The Clinical Validity of Urinary Pellet DNA Monitoring for the Diagnosis of Recurrent Bladder Cancer

Masakazu Abé, Hayato Hiraki, Takashi Tsuyukubo, Sadahide Ono, Shigekatsu Maekawa, Daichi Tamura et al. · 2024 · 11 citationsRead the paper

The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC. The aim of this study was to evaluate the clinical validity of monitoring urine pellet DNA (upDNA) of bladder cancer (BC) by digital PCR (dPCR) as a biomarker for early recurrence prediction, treatment efficacy evaluation, and no-recurrence corroboration. Tumor panel sequencing was first performed to select patient-unique somatic mutations to monitor both upDNA and circulating tumor DNA (ctDNA) by dPCR. For longitudinal monitoring using upDNA as well as plasma ctDNA, an average of 7.2 (range, 2 to 12) time points per case were performed with the dPCR assay for 32 previously treated and untreated patients with BC. Clinical recurrence based on imaging and urine cytology was compared using upDNA variant allele frequency (VAF) dynamics. A continuous increasing trend of upDNA VAF ≥1% was considered to indicate molecular recurrence. Most (30/32; 93.8%) cases showed at least one traceable somatic mutation. In 5 of 7 cases (71.4%) with clinical recurrence, upDNA VAF >1% was detected 7 to 15 months earlier than the imaging diagnosis. The upDNA VAF remained high after initial treatment for locally recurrent cases. The clinical validity of upDNA monitoring was confirmed with the observation that 26 of 30 cases (86.7%) were traceable. Local recurrences were not indicated by ctDNA alone. The results support the clinical validity of upDNA monitoring in the management of recurrent BC. Approximately 75% of patients with bladder cancer (BC) are diagnosed with non–muscle-invasive BC (NMIBC) and subsequently receive transurethral resection of bladder tumor (TURBT).1Babjuk M. Burger M. Capoun O. Cohen D. Compérat E.M. Dominguez Escrig J.L. Gontero P. Liedberg F. Masson-Lecomte A. Mostafid A.H. Palou J. van Rhijn B.W.G. Rouprêt M. Shariat S.F. Seisen T. Soukup V. Sylvester R.J. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ).Eur Urol. 2022; 81: 75-94Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar Among patients with high-risk BC, 75% experience recurrence within 10 years of diagnosis, with most recurrences seen within the first 2 years of diagnosis.2Chamie K. Litwin M.S. Bassett J.C. Daskivich T.J. Lai J. Hanley J.M. Konety B.R. Saigal C.S. Urologic Diseases in America ProjectRecurrence of high-risk bladder cancer: a population-based analysis.Cancer. 2013; 119: 3219-3227Crossref PubMed Scopus (236) Google Scholar The current standard of care for BC diagnosis involves cystoscopy and urine cytology at 3- or 6-month intervals for the first 2 years after TURBT.1Babjuk M. Burger M. Capoun O. Cohen D. Compérat E.M. Dominguez Escrig J.L. Gontero P. Liedberg F. Masson-Lecomte A. Mostafid A.H. Palou J. van Rhijn B.W.G. Rouprêt M. Shariat S.F. Seisen T. Soukup V. Sylvester R.J. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ).Eur Urol. 2022; 81: 75-94Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar,3Flaig T.W. Spiess P.E. Agarwal N. Bangs R. Boorjian S.A. Buyyounouski M.K. Chang S. Downs T.M. Efstathiou J.A. Friedlander T. Greenberg R.E. Guru K.A. Guzzo T. Herr H.W. Hoffman-Censits J. Hoimes C. Inman B.A. Jimbo M. Kader A.K. Lele S.M. Michalski J. Montgomery J.S. Nandagopal L. Pagliaro L.C. Pal S.K. Patterson A. Plimack E.R. Pohar K.S. Preston M.A. Sexton W.J. Siefker-Radtke A.O. Tward J. Wright J.L. Gurski L.A. Johnson-Chilla A. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology.J Natl Compr Canc Netw. 2020; 18: 329-354Crossref PubMed Google Scholar,4Powles T. Bellmunt J. Comperat E. De Santis M. Huddart R. Loriot Y. Necchi A. Valderrama B.P. Ravaud A. Shariat S.F. Szabados B. van der Heijden M.S. Gillessen S. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2022; 33: 244-258Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Urine cytology has high specificity but low sensitivity, especially for B. of carcinoma Full Text Full Text PDF PubMed Scopus Google Scholar and has to indicate recurrence and carcinoma in J.A. and cystoscopy for of carcinoma in of the Oncol. PubMed Scopus Google Scholar and and bladder tumor M.S. J. M.A. B.A. of a using the to monitor for and recurrent bladder Urol. PubMed Scopus Google M.S. V. P. E. of a tumor in the of or carcinoma of the Urol. PubMed Scopus Google Scholar for but specificity compared with V. E. and in after of recurrent carcinoma of the Urol. PubMed Scopus Google Scholar and are In BC DNA was detected in DNA that both DNA and pellet DNA but clinical as a recurrent monitoring biomarker was not K. E. S. T. S. M. M. L. in patients with bladder Urol. Full Text Full Text PDF PubMed Scopus Google J.C. J. M.S. D. J.C. M. and of bladder cancer using urine tumor PubMed Scopus Google K. N. A. K. A. L. F. L. D. M.A. Urine tumor DNA of in bladder cancer treated with a van der F. D. J. D. F. van D. T. van Rhijn N. van der Heijden M.S. Association of plasma and DNA with clinical in bladder PubMed Scopus Google K. E. M. A. S. P. M. L. treatment and in bladder cancer by Urol. Full Text Full Text PDF PubMed Scopus Google L. S. J. P. K. L. 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Rouprêt M. Shariat S.F. Seisen T. Soukup V. Sylvester R.J. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ).Eur Urol. 2022; 81: 75-94Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar,3Flaig T.W. Spiess P.E. Agarwal N. Bangs R. Boorjian S.A. Buyyounouski M.K. Chang S. Downs T.M. Efstathiou J.A. Friedlander T. Greenberg R.E. Guru K.A. Guzzo T. Herr H.W. Hoffman-Censits J. Hoimes C. Inman B.A. Jimbo M. Kader A.K. Lele S.M. Michalski J. Montgomery J.S. Nandagopal L. Pagliaro L.C. Pal S.K. Patterson A. Plimack E.R. Pohar K.S. Preston M.A. Sexton W.J. Siefker-Radtke A.O. Tward J. Wright J.L. Gurski L.A. Johnson-Chilla A. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology.J Natl Compr Canc Netw. 2020; 18: 329-354Crossref PubMed Google Scholar,4Powles T. Bellmunt J. Comperat E. De Santis M. Huddart R. Loriot Y. Necchi A. Valderrama B.P. Ravaud A. Shariat S.F. 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