Circulating tumor DNA (ctDNA) can be used for sensitive detection of minimal residual disease (MRD). However, the probability of detecting ctDNA in settings of low tumor burden is limited by the number of mutations analyzed and the plasma volume available. We used a whole-genome sequencing (WGS) approach for ctDNA detection in patients with urothelial carcinoma.
We used a tumor-informed WGS approach for ctDNA-based detection of MRD and evaluation of treatment responses. We analyzed 916 longitudinally collected plasma samples from 112 patients with localized muscle-invasive bladder cancer who received neoadjuvant chemotherapy (NAC) before radical cystectomy. Recurrence-free survival (primary endpoint), overall survival, and ctDNA dynamics during NAC were assessed.
We found that WGS-based ctDNA detection is prognostic for patient outcomes with a median lead time of 131 d over radiographic imaging. WGS-based ctDNA assessment after radical cystectomy identified recurrence with sensitivity of 91% and specificity of 92%. In addition, genomic characterization of post-treatment plasma samples with a high ctDNA level revealed acquisition of platinum therapy-associated mutational signatures and copy number variations not present in the primary tumors. The sequencing depth is a limitation for studying tumor evolution.
Our results support the use of WGS for ultrasensitive ctDNA detection and highlight the possibility of plasma-based tracking of tumor evolution. WGS-based ctDNA detection represents a promising option for clinical use owing to the low volume of plasma needed and the ease of performing WGS, eliminating the need for personalized assay design.
Detection of tumor DNA in blood samples from patients with cancer of the urinary tract is associated with poorer outcomes. Disease recurrence after surgery can be identified by the presence of tumor DNA in blood before it can be detected on radiography scans.
European urology. 2024 May 28 [Epub ahead of print]
Iver Nordentoft, Sia Viborg Lindskrog, Karin Birkenkamp-Demtröder, Santiago Gonzalez, Maja Kuzman, Jurica Levatic, Dunja Glavas, Ryan Ptashkin, James Smadbeck, Danielle Afterman, Tomer Lauterman, Yarin Cohen, Zohar Donenhirsh, Iman Tavassoly, Ury Alon, Amanda Frydendahl, Mads Heilskov Rasmussen, Claus Lindbjerg Andersen, Philippe Lamy, Michael Knudsen, Paz Polak, Asaf Zviran, Boris Oklander, Mads Agerbæk, Jørgen Bjerggaard Jensen, Lars Dyrskjøt
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: ., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark., C2i Genomics, New York, NY, USA., C2i Genomics, Haifa, Israel., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Department of Oncology, Aarhus University Hospital, Aarhus, Denmark., Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Urology, Aarhus University Hospital, Aarhus, Denmark., Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. Electronic address: .