Clinical Translation of a Urine-Based Biomarker for the Detection of Residual Disease in Radical Cystectomy Candidates

/ABSTRACT Radical cystectomy, which is used to treat some patients with localized bladder cancer, is associated with significant lifestyle changes due to the requirement of urinary diversion through a urostomy, significant financial costs, and significant risk for perioperative surgical morbidity and mortality. Because of negative outcomes associated with radical cystectomy, and because 30-40% of patients who receive neoadjuvant chemotherapy are found to have no residual pathological disease at the time of surgery, physicians and patients have been attempting to identify patients prospectively for radical cystectomy avoidance for decades. These attempts have primarily focused on clinical assessment of residual bladder cancer after primary treatments such as cystoscopic resection, neoadjuvant chemotherapy, and intravesical therapies. Clinical assessment entails cystoscopy, cross sectional imaging, urine cytology, and clinical judgement but is well known to be unreliable (unsafe). It is foreseeable that prospective identification of patients with residual tumor using a more sensitive urine biomarker could distinguish between cystectomy candidates with residual disease and those without in order to avoid surgery in patients with pathologic complete response. To address this need, Dr. Abbosh’s lab has developed a Noninvasive Test for the Assessment of Cancerous Tumors (NTACT). This test reliably identifies patients with residual disease in patients undergoing radical cystectomy by virtue of identifying variant alleles in DNA isolated from urine using next generation sequencing. Presence of variants strongly correlates with presence of residual disease. In the UH2 portion of the proposal, (1) Urine Reference Material will be developed from bladder cancer cell lines with known mutations to be used as a positive control for all sequencing runs and to define the limit of detection of variant alleles, (2) DNA copy number and tumor tissue biomarkers will be assessed to determine whether they improve test performance, (3) inter- and intra-observer variability (i.e. precision) will be defined, (4) urine and library stability will be assessed, (5) NTACT will be orthogonally validated, (6) and compatibility with automation will be assessed. Furthermore, the UH2 phase will establish an expected turnaround time to inform its clinical utility and the finalized laboratory and data analysis protocols for clinical deployment. In the UH3 portion of the project, NTACT will be validated to the clinical endpoint, residual disease at the time of radical cystectomy, in patients undergoing surgery. As the clinical endpoint is a pathologic outcome not a survival outcome, the validation should be highly achievable in the proposed funding period given the high surgical volume at Fox Chase. As Fox Chase has now completed accrual of two clinical trials evaluating biomarker- directed radical cystectomy avoidance, we anticipate using this lab developed test in a subsequently iterative trial quickly following completion of the research. Project Number: 1UH2CA299386-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Philip Abbosh (+1 co-PI) | Institution: RESEARCH INST OF FOX CHASE CAN CTR, PHILADELPHIA, PA | Award Amount: $263,670 | Activity Code: UH2 | Study Section: Special Emphasis Panel[ZRG1 CDPT-H (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11285636