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 profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, 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.

Nature communications. 2021 Jan 08*** epublish ***

Gillian Vandekerkhove, Jean-Michel Lavoie, Matti Annala, Andrew J Murtha, Nora Sundahl, Simon Walz, Takeshi Sano, Sinja Taavitsainen, Elie Ritch, Ladan Fazli, Antonio Hurtado-Coll, Gang Wang, Matti Nykter, Peter C Black, Tilman Todenhöfer, Piet Ost, Ewan A Gibb, Kim N Chi, Bernhard J Eigl, Alexander W Wyatt

Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada., Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium., Department of Urology, University Hospital Tübingen, Tübingen, Germany., Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre, Tampere, Finland., Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, BC, Canada., Studienpraxis Urologie, Nuertingen, Germany., Decipher Biosciences, Inc., Vancouver, BC, Canada., Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada. ., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada. .

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