Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profiled minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compared to same-patient tumour tissue obtained during invasive surgery. Patient ctDNA abundance was independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduced the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue was 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations were identified across serial ctDNA samples, concordance for serial tumor tissue was below 50%. Overall, our findings demonstrate that ctDNA analysis is a reliable and practical method for genomic profiling of mUC, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.EGA study EGAS00001004615