cytology (44.8% sensitivity and 97.2% NPV). Although protein biomarkers generally have lower sensitivity than epigenetic and nucleic acid assays, their rapid turnaround, low cost, and accessible sample processing may offer practical advantages. Selected studies of NMIBC detection are summarized in Table 2.13-17,22

Table 2

StudyBiomarkerNo. of patients enrolledNo. of patients with bladder cancerResultsComparator
Xpert175 mRNAs82859Sensitivity: 78%; Specificity: 84%; Positive predictive value: 27%; Negative predictive value: 98%Cytology and UroVysion
Oncuria-Detect2210 proteins29222Sensitivity: 82.0%; Specificity: 37.8%; Positive predictive value: 6.5%; Negative predictive value: 97.5%BladderChek™ and cytology
EpiCheck1315 methylation biomarkers254146Sensitivity: 73%; Specificity: 99%Cytology
UriFind142 methylation biomarkers175109Sensitivity: 91.7%; Specificity: 77.3%; Positive predictive value: 87.0%; Negative predictive value: 85%Cytology and FISH
AssureMDx153 mutations and 3 methylations20097Sensitivity: 93%; Specificity: 86%; Positive predictive value: 87%; Negative predictive value: 93%Cystoscopy (reference standard)
mt-utDNA162 mutations and 2 methylations947417Sensitivity: 91.37%; Specificity: 95.09%; Positive predictive value: 93.61%; Negative predictive value: 93.33%Cytology, the NMP22 test, and UroVysion FISH

FISH, fluorescence in situ hybridization; mRNA, messenger RNA; mt-utDNA, multitarget urinary tumor DNA; NMP22, nuclear matrix protein 22.

Advances in NGS have positioned ctDNA as a potential diagnostic modality for bladder cancer. Available evidence suggests that utDNA may have higher detection sensitivity than plasma ctDNA for localized NMIBC.23-26 Nevertheless, utDNA sequencing remains costly, whereas multiplex protein immunoassays are more accessible and less expensive. Cystoscopy with histopathological biopsy remains the definitive diagnostic standard for primary bladder cancer, although flexible cystoscopy may reduce procedural discomfort. Given its high throughput, rapid turnaround, and minimal invasiveness, liquid biopsy may have value in the diagnostic evaluation of selected high-risk or symptomatic populations.

Auxiliary molecular staging for pathological evaluation

Approximately 10–20% of initial TURBT specimens may be inaccurately staged, predominantly because of understaging of T1 lesions. Liquid biopsy may provide additional molecular information to refine pathological risk assessment. Plasma ctDNA positivity exceeds 80% in MIBC but ranges from 10% to 30% in NMIBC. Accordingly, a positive plasma ctDNA result may indicate occult muscle-invasive or otherwise high-risk disease and may prompt further clinicopathological assessment; treatment decisions should not be based on ctDNA status alone.24,27 CTC detection may provide similar adjunctive information when differentiating invasive from noninvasive urothelial tumors.20 These findings suggest that liquid biopsy may help identify clinically silent advanced disease that appears localized on cross-sectional imaging. However, large prospective trials are required before liquid biopsy can be routinely integrated into standardized NMIBC management algorithms.

Liquid biopsy for NMIBC risk stratification

Postoperative minimal residual disease (MRD) detection to guide repeat TURBT

Residual tumor after initial TURBT is common in NMIBC, with reported residual lesion rates of 31.6% for Ta tumors and 44.5% for T1 tumors.28 Major international guidelines, including those from the European Association of Urology and the American Urological Association/Society of Urologic Oncology, recommend repeat TURBT for high-risk patients with suspected residual disease, particularly those with T1 or multifocal tumors.2,3

Postoperative MRD is an important predictor of NMIBC recurrence, but molecular detection becomes more difficult at low residual tumor burdens after resection.29 One prospective analysis enrolled 50 candidates for repeat TURBT, 22 of whom had histologically confirmed residual disease; preoperative Bladder EpiCheck methylation testing yielded 78.6% specificity and a 73.3% NPV for residual tumor prediction.30 A prospective multicenter Chinese study evaluating OncoUrine, which combines mutation and methylation biomarkers, reported 77% sensitivity, 78% specificity, and an 88% NPV, with positive OncoUrine results independently predicting postoperative recurrence.31 Collectively, these studies suggest that liquid biopsy may help refine candidate selection for repeat TURBT in research settings. For this proposed application, specificity and NPV may be clinically informative; however, a negative molecular result should not override guideline-based indications for repeat resection.

In a potential future workflow, utDNA testing could help identify postoperative MRD, supporting risk-adapted evaluation after TURBT. Meanwhile, plasma ctDNA profiling may provide information on the risk of tumor progression and distant metastasis in selected NMIBC cohorts. Multiple prospective trials investigating utDNA-guided risk-adapted therapy are currently underway (www.chictr.org.cn: ChiCTR2600128255, Beijing Hospital; ClinicalTrials.gov: NCT07187635, The Second Hospital of Tianjin Medical University). In NCT07187635, patients with positive utDNA undergo repeat TURBT, whereas those with negative utDNA may omit repeat TURBT and proceed with guideline-based treatment or surveillance.

Prognostic biomarkers for recurrence and progression risk stratification

Conventional clinicopathological risk scores may not fully individualize treatment stratification, highlighting the potential value of molecular profiling for prognostic refinement. As in auxiliary staging, persistent ctDNA positivity may reflect subclinical metastatic disease that is not detected by conventional imaging.

Available studies suggest that postoperative utDNA positivity is associated with an increased risk of recurrence, although testing time points, specimen types, and assay designs vary.29 Both tumor-informed and tumor-naïve approaches have shown prognostic potential, but direct comparisons remain limited. A cohort of 52 patients with high-risk NMIBC found that longitudinal tumor-informed ctDNA monitoring identified individuals at increased risk of pathological upstaging.32 A separate study of the tumor-naïve UroAmp utDNA panel associated positive utDNA status with tumor recurrence and enabled longitudinal response monitoring during intravesical bacillus Calmette-Guérin therapy.33 Existing evidence is limited by retrospective designs and small sample sizes; large prospective treatment-focused trials are needed to validate liquid biopsy-guided NMIBC management strategies.

Dynamic postoperative surveillance guided by liquid biopsy

Approximately half of patients with NMIBC experience tumor recurrence within 5 years of TURBT, with approximately 70% of recurrences occurring within the first 2 postoperative years. Early detection and treatment of recurrence may help prevent disease progression, supporting intensive surveillance schedules for high-risk patients. However, cystoscopy and cross-sectional imaging may miss microscopic residual or recurrent lesions, and repeated cystoscopy imposes a substantial physical and psychological burden on patients.

Early detection of recurrent lesions during surveillance

Urinary methylation assays are increasingly studied for molecular recurrence monitoring, analogous to their role in primary diagnosis. Some studies suggest that molecular recurrence signals may precede abnormalities detected by imaging or cystoscopy, but the lead time varies by assay and population.29 Tumor-informed panels (e.g., Signatera), which generate patient-specific somatic mutation profiles from primary tumor tissue, have shown potential for NMIBC recurrence surveillance.27 A key limitation of tumor-informed sequencing is its inability to capture novel subclonal mutations that emerge during treatment or recurrence; tumor-naïve broad-spectrum panels may partly address this limitation by covering a wider range of recurrent clones.

A prospective study compared Bladder EpiCheck, a 15-methylation-biomarker panel, with combined cystoscopy and cytology, with recurrence confirmed histopathologically.13 In the surveillance cohort, the assay showed an overall sensitivity of 55% and a specificity of 91%; sensitivity for high-grade recurrence was 87%.

The Xpert Bladder Cancer Monitor mRNA panel was prospectively evaluated before surveillance cystoscopy, with performance compared with urine cytology and UroVysion FISH.34 Xpert achieved an overall sensitivity of 74% (95% confidence interval [CI]: 60–85) and a sensitivity of 83% (95% CI: 64–93) for high-grade lesions; the overall NPV was 93% (95% CI: 89–96), the high-grade-specific NPV was 98% (95% CI: 94–99), and overall specificity was 80% (95% CI: 73–85). Xpert had higher sensitivity and NPV than both cytology and FISH in this study.

The Oncuria-Monitor multiplex protein panel measures 10 urinary biomarkers (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGF) for recurrence surveillance.35 The study enrolled 300 patients who provided 1,248 serial urine samples; 93 patients experienced 143 recurrence events. Oncuria-Monitor achieved 85.6% sensitivity (95% CI: 78.1–92.2%) and a 93.0% NPV (95% CI: 89.2–96.4%), compared with BladderChek (NMP22; 20.0% sensitivity and 88.0% NPV) and conventional cytology (36.9% sensitivity and 91.6% NPV). Several studies have reported higher sensitivity or NPV for nucleic acid and multiplex protein assays than for cytology or FISH, although cross-study comparisons are limited by heterogeneous populations and study designs (Table 3).13,34-36

Table 3

StudyBiomarkerStudy population/samplesRecurrence dataResultsComparator
Xpert345 mRNAs23943Sensitivity: 74%; Specificity: 80%; Positive predictive value: 44%; Negative predictive value: 93%Cytology and UroVysion
Oncuria-Monitor3510 proteins300 patients; 1,248 serial urine samples93 patients; 143 recurrence eventsValidation cohort: Sensitivity: 85.6%; Specificity: 32.6%; Positive predictive value: 17.6%; Negative predictive value: 93.0%BladderChek, cytology
Marker-guided36Marker-guided surveillance algorithm105 patients in marker-guided arm; 214 randomized overall29 recurrences in marker-guided arm; 30 in standard armMarker-guided algorithm sensitivity: 81.5%Standard cystoscopy-based surveillance
EpiCheck1315-methylation biomarker138 patients; 161 urine samples116 recurrence-positive samplesSensitivity: 55%; Specificity: 91%; High-grade sensitivity: 87%Cystoscopy and cytology

mRNA, messenger RNA.

Collectively, utDNA, mRNA, and multiplex protein urine assays have shown potential for early detection of recurrent disease. Nevertheless, the clinical significance of early molecular recurrence remains incompletely defined. A phase 3 randomized trial in colorectal cancer found that adjuvant chemotherapy initiated for ctDNA-positive patients without radiographically visible lesions did not improve disease-free survival, illustrating that molecular positivity alone should not serve as an independent indication for early intensified treatment; however, extrapolation of these findings to NMIBC is uncertain.37 Key questions requiring prospective validation include (1) whether liquid biopsy-enabled early recurrence detection improves long-term oncological outcomes and (2) which intensified treatment strategies, if any, benefit patients with subclinical molecular recurrence.

De-escalation of cystoscopy frequency based on negative liquid biopsy results

Frequent long-term cystoscopy can adversely affect patient quality of life, particularly in men. The high NPV reported for some assays provides a rationale for evaluating biomarker-guided reductions in cystoscopy within defined clinical protocols.36,38 However, negative biomarker results alone do not currently establish a general schedule for reducing cystoscopy frequency.

The 2026 National Comprehensive Cancer Network Bladder Cancer Guidelines acknowledge urinary biomarkers as an adjunctive surveillance tool within prospective clinical trial frameworks.12 The prospective randomized UroFollow trial compared standard cystoscopy-only surveillance with biomarker-guided surveillance for low- and intermediate-risk NMIBC.36 Standard-of-care cystoscopy achieved 96.5% sensitivity, whereas biomarker-guided surveillance achieved 81.5% sensitivity (P = 0.1); no high-grade progressive lesions were missed in either arm, with one low-grade Ta tumor missed in the standard group and five in the biomarker group. The long-term oncological impact of missed low-grade Ta lesions remains uncertain; these findings suggest that this marker-guided surveillance algorithm may reduce cystoscopy use in selected patients with low- or intermediate-risk disease, but broader applicability requires further study.

The DaBlaCa-15 randomized noninferiority trial compared alternating Xpert urine testing and cystoscopy with quarterly standard cystoscopy in patients with high-risk NMIBC.39 After a median follow-up of 24–25 months, 43 high-grade recurrences were detected, with no apparent difference in recurrence-free survival risk between groups; the biomarker-guided arm required significantly fewer surveillance cystoscopies. Longer follow-up and larger multicenter cohorts are needed to confirm sustained noninferior oncological outcomes.

These randomized trials provide preliminary evidence supporting further evaluation of biomarker-guided reductions in cystoscopy. Multiplex protein urine assays may offer practical advantages in accessibility and cost compared with utDNA sequencing. However, no liquid biopsy platform has achieved universal consensus for standardized routine use. Tumor-informed sequencing requires paired profiling of primary tumor tissue, and standardized protocols for specimen processing, testing workflows, and result interpretation remain lacking across commercial panels.

Clinical challenges and future perspectives

Despite its potential across the NMIBC care continuum, widespread clinical adoption of liquid biopsy faces several translational barriers:

Suboptimal analytical sensitivity: Low-grade and small-volume NMIBC lesions may shed little tumor-derived nucleic acid into urine or blood, resulting in false-negative results; utDNA testing may partly mitigate this limitation.

Clonal hematopoiesis interference: False-positive plasma ctDNA findings can arise from benign hematopoietic somatic mutations (e.g., DNMT3A and TET2), necessitating matched leukocyte sequencing for signal correction.

Absence of standardized workflows: Consensus is lacking regarding preanalytical processing (urine collection and preservation), detection technology (NGS vs. droplet digital polymerase chain reaction), testing strategy (tumor-informed vs. tumor-naïve), and uniform result-interpretation thresholds.

Insufficient high-level clinical evidence: Most existing studies are retrospective and single-center; large prospective randomized controlled trials are required to determine whether biomarker-guided surveillance is noninferior to standard surveillance.

Future translational research priorities for NMIBC liquid biopsy include the following:

Develop multi-omics predictive models integrating somatic mutations, DNA methylation, proteomic, single-cell sequencing, and radiomic data to evaluate whether integration improves diagnostic accuracy.

Develop home-based urine sampling kits and point-of-care testing devices to support remote longitudinal monitoring.

Establish industry-wide standardized preanalytical, analytical, and postanalytical workflows together with unified criteria for interpreting molecular results.

Evaluate incorporation of liquid biopsy into international NMIBC diagnosis and treatment guidelines as a complementary surveillance tool rather than a replacement for cystoscopy.

Evaluate artificial intelligence and machine-learning algorithms for individualized recurrence-risk prediction and early warning.

In addition, many advanced liquid biopsy assays are costly; formal health economic and cost-effectiveness analyses are needed to define appropriate clinical scenarios for targeted use across the NMIBC care continuum.

Limitations

This mini review has several limitations. As a narrative review, it may be subject to literature-selection bias, and no formal quality assessment of the included studies was performed. Heterogeneity in patient populations, specimen types, assay platforms, positivity thresholds, and clinical endpoints limits direct comparisons across studies. In addition, some evidence comes from retrospective studies, small cohorts, or preliminary reports, and findings from MIBC or other tumor types may not be directly generalizable to NMIBC.

Conclusions

Liquid biopsy may complement current approaches to the detection, risk stratification, and surveillance of NMIBC. At the primary diagnostic stage, selected assays may help refine evaluation and, in some patients with hematuria, reduce unnecessary cystoscopy. During postoperative surveillance, MRD testing may support risk-stratified follow-up. For recurrence-risk assessment, liquid biopsy may provide additional molecular information but should not independently direct treatment. Because challenges remain regarding technical standardization and high-level prospective clinical validation, routine implementation remains premature.

Declarations

Acknowledgments

None.

Funding

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

YLY has been an editorial board member of Cancer Screening and Prevention since March 2022. The other authors declare no competing interests.

Author contributions

Conceptualization and manuscript design (YLY); literature retrieval and data collation (YMG, TXC, HTL); drafting the manuscript (YMG, TXC, HTL); interpretation of the evidence and critical revision of the manuscript (YLY); and approval of the final manuscript (YMG, TXC, HTL, YLY).

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Copyright © 2026 Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Gao YM, Chen TX, Liang HT, Ye YL. The Role of Liquid Biopsy in the Detection, Risk Stratification, and Surveillance of Non-muscle-invasive Bladder Cancer: A Mini Review. Cancer Screen Prev. Published online: Sep 8, 2026. doi: 10.14218/CSP.2026.00007.
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Article History
Received Revised Accepted Published
June 2, 2026 July 22, 2026 August 21, 2026 September 8, 2026
DOI http://dx.doi.org/10.14218/CSP.2026.00007
  • Cancer Screening and Prevention
  • pISSN 2993-6314
  • eISSN 2835-3315
  • © 2026 Xia & He Publishing Inc.
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The Role of Liquid Biopsy in the Detection, Risk Stratification, and Surveillance of Non-muscle-invasive Bladder Cancer: A Mini Review

Yun-Mao Gao, Tian-Xiang Chen, Hai-Tao Liang, Yun-Lin Ye
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