2. UroToday Home
  3. Conference Highlights
  4. ASTRO 2025
  5. ASTRO 2025 Bladder Cancer

ASTRO 2025

ASTRO 2025: Early Detection of Metastatic Progression by Circulating Tumor DNA in Patients Undergoing Bladder-Preserving Trimodality Therapy

(UroToday.com) The 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting held in San Francisco, CA, between September 28th and 30th, 2025, was host to a bladder and post-prostatectomy radiation session. Dr. Dekuang Zhao presented a study of early detection of metastatic progression using circulating tumor DNA in patients undergoing bladder-preserving trimodality therapy (TMT).

Dr. Zhao noted that the current standard of care options for patients with muscle-invasive bladder cancer (MIBC) are:

  • Neoadjuvant chemotherapy followed by radical cystectomy
  • TMT in well-selected patients 

Dr. Zhao noted that the current standard of care options for patients with muscle-invasive bladder cancer (MIBC) are: 

In well-selected patients with cT2-4N0M0 MIBC (i.e., tumors <7 cm, no or unilateral hydronephrosis, no extensive or multifocal CIS), radical cystectomy and TMT were associated with comparable metastasis-free and cancer-specific survival rates. However, distant metastatic rates remain high after either approach (~25%),1 and the early detection of metastases remains a major clinical challenge. Can we add circulating tumor DNA (ctDNA) to traditional surveillance protocols? 

In well-selected patients with cT2-4N0M0 MIBC (i.e., tumors <7 cm, no or unilateral hydronephrosis, no extensive or multifocal CIS), radical cystectomy and TMT were associated with comparable metastasis-free and cancer-specific survival rates. However, distant metastatic rates remain high after either approach (~25%),1 and the early detection of metastases remains a major clinical challenge. Can we add circulating tumor DNA (ctDNA) to traditional surveillance protocols?  

ctDNA refers to tumor-derived fragments of DNA that are released into the bloodstream and can potentially allow for:

  • Early cancer detection
  • Treatment monitoring
  • Detection of minimal residual disease
  • Surveillance 

ctDNA refers to tumor-derived fragments of DNA that are released into the bloodstream and can potentially allow for:
Prior studies have demonstrated that ctDNA positivity predicts recurrence-free and overall survivals following radical cystectomy.2,3

Prior studies have demonstrated that ctDNA positivity predicts recurrence-free and overall survivals following radical cystectomy.2,3 

Accordingly, Dr. Zhao and colleagues hypothesized that post-TMT ctDNA positivity may be an early biomarker for metastatic progression.

This was a single-center, retrospective analysis of 42 patients with MIBC who underwent TMT at the Moffitt Cancer Center between October 2019 and April 2024 and had ≥1 post-TMT ctDNA (SignateraTM) measurement available. Patients were stratified by their post-TMT ctDNA status. The study outcomes were:

  • Metastasis-free survival: Time from end of TMT to clinical detection of metastases
  • Recurrence-free survival: Time from end of TMT to either local recurrence and/or metastases

This was a single-center, retrospective analysis of 42 patients with MIBC who underwent TMT at the Moffitt Cancer Center between October 2019 and April 2024 and had ≥1 post-TMT ctDNA (SignateraTM) measurement available. Patients were stratified by their post-TMT ctDNA status. The study outcomes were:
The study cohort characteristics are summarized below. 76% of patients were male, 71% had cT2 disease, and 98% had N0 disease. 62% of patients had pure urothelial carcinoma, and 38% had urothelial carcinoma with variant histology. All patients received radiation to the bladder (median: 55 Gy) and 98% to the pelvic nodes (median: 40 Gy). Half of the patients received concurrent chemotherapy with weekly cisplatin, and the other half received bi-weekly gemcitabine. 

The study cohort characteristics are summarized below. 76% of patients were male, 71% had cT2 disease, and 98% had N0 disease. 62% of patients had pure urothelial carcinoma, and 38% had urothelial carcinoma with variant histology. All patients received radiation to the bladder (median: 55 Gy) and 98% to the pelvic nodes (median: 40 Gy). Half of the patients received concurrent chemotherapy with weekly cisplatin, and the other half received bi-weekly gemcitabine. The study cohort characteristics are summarized below. 76% of patients were male, 71% had cT2 disease, and 98% had N0 disease. 62% of patients had pure urothelial carcinoma, and 38% had urothelial carcinoma with variant histology. All patients received radiation to the bladder (median: 55 Gy) and 98% to the pelvic nodes (median: 40 Gy). Half of the patients received concurrent chemotherapy with weekly cisplatin, and the other half received bi-weekly gemcitabine.  2
Overall, 6 patients were ctDNA(+), and 36 were ctDNA(-). At a median follow-up of ~15 months (range: 100–1,555 days), metastatic progression was observed in 5/6 (83%) ctDNA(+) patients, and none of those who were ctDNA(-). The sites of metastases were the lymph nodes (n=2) and lung (n=3). Among those who were ctDNA(-), no metastases or MIBC recurrences were observed; however, 8/36 (19%) experienced a NMIBC recurrence. 

Overall, 6 patients were ctDNA(+), and 36 were ctDNA(-). At a median follow-up of ~15 months (range: 100–1,555 days), metastatic progression was observed in 5/6 (83%) ctDNA(+) patients, and none of those who were ctDNA(-). The sites of metastases were the lymph nodes (n=2) and lung (n=3). Among those who were ctDNA(-), no metastases or MIBC recurrences were observed; however, 8/36 (19%) experienced a NMIBC recurrence. 
A time-restricted analysis at 1-year post-TMT surveillance identified metastatic progression with 100% sensitivity and 95% specificity.

The Kaplan Meier estimated 1-year post-TMT metastasis-free survivals in the ctDNA(+) and ctDNA(-) groups were 22% and 100%, respectively. 

The Kaplan Meier estimated 1-year post-TMT metastasis-free survivals in the ctDNA(+) and ctDNA(-) groups were 22% and 100%, respectively.  

The median lead time with ctDNA testing (compared to cross-sectional imaging) was 57 days.

The median lead time with ctDNA testing (compared to cross sectional imaging) was 57 days.

ctDNA(+) was associated with disease recurrence. The median recurrence-free survivals were as follows:

  • ctDNA(+): 211 days
  • ctDNA(-): 1,212 days

The Kaplan Meier-estimated 1-year recurrence-free survivals in the ctDNA(+) and ctDNA(-) groups were 22% and 83%, respectively. 

The Kaplan Meier-estimated 1-year recurrence-free survivals in the ctDNA(+) and ctDNA(-) groups were 22% and 83%, respectively.  

On univariable analysis, ctDNA(+) status (HR: 6.36, 95% CI: 1.9–21.0, p=0.0024) was the only variable significantly associated with worse recurrence-free survival following TMT.

On univariable analysis, ctDNA(+) status (HR: 6.36, 95% CI: 1.9–21.0, p=0.0024) was the only variable significantly associated with worse recurrence-free survival following TMT.
Dr. Zhao concluded as follows:

  • ctDNA may serve as an early biomarker for metastatic progression following bladder-preserving trimodality therapy
  • ctDNA positivity identified metastatic progression with a positive lead time of almost two months
  • ctDNA positivity may provide an opportunity for surveillance intensification and identify patients for early salvage therapy
  • Limitations to this study included its retrospective single-institution study design and lack of upfront standardization of ctDNA assessments

Presented by: Dekuang Zhao, DO, PhD, Resident Physician, Department of Radiation Oncology, University of South Florida and Moffitt Cancer Center, Tampa, FL

Written by: Rashid K. Sayyid, MD, MSc, Urologic Oncologist, Department of Urology, The University of Arizona, @rksayyid on X during the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting, San Francisco, CA, September 28th – 30th, 2025 

References:
  1. Zlotta AR, Ballas LK, Niemierko A, et al. Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis. Lancet Oncol. 2023; 24(6):669-681.
  2. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019; 37(18):1547-1557.
  3. Lindskrog SV, Birkenkamp-Demtröder K, Nordentoft I, et al. Circulating Tumor DNA Analysis in Advanced Urothelial Carcinoma: Insights from Biological Analysis and Extended Clinical Follow-up. Clin Cancer Res. 2023; 29(23):4797-4807.