Whole genome mutational analysis for tumor-informed ctDNA based MRD surveillance, treatment monitoring and biological characterization of urothelial carcinoma

Abstract

Abstract Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA at low tumor burden is limited by the number of mutations analyzed and available plasma volume. Here we applied a tumor-informed whole genome sequencing (WGS) approach for ctDNA-based MRD detection (91% sensitivity, 92% specificity) and treatment response evaluation in 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer. We show that WGS-based ctDNA detection is prognostic of patient outcomes with a median lead time of 131 days over radiographic imaging. We performed genomic characterization of post-treatment plasma samples with a high ctDNA level and observed acquisition of the platinum therapy-associated mutational signatures and copy number variations not present in the primary tumors. Our results support the use of WGS for ultra-sensitive ctDNA detection and highlight the additional possibility for plasma-based tracking of tumor evolution. Statement of significance Our study supports the clinical potential of using a WGS-based strategy for sensitive ctDNA detection in patients with MIBC. Thus, WGS-based ctDNA detection constitutes a promising option for clinical use due to low requirements for plasma input and the ease of performing WGS, eliminating the need for personalized assay design.