Circulating tumor DNA reveals clinically-actionable somatic genome of metastatic bladder cancer

Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), 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 under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease.</p> <p>Results: The majority of metastatic patients, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9 - 72.6%). 12% of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic BCa with 95% of patients harboring deleterious alterations to TP53, RB1 or MDM2, and 70% harbouring 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.</p> <p>Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic BCa. 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 metastatic BCa.

http://ift.tt/2ue2Swr