Fugitives on the run: circulating tumor cells (CTCs) in metastatic diseases

Abstract

The presence of circulating tumor cells (CTCs) in the bloodstream signals the existence of a tumor and denotes risk of metastatic spread. CTCs can be isolated and analyzed to monitor cancer progression and therapeutic response. However, CTC isolation devices have shown considerable variation in detection rates, limiting their use as a routine diagnostic and monitoring tool. In this review, we discuss recent advances in CTC detection methodologies and associated clinical studies. We provide perspective on the future direction of CTC isolation and molecular characterization towards developing reliable biomarkers that monitor disease progression or therapeutic response.

Keywords: Biomarker; Circulating tumor cells; Liquid biopsy; Metastasis.

Fig. 1

Trends in CTC evaluation. Number of clinical studies using each type of CTC evaluation between 1999 and 2017. Data were obtained from ClinicalTrials.gov by searching the terms “circulating tumor cells” and “cancer”, revealing 493 clinical programs involving CTC evaluation. The use of CTCs in clinical trials has been increasing over the past 20 years. These trials include enumeration, characterization, or a combination. Molecular characterization (blue), which encompasses genetic and proteomic characterization of CTCs, shows a steady increase and signals a trend in cancer therapeutic development

Fig. 2

Exploration of CTCs in common cancers. Number of clinical trials conducted between 1999 and 2017 evaluating CTCs in common primary cancer types (left axis, bar graph). Primary cancer types are labeled in ascending order based on the estimated number of deaths in 2018 in the U.S. [7](right axis, line graph). Red bars indicate tumors of non-epithelial origin. +Incidence not reported, excluded from SEER common cancer list

Fig. 3

Proportion of clinical studies between 1999 and 2017 using specific isolation markers (top panel) and specific techniques for enrichment/analysis (bottom panel). Lab-technique was a classification used for clinical studies in which the disclosed device was unique/not commercially available. Abbreviations: epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), cluster of differentiation 146 (CD146), prostate-specific membrane antigen (PSMA), cytokeratin 19 (CK19), isolation by size of tumor cells (ISET), reverse transcription polymerase chain reaction (RT-PCR), epithelial immunoSPOT assay (EPISPOT), fluorescence in situ hybridization (FISH)