{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T23:28:11Z","timestamp":1768951691200,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,16]]},"group-title":"Oncology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>We previously reported initial results from a clinical trial testing a strategy in which patients with muscle-invasive bladder cancer (MIBC) achieving a clinical complete response after cystoscopic resection of the bladder tumor plus systemic therapy could forgo removal of their entire bladder (cystectomy). While the results were highly promising, a subset of patients omitting initial cystectomy developed recurrence highlighting the need for biomarkers to refine selection of patients for this approach. We here report long-term follow-up of these patients and investigate whether tumor DNA in the plasma (ctDNA) or urine (utDNA) could inform prognosis and the need for cystectomy. Three-year bladder-intact survival among patients with a complete clinical response following four rounds of systemic therapy was 69%. Metastatic risk was significantly higher for patients with detectable versus undetectable ctDNA pre-systemic therapy (HR 4.68; 95% CI 1.10-43.35; log-rank p=0.036). Only 4.5% of patients with undetectable baseline ctDNA developed metastatic disease. Undetectable ctDNA before or after systemic therapy was associated with extremely low metastatic risk. Urine utDNA was more sensitive than plasma ctDNA at detecting residual disease within the bladder, and detectable urine utDNA in patients with a complete clinical response was associated with shorter bladder-intact survival (HR 6.47, 95% CI 1.34-31.31; log-rank p=0.008). These findings establish the conceptual and experimental foundation for incorporating ctDNA and utDNA assays into the management of patients with MIBC, particularly with respect to the need for cystectomy.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Radical cystectomy\u2014surgical removal of the bladder and creation of permanent urinary diversion\u2014has historically been used to treat muscle-invasive bladder cancer, but is life-altering with permanent changes to urinary function, sexuality, and daily routine. We show here that systemic therapy, without cystectomy, can lead to durable remission in a subset of patients with muscle-invasive bladder cancer. Furthermore, we show that the measurement of circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA) can identify patients who are most likely to remain cancer-free following this systemic therapy and bladder-preserving approach.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.14.26344033","type":"posted-content","created":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T02:50:12Z","timestamp":1768618212000},"source":"Crossref","is-referenced-by-count":0,"title":["Monitoring of plasma and urine tumor-derived DNA to inform bladder-sparing approaches for patients with muscle-invasive bladder cancer"],"prefix":"10.64898","author":[{"given":"Matthew D.","family":"Galsky","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudeh","family":"Izadmehr","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menggang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel D.","family":"Curtis","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Douville","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Popoli","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Ptak","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Dobbyn","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Silliman","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin G.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Urology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya B.","family":"Dorff","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy P.","family":"Cetnar","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brock","family":"O\u2019Neil","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Utah, Salt Lake City, UT 84132"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anishka","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, CA 90089"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronac","family":"Mamtani","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christos E.","family":"Kyriakopoulos","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, University of Wisconsin Carbone Cancer Center, Madison, WI 53792"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Brody","sequence":"additional","affiliation":[{"name":"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evita","family":"Sadimin","sequence":"additional","affiliation":[{"name":"Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reza","family":"Mehrazin","sequence":"additional","affiliation":[{"name":"Department of Urology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Chowell","sequence":"additional","affiliation":[{"name":"Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029"},{"name":"Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 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