Genomic alteration and clinical significance of circulating tumor DNA in patients with advanced urothelial cancer: SCRUM-Japan monstar screen project.

This prospective study evaluated the clinical significance of circulating tumor DNA (ctDNA) profiling in patients with advanced urothelial carcinoma (aUC) using FoundationOne®Liquid CDx. A total of 133 Japanese patients (SCRUM-Japan cohort) were analyzed, including serial ctDNA sampling before and after platinum-based chemotherapy or pembrolizumab. Cross-sectional comparison was made with 1059 patients from the U.S.-based Foundation Medicine cohort (FMI cohort). The most frequent genomic alterations in the SCRUM-Japan cohort were TP53 (43%), MLL2 (26%), and TERT (19%). Compared to the FMI cohort, the prevalence of TP53 and TERT alterations was lower, while KRAS alterations were more frequent in upper tract urothelial carcinoma (UTUC) than in bladder cancer (BC) across both cohorts. High ctDNA tumor fraction (≥10%) was associated with significantly worse overall survival, and alterations in TERT, and TP53 were also linked to significantly worse prognosis. The concordance rate of gene alterations before and after chemotherapy was 61%, and 66% for pembrolizumab. In contrast, concordance between tissue and ctDNA profiling was only 46%, with ctDNA identifying additional actionable mutations not detected in tissue. These findings underscore the potential of ctDNA as a non-invasive tool for dynamic molecular monitoring and prognostication in aUC, supporting its integration into clinical practice.