The use of circulating tumor DNA (ctDNA) as a biomarker for disease staging at diagnosis (DX), treatment response, and recurrence monitoring is an emerging field in many cancer types. In bladder cancer, the utility of ctDNA has shown promising results. Here we present a highly sensitive and specific NGS-based approach to ctDNA monitoring.
A cohort of 50 patients with locally advanced muscle-invasive bladder cancer treated with neoadjuvant chemotherapy were included prospectively. For each patient, a panel of 16 tumor-specific mutations was designed (SignateraTM RUO) based on whole-exome sequencing of tumor and germline DNA. In total, we analyzed ctDNA from longitudinally collected plasma samples from 386 time points procured at diagnosis, during treatment, at cystectomy (Cx), and during monitoring until disease recurrence or up to 2 years follow-up. Results of ctDNA analyses were compared to radiographic imaging and clinical outcomes. ctDNA from longitudinally-collected urine samples will also be analyzed for treatment response and disease recurrence.
At DX, plasma ctDNA status was strongly prognostic of recurrence-free survival. Specifically, 62% (8/13) of the ctDNA+ patients at DX recurred after neoadjuvant treatment and Cx; conversely, none (0/22) of the ctDNA- patients recurred (log-rank; p < 0.0001). In addition, a strong correlation was also observed between presence of ctDNA after CX and disease relapse. Specifically, relapse after Cx was detected in 100% (10/10) of ctDNA+ patients ∼120 days (0–245 days) prior to radiographic imaging, while 0% (0/38) of ctDNA- patients relapsed (log-rank; p < 0.0001).
We demonstrate a strong prognostic potential of ctDNA in bladder cancer at time of DX, suggesting a potential role for ctDNA in the staging of bladder cancer. Furthermore, we show ctDNA is detected in all patients with disease recurrence after Cx. Incorporation of ctDNA analysis into routine follow-up for early detection of relapse may allow earlier initiation of alternate treatment modalities.
Clinical trial identification
Legal entity responsible for the study
The National Committee on Health Research Ethics (#1302183), Denmark.
Novo Nordisk Foundation, Danish Cancer Society, Natera Inc San Carlos USA.
H. Sethi, S. Sharma, H-T. Wu, R. Swenerton, R. Salari, D. Hafez, R. Srinivasan, M. Balcioglu, S. Navarro, Z. Assaf, B. Zimmermann, J. Lin: Employee, stockownership or options to stock: Natera, Inc. All other authors have declared no conflicts of interest.