Urinary Tumor DNA for the Detection of Field Cancerization - Expert Commentary
The cohort consisted of 136 patients with non-muscle invasive bladder cancer (NMIBC) who received treatment of at least five installations of Bacillus Calmette-Guérin (BCG). The investigators performed deep sequencing on 751 selected site biopsies (SSBs) from 70 patients over time. Samples included 662 normal tissues, 79 with dysplastic or cancerous lesions, and ten with other abnormal characteristics. Interestingly, 33% of high-impact mutations in cancer driver genes observed in tumor samples were present in normal tissues, including TP53, STAG2, and ARID1A. High field cancerization was associated with worse high-grade recurrence-free survival (HG-RFS, p = 0.029). The level of field cancerization also increased with age (p = 0.0027). High tumor mutational burden (TMB) and neoantigen load in the last tumor sample evaluated before BCG were associated with high pre-BCG levels of field cancerization (p = 0.007, p = 0.029). Deep sequencing of utDNA from 234 voided urine samples from 112 patients revealed that levels of utDNA increased with tumor stage and multiplicity. Unexpectedly, utDNA was detected in patients who did not have a diagnosed tumor. There was a significant difference in post-BCG RFS between patients with and without detectable utDNA after BCG (p = 0.048). Moreover, patients with progression to muscle-invasive bladder cancer (MIBC) after BCG also had higher levels of utDNA after BCG (p = 0.003), and the recurrence rate was positively associated with utDNA level after BCG (p < 0.001).
The investigators then compared SSB samples to urinary DNA samples. They found that mutations in SSBs were also detected in eight out of ten urine samples in the absence of a bladder tumor. Among patients with a diagnosed bladder tumor, sixteen out of eighteen urine samples had mutations detected in SSBs. Using gene expression data, the researchers determined that high CD8 T-cell exhaustion in pre-BCG tumors was associated with a high pre-BCG field cancerization level (p = 0.017) and high pre- and post-BCG levels of utDNA (p = 0.001, p = 0.043). However, pre-BCG field cancerization level was not associated with post-BCG HG-recurrence (p = 0.3), indicating low predictive value.
This study supports the feasibility of field cancerization assessment using utDNA, which is valuable for monitoring disease risk and treatment response and potentially aiding in the diagnosis of tumors. The study is limited by the relatively small number of patients for whom SSBs were available.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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