Current Status of CTCs as Liquid Biopsy in Lung Cancer and Future Directions

Abstract

Circulating tumor cells (CTCs) have garnered a lot of attention in the past few decades. Isolation of these rare cells from the billions of blood cells has been a challenge until recent times. With the advent of new sensitive technologies that permit live cell isolation and downstream genomic analysis, the existing paradigm of CTC research has evolved to explore clinical utility of these cells. CTCs have been identified as prognostic and pharmacodynamic biomarkers in many solid tumors, including lung cancer. As a means of liquid biopsy, CTCs could play a major role in the development of personalized medicine and targeted therapies. This review discusses the state of various isolation strategies, cell separation techniques and key studies that illustrate the application of liquid biopsy to lung cancer.

Keywords: circulating tumor cells; liquid biopsy; lung cancer; non-small-cell lung cancer; prognostic biomarkers; review of literature; small-cell lung cancer.

Figure 1

Liquid biopsy of lung cancer: different applications of using CTCs as surrogate biomarkers in lung cancer.

Figure 2

Application of CTCs in lung cancer: (A) less than 5 CTCs/7.5 ml of blood predicted improved survival by CellSearch system (19). (B,C) Higher numbers of CTCs were detected in metastatic lung cancer than cancer without distant metastasis (35). (D) NSCLC CTCs were detected by ISET technology and stained positive for EGFR (36). (E) NSCLC CTCs were isolated by CellSearch system and stained positive for EGFR and CK (33). (F) Morphologic features of CTCs from different histologies of NSCLC (37). (G) CTCs were detected by HD-CTC assay and stained positive for CK (red) and negative to CD45 (green) (38). (H,I) Mutations were detected in CTCs, primary tumors, and metastatic sites. Copy number variation patterns among single CTCs, primary tumor, and metastatic sites (39). (J) ALK rearrangement patterns in CTCs and primary tumor (40). (K,L) ALK rearranged CTCs stained positive for vimentin (K) and N-Cadherin (L) (40). (M) ROS1-rearranged CTCs were compared to primary tumor (41). (N) CTCs isolated from SCLC patients generated tumor in a mouse (42). (O) CTC-derived xenografts were stained for different protein markers (42). (P) NSCLC CTCs were isolated and expanded by a microfluidic co-culture model and stained positive for CK (27).