Circulating Tumor Cells

Over 140 years ago, the discovery was made that tumor cells morphologically resembling those in the primary tumor of a patient can be found in the patients’ circulation (1). The notion that these cells in the circulation are probably shed from the patient’s primary tumor was confirmed upon advancement in cytogenetic techniques that demonstrated that these circulatory cells can also carry genetic abnormalities detected in primary tumors (2). However, it is only recently that these circulating tumor cells (CTCs) have started being investigated for their possible use as a marker for diagnosis or prognosis in cancer patients. The progress has been slow because CTCs are extremely rare. In addition, like primary tumors or metastatic spreads, from which they originate, these cells can be extremely heterogeneous. The development of new technologies for CTC isolation over the last decade, spurred great interest in CTCs, but the variability of these methods and the lack of reproducibility across different laboratories made data interpretation difficult (3). So far, the only validated assay, considered to produce reliable and reproducible CTC enumeration across clinical studies, is the CellSearch system (Veridex, Raritan, NJ). This technology received the U.S. Food and Drug Administration (FDA) approval to be used as an aid to monitor patients with metastatic breast, colon, and prostate cancer, due to demonstration of prognostic significance of CTCs in these indications, where changes in CTC numbers upon therapy have also been shown to be a predictive biomarker. More recently, prognostic significance of CTCs has begun to be elucidated also in non-small-cell lung carcinoma (NSCLC). Using CellSearch for CTC enumeration, Krebs and colleagues have demonstrated that metastatic NSCLC patients with fewer number of CTCs before chemotherapy (less than 5 per 7.5 mL of blood) had better overall survival compared to patients with CTCs above this cut off. Further evidence of prognostic significance of CTC number came from a study of resectable NSCLC, showing that the increased CTC number was associated with shorter disease free survival (4). Another group has addressed the utility of CTC numbers in monitoring the efficacy of standard therapy suggesting that decrease in CTCs may be indicative of early response to erlotinib and ertuzumab therapy in this study of relapse/refractory NSCLC (5). This study is an example of what is considered to be one of the most exciting clinical utilities of CTCs, also termed “liquid biopsy” that uses changes in the number of peripheral blood CTCs for real-time monitoring of response to therapy, thereby substituting the need for painful and often inaccessible biopsies of primary tumor. Clinical utility of such monitoring of therapeutic effectiveness lies in the opportunity to rapidly terminate ineffective treatment in order to prevent side effects and unnecessary costs (6), although such utility remains to be demonstrated for NSCLC. In addition, the good correlation between CTC enumeration and imaging data (obtained by PET and CT scans) in this study (5), opens a possible future clinical utility of CTCs in NSCLC as a prognostic factor that can be complementary to conventional imaging or even superior to it. CTC counts may also be used to monitor cancer recurrence/progression by substituting for a CT scan, a less patient-friendly option. However, further studies are needed to explore these possibilities and validate such clinical utilities for NSCLC. In addition to CTC enumeration, characterization of these cells can provide invaluable insight into tumor properties and the complex biology of tumor cell dissemination. A recent NSCLC study provided evidence that phenotypic analyses of CTCs are feasible, showing that cell surface expression of tyrosine kinases in CTC is possible to assess. Although the expression of EGFR on CTCs in this study was not correlated with clinical benefit (5), these results suggested that EGFR expression on the surface of CTCs may determine whether CTCs can be used as predictive biomarkers in situations where EGFR expression levels would be Clinical utility of circulating tumor cells in non-small-cell lung carcinoma: are we there yet?