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Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer.

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Detecting mutant DNA in body fluids can non-invasively identify muscle-invasive bladder cancer (MIBC) treatment failure. Persistent mutant DNA during neoadjuvant chemotherapy (NAC) accurately predicts disease recurrence, offering a promising biomarker.

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Area of Science:

  • Oncology
  • Genetics
  • Biomarkers

Background:

  • Muscle-invasive bladder cancer (MIBC) presents a significant clinical challenge with limited treatment response.
  • Neoadjuvant chemotherapy (NAC) offers a survival benefit for some MIBC patients, but predicting response remains difficult.

Purpose of the Study:

  • To investigate the utility of circulating tumor DNA (ctDNA) in body fluids as a non-invasive biomarker for predicting NAC response in MIBC.
  • To assess the potential of mutant DNA (mutDNA) levels and dynamics to track tumor evolution and predict treatment outcomes.

Main Methods:

  • Collection of 248 liquid biopsy samples (plasma, urine cell pellet, urine supernatant) from 17 MIBC patients undergoing NAC.
  • Analysis of single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing.
  • Longitudinal monitoring of mutDNA levels to assess tumor heterogeneity and treatment response.

Main Results:

  • MutDNA was detected in plasma, urine cell pellet, and urine supernatant, with significantly higher levels in urine samples (p < 0.001).
  • Longitudinal mutDNA analysis revealed tumor evolution under NAC pressure, tracking distinct clones with varying sensitivities.
  • Persistent mutDNA detection during NAC was a significant predictor of disease recurrence (p = 0.003).

Conclusions:

  • Urine-based liquid biopsies are a sensitive source of mutDNA for monitoring MIBC.
  • Dynamic changes in mutDNA during NAC can reflect tumor evolution and heterogeneity.
  • Persistent mutDNA during NAC is a strong early indicator of treatment failure and disease recurrence in MIBC.