Current Treatment Options in Oncology

, Volume 14, Issue 4, pp 610–622 | Cite as

Clinical Utility of Circulating Tumour Cell Detection in Non-Small-Cell Lung Cancer

  • Alberto Fusi
  • Robert Metcalf
  • Matthew Krebs
  • Caroline Dive
  • Fiona Blackhall
Lung Cancer (HA Wakelee, Section Editor)

Opinion statement

Recent years have witnessed increased interest in the detection of circulating tumour cells (CTCs) for diagnosis, monitoring, and treatment decision making in patients with cancer. Factors that have led to accelerated research in this field include advances in technologies for examination of intact CTCs, personalised medicine with treatment selection according to molecular characteristics, and continued lack of understanding of the biology of treatment resistance and metastasis. CTCs offer promise as a surrogate for tissue where there is insufficient tissue for molecular analysis and where there is a requirement to serially monitor molecular changes in cancer cells through treatment or on progression. In patients with either small cell or non-small cell lung cancer (NSCLC), there is evidence that CTC number is prognostic and that CTCs counted before and after treatment mirror treatment response. In patients with molecularly defined subtypes of NSCLC, CTCs demonstrate the same molecular changes as the cancer cells of the tumour. However, CTCs are not quite ready for “primetime” in the lung cancer clinic. There are still more questions than answers with respect to the optimal technologies for their detection and analysis, their biological significance, and their clinical utility. Despite this the current pace of progress in CTC technology development seems set to make “liquid biopsies” a clinical reality within the next decade. For the everyday clinician and clinical trialist, it will be important to maintain knowledge of the strengths and weaknesses of the technologies and evolving evidence base for CTCs as a routinely used diagnostic tool.


Circulating tumour cells NSCLC Review Biomarkers 


Conflict of Interest

Alberto Fusi, Robert Metcalf, Matthew Krebs, Caroline Dive, and Fiona Blackhall declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.PubMedCrossRefGoogle Scholar
  2. 2.
    Meropol NJ, Cohen SJ, Iannotti N, et al. Circulating tumour cells (CTC) predict progression free (PFS) and overall survival (OS) in patients with metastatic colorectal cancer. J Clin Oncol. 2007;25:4010–6.Google Scholar
  3. 3.
    Danila DC, Heller G, Gignac GA, et al. Circulating tumour cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13:7053–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Pachmann K, Camara O, Kavallaris, et al. Monitoring the response of circulating epithelial tumour cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol. 2008;26:1208–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Cristofanilli M, Hayes DF, Budd GT, et al. Circulating tumour cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol. 2005;23:1420–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Cohen SJ, Punt CJ, Iannotti N, et al. Relationship of circulating tumour cells to tumour response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol; 26:3213–3221.Google Scholar
  7. 7.
    Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumour cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.PubMedCrossRefGoogle Scholar
  8. 8.
    de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumour cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14:6302–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Yamashita J, Matsuo A, Kurusu Y, et al. Preoperative evidence of circulating tumour cells by means of reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen messenger RNA is an independent predictor of survival in non-small cell lung cancer: a prospective study. J Thorac Cardiovasc Surg. 2002;124:299–305.PubMedCrossRefGoogle Scholar
  10. 10.
    Sher YP, Shih JY, Yang PC, et al. Prognosis of non-small cell lung cancer patients by detecting circulating cancer cells in the peripheral blood with multiple marker genes. Clin Cancer Res. 2005;11:173–9.PubMedGoogle Scholar
  11. 11.
    Chen TF, Jiang GL, Fu XL, et al. CK19 mRNA expression measured by reverse-transcription polymerase chain reaction (RT-PCR) in the peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation: an independent prognostic factor. Lung Cancer. 2007;56:105–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu L, Liao GQ, He P, et al. Detection of circulating cancer cells in lung cancer patients with a panel of marker genes. Biochem Biophys Res Commun. 2008;372:756–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Yie S, Lou B, Ye S, et al. Clinical significance of detecting survivin-expressing circulating cancer cells in patients with non-small cell lung cancer. Lung Cancer. 2009;63:284–90.PubMedCrossRefGoogle Scholar
  14. 14.
    Yoon SO, Kim YT, Jung KC, et al. TTF-1 mRNA-positive circulating tumour cells in the peripheral blood predict poor prognosis in surgically resected non-small cell lung cancer patients. Lung Cancer. 2011;71:209–16.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu Z, Fusi A, Klopocki E, et al. Negative enrichment by immunomagnetic nanobeads for unbiased characterization of circulating tumour cells from peripheral blood of cancer patients. J Transl Med. 2011;9:70.PubMedCrossRefGoogle Scholar
  16. 16.
    •• Allard WJ, Matera J, Miller MC, et al. Tumour cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904. This is the first large study to evaluate systematically the accuracy and reproducibility of the CellSearch system. The prevalence of CTCs in 964 patients with metastatic carcinomas also was assessed.PubMedCrossRefGoogle Scholar
  17. 17.
    Riethdorf S, Fritsche H, Müller W, et al. Detection of circulating tumour cells in peripheral blood of patients with metastatic breast cancer: a validation study of the Cell Seach system. Clin Cancer Res. 2007;13:920–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Talasaz AH, Powell AA, Huber DE, et al. Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc Natl Acad Sci USA. 2009;106:3970–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Cann GM, Gulzar ZG, Cooper S, et al. mRNA-Seq of single prostate cancer circulating tumor cells reveals recapitulation of gene expression and pathways found in prostate cancer. PLoS One. 2012;7:e49144.PubMedCrossRefGoogle Scholar
  20. 20.
    Nagrath S, Sequist LV, Maheswaran S, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Stott SL, Hsu CH, Tsukrov DI, et al. Isolation of circulating tumour cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A. 2010;107:1832–7.CrossRefGoogle Scholar
  22. 22.
    Ozkumur E, Shah AM, Ciciliano JC, et al. Inertial focusing for tumour antigen-dependent and -independent sorting of rare circulating tumour cells. Sci Transl Med. 2013;5:179ra47.PubMedCrossRefGoogle Scholar
  23. 23.
    Hofman V, Bonnetaud C, Ilie MI, et al. 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;17:827–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Hofman V, Ilie MI, Long E, et al. 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 Cell Search Assay™ and the isolation by size of epithelial tumour cell method. Int J Cancer. 2011;129:1651–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Hou JM, Krebs M, Ward T, et al. Circulating tumour cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011;178:989–96.PubMedCrossRefGoogle Scholar
  26. 26.
    •• Krebs MG, Sloane R, Priest L, et al. Evaluation and prognostic significance of circulating tumour cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011;29:1556–63. This study showed CellSearch detected CTCs as an adverse prognostic factor in stage III-IV NSCLC. PFS and OS were significantly shorter in patients with ≥5 CTCs per 7.5 ml of blood. CTCs were an independent worse prognostic factor for PFS and OS in the multivariate analysis.PubMedCrossRefGoogle Scholar
  27. 27.
    •• Punnoose EA, Atwal S, Liu W, et al. Evaluation of circulating tumour cells and circulating tumour 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;18:2391–401. This study analysed CTCs for EGFR expression and for mutational status of a panel of genes. EGFR protein expression in CTCs was heterogeneous not associated with response or expression at primary tumour. Detected mutations in CTCs were however concordant with mutational status in matched tumour.PubMedCrossRefGoogle Scholar
  28. 28.
    •• Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359:366–77. This is the first study published that describes the potential of CTC genotypic characterization to predict tumour response and early resistance in NSCLC patients receiving EGFR-inhibitor.PubMedCrossRefGoogle Scholar
  29. 29.
    Ilie M, Long E, Butori C, et al. ALK-gene rearrangement: a comparative analysis on circulating tumour cells and tumour tissue from patients with lung adenocarcinoma. Ann Oncol. 2012;23:2907–13.PubMedCrossRefGoogle Scholar
  30. 30.
    Pailler E, Adam J, Barthélémy A, et al. Detection of circulating tumour cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2013;31:2273–81.PubMedCrossRefGoogle Scholar
  31. 31.
    Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.PubMedCrossRefGoogle Scholar
  32. 32.
    Heitzer E, Auer M, Gasch C, et al. Complex tumour genomes inferred from single circulating tumour cells by Array-CGH and next-generation sequencing. Cancer Res. 2013;73:2965–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Powell AA, Talasaz AH, Zhang H, et al. Single cell profiling of circulating tumour cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One. 2012;7:e33788.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Alberto Fusi
    • 1
  • Robert Metcalf
    • 1
    • 2
  • Matthew Krebs
    • 1
    • 2
  • Caroline Dive
    • 2
  • Fiona Blackhall
    • 1
    • 2
  1. 1.Department of Medical OncologyThe Christie NHS Foundation TrustManchesterUK
  2. 2.Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Research InstituteUniversity of ManchesterManchesterUK

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