Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non–organ-confined Upper Tract Urothelial Carcinoma

The detection of plasma circulating tumor DNA (ctDNA) in high-risk upper tract urothelial carcinoma prior to extirpative surgery was highly predictive of muscle-invasive and non–organ-confined staging, and strongly prognostic for progression-free and overall survival. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy. Optimal 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). To investigate whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle-invasive (MI) and non–organ-confined (NOC) UTUC. Plasma 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 the area under a receiver-operating curve, and a variant count threshold for predicting MI/NOC disease was determined by maximizing Youden’s J statistic. Kaplan-Meier methods estimated survival, and Mantel-Cox log-rank testing assessed the association between preoperative ctDNA positivity and clinical outcomes. Of 30 patients enrolled prospectively, 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 yielded 71% sensitivity at 94% specificity to predict MI/NOC UTUC. Imposing this threshold in combination with a plasma copy number burden score of >6.5 increased sensitivity to 79% at 94% specificity. Furthermore, the presence of ctDNA was strongly prognostic for progression-free survival (PFS; 1-yr PFS 69% vs 100%, p