Whole-Genome Mutational Analysis for ctDNA Detection Shows Potential for UC

Circulating tumor DNA (ctDNA) has been utilized for the detection of minimal residual disease in solid tumors, but the success of detecting ctDNA in areas of low tumor burden is limited by the available plasma volume as well as the number of mutations analyzed. The detection of tumor DNA in blood samples from patients with urinary tract cancer is also associated with poorer outcomes.

A recent study by Iver Nordentoft, PhD, MSc, and colleagues used a tumor-informed whole-genome sequencing (WGS) approach for ctDNA-based detection of MRD in patients with urothelial carcinoma (UC) to evaluate treatment responses.

A total of 112 patients with localized muscle-invasive bladder cancer who underwent neoadjuvant chemotherapy (NAC) before radical cystectomy were enrolled in the study. From these patients, 916 plasma samples were collected and analyzed. The primary endpoint was recurrence-free survival, and overall survival and ctDNA dynamics during NAC were also analyzed.

WGS-based ctDNA detection offered a median lead time of 131 days over radiographic imaging. After radical cystectomy, it identified recurrence with a 91% sensitivity rate and a 92% specificity rate.

Genomic characterization of post-treatment plasma samples with a high ctDNA level also showed the acquisition of platinum therapy-based mutational signatures and copy number variations that were not present in the patients’ primary tumors.

While sequencing depth serves as a limitation for studying tumor evolution, these study results support the use of WGS for sensitive ctDNA detection and show potential for the plasma-based tracking of tumor evolution. With a low volume of plasma needed and ease of performance, WGS-based ctDNA testing can serve as a promising option for patients with UC.