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

Background: 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). Objective: To investigate whether the detection of plasma circulating tumor DNA (ctDNA) can predict muscle -invasive (MI) and non-organ-confined (NOC) UTUC. Design, setting, and participants: Plasma cell -free DNA was prospectively collected from chemotherapy -naive, high -risk UTUC patients undergoing surgical extirpation and sequenced using a 152 -gene panel and low-pass whole-genome sequencing. Outcome measurements and statistical analysis: 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. Results and limitations: 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 < 0.001) and cancer -specific survival (CSS; 1-yr CSS 56% vs 100%, p = 0.016). Conclusions: The detection of plasma ctDNA prior to extirpative surgery was highly predictive of MI/NOC UTUC and strongly prognostic of PFS and CSS. Preoperative ctDNA demonstrates promise as a biomarker for selecting patients to undergo neoadjuvant chemotherapy prior to nephroureterectomy.