Circulating Tumor Cell and Circulating Tumor DNA Assays Reveal Complementary Information for Patients with Metastatic Urothelial Cancer

Despite considerable advances in the management of urothelial carcinoma (UC), better risk stratification and enhanced detection of minimal residual disease are still urgent priorities to prolong survival while avoiding the morbidity of overtreatment. Circulating tumor cells and DNA (CTCs, ctDNA) are two biologically distinct “liquid biopsies” that may potentially address this need, although they have been understudied in UC to date and their relative utility is unknown. To this end, matched CTC and ctDNA samples were collected for a head-to-head comparison in a pilot study of 16 patients with metastatic UC. CTCs were defined as cytokeratin- and/or EpCAM-positive using the RareCyte direct imaging platform. ctDNA was assayed using the PlasmaSelect64 probe-capture assay. 75% of patients had detectable CTCs, and 73% had detectable somatic mutations, with no correlation between CTC count and ctDNA. 91% of patients had tissue confirmation of at least one plasma mutation and, importantly, several clinically actionable mutations were detected in plasma that were not found in the matching tumor. A ctDNA fraction of >2% was significantly associated with worse overall survival (p=0.039) whereas CTC detection was not (p=0.46). Notably, using a predefined gene panel for ctDNA detection had a high but not complete detection rate in metastatic UC, similar to what has been described for a custom tissue-personalized assay approach. In sum, both liquid biopsies show promise in UC and deserve further investigation.