Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a ‘liquid biopsy’ is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment.

Punnoose EA, Atwal S, Liu W, Raja R, Fine BM, Hughes BG, Hicks RJ, Hampton GM, Amler LC, Pirzkall A, Lackner MR: Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin Cancer Res 2012;18:2391–2401.
Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1889;133:571–573.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF: Circulating tumour cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781–791.
Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ: Relationship of circulating tumour cells to tumour response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:3213–3221.
Hou JM, Greystoke A, Lancashire L, Cummings J, Ward T, Board R, Amir E, Hughes S, Krebs M, Hughes A, Ranson M, Lorigan P: Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy. Am J Pathol 2009;175:808–816.
Gallagher DJ, Milowsky MI, Ishill N, Trout A, Boyle MG, Riches J: Detection of circulating tumor cells in patients with urothelial cancer. Ann Oncol 2009;20:305–308.
De Bono JS, Scher HI, Mongomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D: Circulating tumour cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008;14:6302–6309.
Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV: Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008;359:366–377.
Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, Blackhall FH: Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 2011;20:1556–1563.
Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C: Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 2012;30:525–532.
Lecharpentier A, Vielh P, Perez-Moreno P, Planchard D, Soria JC, Farace F: Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer 2011;105:1338–1341.
Farace F, Massard C, Vimond N, Drusch F, Jacques N, Billiot F, Laplanche A, Chauchereau A, Lacroix L, Planchard D, Le Moulec S, Andre F, Fizazi K, Soria JC, Vielh P: A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Br J Cancer 2011;105:847–853.
Hofman V, Bonnetaud C, Ilie MI, Vielh P, Vignaud JM, Fléjou JF, Lantuejoul S, Piaton E, Mourad N, Butori C, Selva E, Poudenx M, Sibon S, Kelhef S, Vénissac N, Jais JP, Mouroux J, Molina TJ, Hofman P: Preoperative circulating tumour cell detection using the isolation by size of epithelial tumour cell method for patients with lung cancer is a new prognostic biomarker. Clin Cancer Res 2011;17:827–835.
Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, Ward TH, Backen A, Clack G, Hughes A, Ranson M, Blackhall FH, Dive C: Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J Thorac Oncol 2012;7:306–315.
Wittekind C, Neid M: Cancer invasion and metastasis. Oncology 2005;69(suppl 1):14–16.
Weiss L: Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev 2000;19:193–383.
Sahai E: Illuminating the metastatic process. Nat Rev Cancer 2007;7:737–749.
Fidler IJ: Metastasis: quantitative analysis of distribution and fate of tumor emboli labelled with 125I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst 1970;45:733–782.
Polyak K, Weinberg RA: Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009;9:265–273.
Thiery JP, Acloque H, Huang RY, Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871–890.
Mego M, Mani SA, Cristofanilli M: Molecular mechanisms of metastasis in breast cancer-clinincal applications. Nat Rev Clin Oncol 2010;7:693–701.
Christiansen JJ, Rajesekaran AK: Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 2006;66:8319–8326.
Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131–142.
Fizazi K, Morat L, Chauveinc L, Prapotnich D, De Crevoisier R, Escudier B, Cathelineau X, Rozet F, Vallancien G, Sabatier L, Soria JC: High detection rate of circulating tumor cells in blood of patients with prostate cancer using telomerase activity. Ann Oncol 2007;18:518–521.
Balic M, Dandachi N, Hofmann G, Samonigg H, Loibner H, Obwaller A, van der Kooi A, Tibbe AG, Doyle GV, Terstappen LW, Bauernhofer T: Comparison of two methods for enumerating circulating tumor cells in carcinoma patients. Cytometry B Clin Cytom 2005;68:25–30.
Naume B, Borgen E, Tøssvik S, Pavlak N, Oates D, Nesland JM: Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method. Cytotherapy 2004;6:244–252.
Gertler R, Rosenberg R: Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. Recent Results Cancer Res 2003;162:149–155.
Kraan J, Sleijfer S, Strijbos MH, Ignatiadis M, Peeters D, Pierga JY, Farace F, Riethdorf S, Fehm T, Zorzino L, Tibbe AG, Maestro M, Gisbert-Criado R, Denton G, de Bono JS, Dive C, Foekens JA, Gratama JW: External quality assurance of circulating tumor cell enumeration using the CellSearch system: a feasibility study. Cytometry B Clin Cytom 2011;80:112–118.
Katz RL, He W, Khanna A, Fernandez RL, Zaidi TM, Krebs M, Caraway NP, Zhang HZ, Jiang F, Spitz MR, Blowers DP, Jimenez CA, Mehran RJ, Swisher SG, Roth JA, Morris JS, Etzel CJ, El-Zein R: Genetically abnormal circulating cells in lung cancer patients: an antigen-independent fluorescence in situ hybridization-based case-control study. Clin Can Res 2010;16:3976–3987.
Hofman V, Ilie MI, Long E, Selva E, Bonnetaud C, Molina T, Vénissac N, Mouroux J, Vielh P, Hofman P: Detection of circulating tumour cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma: comparison of the efficacy of the CellSearch assay and the isolation by size of epithelial tumour cell method. Int J Cancer 2010;129:1651–1660.
Sequist LV, Bell DW, Lynch TJ, Haber DA: Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007;25:587–595.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L: Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007;450:1235–1239.
Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
Pao W, Miller V, Zakowski M: EGF receptor gene mutations are common in lung cancers from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004;101:13306–13311.
Kobayashi S, Boggon TJ, Dayaram T: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.
Kwak EL, Sordella R, Bell DW: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005;102:7665–7670.
Pao W, Miller VA, Politi KA: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
Flores LM, Kindelberger DW, Ligon AH, Capelletti M, Fiorentino M, Loda M, Cibas ES, Jänne PA, Krop IE: Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. Br J Cancer 2010;102:1495–1502.
Nadel EM: Symposium on tumor cells in the circulating blood: part I and part II. Acta Cytologica 1965;9:1–184.
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