Emerging Roles of Urine-Based Tumor DNA Analysis in Bladder Cancer Management

Chaudhuri, Aadel A.; Pellini, Bruna; Pejovic, Nadja; Chauhan, Pradeep S.; Harris, Peter K.; Szymanski, Jeffrey J.; Smith, Zachary L.; Arora, Vivek

doi:10.1200/po.20.00060

Cited by 13 publications

(12 citation statements)

References 77 publications

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“…on June 20, 2021. © 2021 American Association for Cancer clincancerres.aacrjournals.org Downloaded from development of urine-based screening and surveillance biomarkers that detect TERT promoter mutations in urinary cell free DNA to identify aggressive bladder tumors earlier (26). We also found UROMOL molecular subtypes correlated with expected clinicopathologic characteristics but were not associated with BCG response.…”

Section: Discussionmentioning

confidence: 71%

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Damrauer

Roell

Smith

et al. 2021

Clinical Cancer Research

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Translational Relevance Statement: We performed RNA-based profiling by NanoString nCounter on non-muscle invasive bladder cancer (NMIBC) clinical specimens and found that a novel expression signature of an inflamed tumor microenvironment (TME), but not molecular subtyping, was associated with improved recurrence-free survival after bacillus Calmette-Guerin (BCG) immunotherapy. We further demonstrate that immune checkpoint gene expression was not associated with higher recurrence rates after BCG. These findings were externally validated in a large RNAseq dataset of NMIBC suggesting our immune signature could be a robust predictive biomarker for BCG response and that an immunologically "cold" TME is a mechanism of resistance to BCG. Our results also raise concerns about treatment strategies combining BCG and immune checkpoint blockade in NMIBC and instead support approaches focused on modulating the TME. Our integrated transcriptomic and panel sequencing found FGFR3 overexpression and mutations to be associated with an "cold" TME, further supporting investigations into FGFR inhibitors for NMIBC.Research.

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Section: Discussionmentioning

confidence: 71%

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Damrauer

Roell

Smith

et al. 2021

Clinical Cancer Research

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“…The ROC curve for non-silent mutations achieved a sensitivity of 81% and specificity of 81% (AUC = 0.78; 95% CI: 0.62 to 0.93), whereas the ROC curve for silent mutations achieved a sensitivity of only 12% (AUC = 0.53; 95% CI: 0.35 to 0.71) ( Fig 2C ). These results indicate that non-silent mutations classify pathologic response much more accurately than silent mutations, potentially because silent mutations are more likely to represent background field effect [ 18 , 46 ].…”

Section: Resultsmentioning

confidence: 99%

“…Here we present a cohort study that demonstrates the significant correlation between utDNA MRD detected by uCAPP-Seq prior to curative-intent radical cystectomy and pathologic response determined by analysis of the surgical specimen. We demonstrated this by utDNA analysis with a focused gene panel of non-silent mutations in consensus driver genes, which indicates that association with pathologic response is strongly linked to the detection of mutations that impact the phenotype of bladder cancer and are less likely to be confounded by background field effect [ 18 , 46 ]. As expected, the most commonly mutated genes detected in urine cfDNA in our cohort were TERT and TP53 , consistent with the results of larger tumor sequencing studies [ 18 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated this by utDNA analysis with a focused gene panel of non-silent mutations in consensus driver genes, which indicates that association with pathologic response is strongly linked to the detection of mutations that impact the phenotype of bladder cancer and are less likely to be confounded by background field effect [ 18 , 46 ]. As expected, the most commonly mutated genes detected in urine cfDNA in our cohort were TERT and TP53 , consistent with the results of larger tumor sequencing studies [ 18 , 38 , 39 ]. Our approach also demonstrates an 85% level of concordance among mutations detected between tumor and utDNA for the subset of patients with tumor tissue available for analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma- and urine-based biomarkers present a promising opportunity for noninvasive management of localized bladder cancer [ 18 , 19 ]. Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) with integrated digital error suppression (iDES) is an ultrasensitive method of high-throughput sequencing used to detect circulating tumor DNA (ctDNA) [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

et al. 2021

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Background The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods and findings We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4–38.9; p = 0.02) compared to utDNA MRD–negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD–positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. Conclusions utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

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Unlocking the potential of tumor‐derived DNA in urine for cancer detection: methodological challenges and opportunities

Wever,

Steenbergen

2024

Molecular Oncology

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High cancer mortality rates and the rising cancer burden worldwide drive the development of innovative methods in order to advance cancer diagnostics. Urine contains a viable source of tumor material and allows for self‐collection from home. Biomarker testing in this liquid biopsy represents a novel approach that is convenient for patients and can be effective in detecting cancer at a curable stage. Here, we set out to provide a detailed overview of the rationale behind urine‐based cancer detection, with a focus on non‐urological cancers, and its potential for cancer diagnostics. Moreover, evolving methodological challenges and untapped opportunities for urine biomarker testing are discussed, particularly emphasizing DNA methylation of tumor‐derived cell‐free DNA. We also provide future recommendations for technical advancements in urine‐based cancer detection and elaborate on potential mechanisms involved in the transrenal transport of cell‐free DNA.

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Emerging Roles of Urine-Based Tumor DNA Analysis in Bladder Cancer Management

Abstract: Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 13 publications

References 77 publications

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

Unlocking the potential of tumor‐derived DNA in urine for cancer detection: methodological challenges and opportunities

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