Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Vandekerkhove, Gillian; Lavoie, Jean‐Michel; Annala, Matti; Murtha, Andrew J.; Sundahl, Nora; Walz, Juliane S.; Sano, Tsuyoshi; Taavitsainen, Sinja; Ritch, Elie; Fazli, Ladan; Hurtado-Coll, Antonio; Wang, Gang; Nykter, Matti; Black, Peter C.; Todenhöfer, Tilman; Ost, Piet; Gibb, Ewan A.; N., Kim; Eigl, Bernhard J.; Wyatt, Alexander W.

doi:10.1038/s41467-020-20493-6

Cited by 107 publications

(97 citation statements)

References 63 publications

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“…With the advent of precision and personalized medicine these constraints are becoming both more evident and limiting. Utilization of the genetic material in liquid biopsies offers solutions in a reliable, cost-effective, and minimally invasive way ( Lobo et al, 2019 ; Constâncio et al, 2020 ; Spiller et al, 2020 ; Thakral et al, 2020 ; Wang et al, 2020 ; Vandekerkhove et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Impact of Preanalytical and Analytical Methods on Cell-Free DNA Diagnostics

Krasić

Abramović

Vrtarić

et al. 2021

Front. Cell Dev. Biol.

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Section: Introductionmentioning

confidence: 99%

Impact of Preanalytical and Analytical Methods on Cell-Free DNA Diagnostics

Krasić

Abramović

Vrtarić

et al. 2021

Front. Cell Dev. Biol.

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“…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%

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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“…CtDNA analysis has multiple potential roles, including detection of treatment‐resistant clones, selection of targeted therapy, and monitoring response to therapy in several cancer types. Many patients with other metastatic genitourinary cancer types have significant ctDNA to profile genomic status in cfDNA 23‐25 . Prospective biomarker‐driven trials are currently underway for metastatic CRPC to select optimized treatments based on the results of ctDNA analysis (NCT03385655, NCT03903835, and NCT04015622) 26‐28 .…”

Section: Discussionmentioning

confidence: 99%

“…Many patients with other metastatic genitourinary cancer types have significant ctDNA to profile genomic status in cfDNA. 23 , 24 , 25 Prospective biomarker‐driven trials are currently underway for metastatic CRPC to select optimized treatments based on the results of ctDNA analysis (NCT03385655, NCT03903835, and NCT04015622). 26 , 27 , 28 However, the clinical utility of ctDNA analysis remains understudied in RCC, and RCC is reported to release the least amount of cfDNA among all the extracranial tumors.…”

Section: Discussionmentioning

confidence: 99%

Detection of von Hippel‐Lindau gene mutation in circulating cell‐free DNA for clear cell renal cell carcinoma

et al. 2021

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The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel‐Lindau gene (VHL) using a combination of digital PCR and multiplex PCR–based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell‐free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%‐4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%‐2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.

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Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Cited by 107 publications

References 63 publications

Impact of Preanalytical and Analytical Methods on Cell-Free DNA Diagnostics

Impact of Preanalytical and Analytical Methods on Cell-Free DNA Diagnostics

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

Detection of von Hippel‐Lindau gene mutation in circulating cell‐free DNA for clear cell renal cell carcinoma

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