Monitoring of plasma and urine tumor-derived DNA to inform bladder-sparing approaches for patients with muscle-invasive bladder cancer
Abstract
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 presystemic therapy (HR 4.68; 95% CI 1.10-43.35; log-rank P = 0.036). Only 4.5% (1 of 22) 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (28)
Matthew D. Galsky
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai
Sudeh Izadmehr
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai
Menggang Yu
Department of Biostatistics, University of Michigan
Samuel D. Curtis
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
Christopher Douville
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Maria Popoli
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Janine Ptak
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Lisa Dobbyn
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Natalie Silliman
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Kevin G. Chan
Department of Urology, City of Hope Comprehensive Cancer Center
Tanya B. Dorff
Department of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center
Jeremy P. Cetnar
Division of Hematology and Medical Oncology, Oregon Health and Science University
Brock O’Neil
Department of Urology, University of Utah
Anishka D’Souza
Division of Hematology and Medical Oncology, Keck School of Medicine of University of Southern California, Norris Comprehensive Cancer Center
Ronac Mamtani
Division of Hematology and Medical Oncology, University of Pennsylvania Abramson Cancer Center
Christos E. Kyriakopoulos
Division of Hematology and Medical Oncology, University of Wisconsin Carbone Cancer Center
Rachel Brody
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Evita Sadimin
Department of Pathology, City of Hope Comprehensive Cancer Center
Reza Mehrazin
Department of Urology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute
Diego Chowell
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
John Sfakianos
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
Siamak Daneshmand
Department of Urology, Keck School of Medicine of University of Southern California, Norris Comprehensive Cancer Center
Sumanta K. Pal
Department of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center
Chetan Bettegowda
Kenneth W. Kinzler
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Nickolas Papadopoulos
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Bert Vogelstein
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Yuxuan Wang