Abstract
ABSTRACTPURPOSEOptimal patient selection for neoadjuvant chemotherapy prior to surgical extirpation is limited by the inaccuracy of contemporary clinical staging methods in high-risk upper tract urothelial carcinoma (UTUC). We investigated whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive and non-organ confined (MI/NOC) UTUC.PATIENTS AND METHODSPlasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients undergoing surgical extirpation and sequenced using a 152-gene panel and low-pass whole-genome sequencing. To test for concordance, whole exome sequencing was performed on matching tumor samples. The performance of ctDNA for predicting MI/NOC UTUC was summarized using area under a receiver-operating curve and the optimal variant count threshold determined using Younden’s J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes.RESULTSOf 30 patients prospectively enrolled, 14 were found to have MI/NOC UTUC. At least one ctDNA variant was detected from 21/30 (70%) patients with 52% concordance with matching tumor samples. Detection of at least two panel-based molecular alterations provided the optimal sensitivity and specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score >6.5 achieved a sensitivity of 79% and specificity of 94% in predicting MI/NOC UTUC. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (1-yr PFS 69% vs. 100%, p<0.01) and overall survival (1-yr OS 56% vs. 100%, p<0.02).CONCLUSIONThe detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and OS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy.
Publisher
Cold Spring Harbor Laboratory