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Urine Tumor DNA-Informed Analysis of ctDNA in Patients with Muscle-Invasive Bladder Cancer - Expert Commentary

The presence of circulating tumor DNA (ctDNA) in patients with muscle-invasive bladder cancer (MIBC) is indicative of relapse and worsening prognosis. Due to the practical barriers to sequencing tumor samples for ctDNA measurement, medical researchers have focused efforts on developing alternative assays. BinHumaid et al. describe novel approaches to ctDNA detection using blood serum and urine. The technique relies on combining measurements made in small volumes of serum with a gene panel that detects urinary tumor DNA (utDNA) which now includes both coding and non-coding mutation spots.

The study included forty treatment-naive patients who were recently diagnosed with MIBC. All patients harbored genetic mutations. utDNA testing showed that the most frequently mutated genes were found to be TERT (90%), ADGRG6 (57%), TP53 (45%), PLEKHS1 (35%), and PIK3CA (25%). The average number of mutations in each urine sample was five and mean variant allele frequency (VAF) was 16%. The ctDNA positivity rate was 56% for T2, 64% for T3, and 80% for T4 cases; 47% for N0 versus 71% for N+ cases; and 47% for M0 versus 67% for M+ cases. The five most frequently mutated genes in ctDNA were TERT (45%), ADGRG6 (27%), TP53 (22%), PLEKHS1 (10%), and PIK3CA (7%). The detection of ctDNA was associated with worse overall survival (p = 0.017) and disease-specific survival (p = 0.012). The investigators subsequently used the GALEAS Bladder panel to test ten urine-serum sample pairs. Tissue-informed mutation using the same panel resulted in the detection of ctDNA in 60% of serum samples, which was consistent with urine-informed analyses.

The approach presented in this study is of high clinical value and can prevent the need for more invasive techniques for ctDNA detection. Conveniently, urine DNA sequencing may already be readily accessible as urine is often obtained during diagnostic procedures. This reduces practical barriers to applying this technology in the clinic.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

  1. BinHumaid FS, Goel A, Gordon NS, et al. Circulating Tumour DNA Detection By The Urine-Informed Analysis Of Archival Serum Samples From Muscle-Invasive Bladder Cancer Patients. Eur Urol. Published online January 31, 2024. doi:10.1016/j.eururo.2024.01.016