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 < 0.001) and cancer-specific survival (CSS; 1-yr CSS 56% vs 100%, p = 0.016).
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.
Here, we show that DNA from upper tract urothelial tumors can be detected in the blood prior to surgical removal of the kidney or ureter. This circulating tumor DNA can be used to predict that upper tract urothelial carcinoma is invasive into the muscular lining of the urinary tract and may help identify those patients who could benefit from chemotherapy prior to surgery.
European urology. 2023 Oct 04 [Epub ahead of print]
Heather L Huelster, Billie Gould, Elizabeth A Schiftan, Lucia Camperlengo, Facundo Davaro, Kyle M Rose, Alex C Soupir, Shidong Jia, Tiantian Zheng, Wade J Sexton, Julio Pow-Sang, Philippe E Spiess, G Daniel Grass, Liang Wang, Xuefeng Wang, Aram Vosoughi, Andrea Necchi, Joshua J Meeks, Bishoy M Faltas, Pan Du, Roger Li
Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Predicine Inc., Hayward, CA, USA., Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Department of GU Medical Oncology, IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy., Departments of Urology and Biochemistry, Northwestern University, Chicago, IL, USA., Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37802683