Cell-free urine- and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle invasive bladder cancer

Abstract

AbstractPurposeInvestigate and compare the use of plasma- and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and long-term oncological outcome in patients with muscle invasive bladder cancer.Experimental DesignWhole exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS panel capturing approx. 50 mutations per patient was designed and utilized to track tumor-derived DNA (tdDNA) in liquid biopsies. A total of 447 plasma samples, 281 urine supernatants and 123 urine pellets collected before, during and after treatment were analyzed. Patients were enrolled from 2013-2019 with a median follow-up time of 41.3 months after RC.ResultsWe identified tdDNA before initiation of NAC in 89% of urine supernatants, 85% of urine pellets and 43% of plasma samples. tdDNA levels were higher in urine supernatants and urine pellets compared to plasma samples (p<0.001). In plasma, detection of tdDNA before NAC was associated with a lower NAC response rate (p<0.001). Detection of tdDNA after NAC was associated with lower response rates in plasma, urine supernatant and urine pellet (p<0.001, p=0.03, p=0.002). tdDNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (p=0.006,p=0.002). A combined measure from plasma and urine supernatant tdDNA dynamics stratified patients by outcome (p=0.003).ConclusionsAnalysis of tdDNA in plasma and urine samples both separately and combined has potential to predict treatment response and outcome.