Purpose: Targeted agents and
immunotherapies promise to transform the treatment of metastatic
bladder cancer, but
therapy selection will depend on practical
tumor molecular stratification.
Circulating tumor DNA (ctDNA) is established in several solid
malignancies as a minimally invasive tool to profile the
tumor genome in real-time, but is critically underexplored in
bladder cancer.Experimental Design: We applied a combination of whole-exome sequencing and targeted sequencing across 50
bladder cancer driver genes to plasma cell-free
DNA (
cfDNA) from 51 patients with aggressive
bladder cancer, including 37 with metastatic disease.Results: The majority of patients with
metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total
cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic
bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting
chromatin modifiers such as ARID1A Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1 A novel FGFR3 gene fusion was identified in consecutive samples from one patient.Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic
bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide
therapy selection in patients with metastatic
bladder cancer. Clin
Cancer Res; 23(21); 6487-97. ©2017 AACR.