Skip to main content
Log in

Circulating Tumor Cells as Markers for Cancer Risk Assessment and Treatment Monitoring

  • Current Opinion
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Carcinomas of epithelial origin represent the majority of malignancies in Europe. A substantial number of patients develop recurrent carcinoma, which is explained by tumor-cell dissemination into distant organs, preferentially bone marrow, which often occurs prior to surgery. In contrast to disseminated tumor cells in bone marrow, for which the prognostic value has been demonstrated, the role of circulating tumor cells (CTCs) in blood is not yet completely understood. Since bone marrow aspiration is less accepted by patients than blood withdrawal, it would be highly desirable to replace bone marrow aspiration by blood analysis. Presently, a variety of seemingly promising methods for the detection and characterization of CTCs are under evaluation, including immunocytologic and molecular approaches. However, these methods still need to be proven useful in clinical studies. The majority of studies published on CTCs to date have been related to primary and metastatic breast cancer; therefore, this article mainly addresses the role of CTCs in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumor cells. Nat Rev Cancer 2008 May; 8(5): 329–40

    Article  PubMed  CAS  Google Scholar 

  2. Husemann Y, Geigl JB, Schubert F, et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008 Jan; 13(1): 58–68

    Article  PubMed  Google Scholar 

  3. Braun S, Vogl FD, Naume B, et al. A pooled analysis of bone marrow micro-metastasis in breast cancer. N Engl J Med 2005 Aug 25; 353(8): 793–802

    Article  PubMed  CAS  Google Scholar 

  4. Kasimir-Bauer S, Mayer S, Bojko P, et al. Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy. Clin Cancer Res 2001 Jun; 7(6): 1582–9

    PubMed  CAS  Google Scholar 

  5. Braun S, Kentenich C, Janni W, et al. Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol 2000 Jan; 18(1): 80–6

    PubMed  CAS  Google Scholar 

  6. Wiedswang G, Borgen E, Karesen R, et al. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 2004 Aug 15; 10(16): 5342–8

    Article  PubMed  Google Scholar 

  7. Becker S, Becker-Pergola G, Wallwiener D, et al. Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat 2006 May; 97(1): 91–6

    Article  PubMed  CAS  Google Scholar 

  8. Fehm T, Braun S, Muller V, et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 2006 Sep 1; 107(5): 885–92

    Article  PubMed  Google Scholar 

  9. Borgen E, Pantel K, Schlimok G, et al. A European interlaboratory testing of three well-known procedures for immunocytochemical detection of epithelial cells in bone marrow: results from analysis of normal bone marrow. Cytometry B Clin Cytom 2006 Nov 15; 70(6): 400–9

    PubMed  CAS  Google Scholar 

  10. Nagrath S, Sequist LV, Maheswaran S, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007 Dec 20; 450(7173): 1235–9

    Article  PubMed  CAS  Google Scholar 

  11. Pachmann K, Camara O, Kavallaris A, et al. Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 2008 Mar 10; 26(8): 1208–15

    Article  PubMed  Google Scholar 

  12. Krivacic RT, Ladanyi A, Curry DN, et al. A rare-cell detector for cancer. Proc Natl Acad Sci U S A 2004 Jul 20; 101(29): 10501–4

    Article  PubMed  CAS  Google Scholar 

  13. Hsieh HB, Marrinucci D, Bethel K, et al. High speed detection of circulating tumor cells. Biosens Bioelectron 2006 Apr 15; 21(10): 1893–9

    Article  PubMed  CAS  Google Scholar 

  14. Alix-Panabieres C, Vendrell JP, Pelle O, et al. Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem 2007 Mar; 53(3): 537–9

    Article  PubMed  CAS  Google Scholar 

  15. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004 Aug 19; 351(8): 781–91

    Article  PubMed  CAS  Google Scholar 

  16. Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006 Jul 15; 12 (14 Pt 1): 4218–24

    Article  PubMed  CAS  Google Scholar 

  17. Riethdorf S, Fritsche H, Muller V, et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res 2007 Feb 1; 13(3): 920–8

    Article  PubMed  CAS  Google Scholar 

  18. Shaffer DR, Leversha MA, Danila DC, et al. Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin Cancer Res 2007 Apr 1; 13(7): 2023–9

    Article  PubMed  CAS  Google Scholar 

  19. Bosma AJ, Weigelt B, Lambrechts AC, et al. Detection of circulating breast tumor cells by differential expression of marker genes. Clin Cancer Res 2002 Jun; 8(6): 1871–7

    PubMed  CAS  Google Scholar 

  20. Ring AE, Zabaglo L, Ormerod MG, et al. Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br J Cancer 2005 Mar 14; 92(5): 906–12

    Article  PubMed  CAS  Google Scholar 

  21. Baker MK, Mikhitarian K, Osta W, et al. Molecular detection of breast cancer cells in the peripheral blood of advanced-stage breast cancer patients using multimarker real-time reverse transcription-polymerase chain reaction and a novel porous barrier density gradient centrifugation technology. Clin Cancer Res 2003 Oct 15; 9(13): 4865–71

    PubMed  CAS  Google Scholar 

  22. Hauch S, Zimmermann S, Lankiewicz S, et al. The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients. Anticancer Res 2007 May–Jun; 27(3A): 1337–41

    PubMed  CAS  Google Scholar 

  23. Sieuwerts AM, Kraan J, Bolt J, et al. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 2009 Jan 7; 101(1): 61–6

    Article  PubMed  CAS  Google Scholar 

  24. Demel U, Tilz GP, Foeldes-Papp Z, et al. Detection of tumour cells in the peripheral blood of patients with breast cancer: development of a new sensitive and specific immunomolecular assay. J Exp Clin Cancer Res 2004 Sep; 23(3): 465–8

    PubMed  CAS  Google Scholar 

  25. Zieglschmid V, Hollmann C, Gutierrez B, et al. Combination of immuno-magnetic enrichment with multiplex RT-PCR analysis for the detection of disseminated tumor cells. Anticancer Res 2005 May–Jun; 25(3A): 1803–10

    PubMed  CAS  Google Scholar 

  26. Cristofanilli M, Broglio KR, Guarneri V, et al. Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer 2007 Feb; 7(6): 471–9

    Article  PubMed  Google Scholar 

  27. National Cancer Institute Clinical Trials (PDQ®). Phase III randomized study of treatment decision making based on levels of circulating tumor cells in women with metastatic breast cancer undergoing chemotherapy [online]. Available from URL: http://www.cancer.gov/clinicaltrials/SWOG-S0500 [Accessed 2009 Jun 9]

  28. Tewes M, Aktas B, Welt A, et al. Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat 2009 Jun; 115(3): 581–90

    Article  PubMed  Google Scholar 

  29. Vincent-Salomon A, Couturier C, Nos X, et al. HER2 gene status assessment in micrometastatic cells in bone marrow (BM) of breast cancer patients by fluorescence in situ hybridization [abstract no. 9520]. J Clin Oncol 2004; 22 (14S) [online]. Available from URL: http://meeting.ascopubs.org/cgi/content/abstract/22/14_suppl/9520 [Accessed 2009 Jun 8]

  30. Meng S, Tripathy D, Frenkel EP, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004 Dec 15; 10(24): 8152–62

    Article  PubMed  Google Scholar 

  31. Becker S, Becker-Pergola G, Fehm T, et al. HER2 expression on disseminated tumor cells from bone marrow of breast cancer patients. Anticancer Res 2005 May–Jun; 25(3B): 2171–5

    PubMed  CAS  Google Scholar 

  32. Solomayer EF, Becker S, Pergola-Becker G, et al. Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat 2006 Jul; 98(2): 179–84

    Article  PubMed  CAS  Google Scholar 

  33. Stathopoulou A, Vlachonikolis I, Mavroudis D, et al. Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol 2002 Aug 15; 20(16): 3404–12

    Article  PubMed  CAS  Google Scholar 

  34. Giatromanolaki A, Koukourakis MI, Kakolyris S, et al. Assessment of highly angiogenic and disseminated in the peripheral blood disease in breast cancer patients predicts for resistance to adjuvant chemotherapy and early relapse. Int J Cancer 2004 Feb 10; 108(4): 620–7

    Article  PubMed  CAS  Google Scholar 

  35. Gaforio JJ, Serrano MJ, Sanchez-Rovira P, et al. Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer 2003 Dec 20; 107(6): 984–90

    Article  PubMed  CAS  Google Scholar 

  36. Jotsuka T, Okumura Y, Nakano S, et al. Persistent evidence of circulating tumor cells detected by means of RT-PCR for CEA mRNA predicts early relapse: a prospective study in node-negative breast cancer. Surgery 2004 Apr; 135(4): 419–26

    Article  PubMed  Google Scholar 

  37. Pierga JY, Bonneton C, Vincent-Salomon A, et al. Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 2004 Feb 15; 10(4): 1392–400

    Article  PubMed  CAS  Google Scholar 

  38. Benoy IH, Elst H, Philips M, et al. Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 2006 Mar 13; 94(5): 672–80

    PubMed  CAS  Google Scholar 

  39. Camara O, Rengsberger M, Egbe A, et al. The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Ann Oncol 2007 Sep; 18(9): 1484–92

    Article  PubMed  CAS  Google Scholar 

  40. Pachmann K, Camara O, Kavallaris A, et al. Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring. Breast Cancer Res 2005; 7(6): R975–9

    Article  PubMed  CAS  Google Scholar 

  41. Mehes G, Witt A, Kubista E, et al. Circulating breast cancer cells are frequently apoptotic. Am J Pathol 2001 Jul; 159(1): 17–20

    Article  PubMed  CAS  Google Scholar 

  42. SUCCESS study portal [online]. Available from URL: http://www.success-studie.de/ [Accessed 2009 Jun 9]

  43. Jenderek C, Jückstock J, Schindlbeck C, et al. Minimal residual disease detection in peripheral blood of primary breast cancer patients: translational research in the SUCCESS-study [abstract no. 5019]. San Antonio Breast Cancer Symposium; 2008 Dec 10–14; San Antonio (TX) [online]. Available from URL: http://www.abstracts2view.com/sabcs/view.php?nu=SABCS08L__772&terms = [Accessed 2009 Jun 9]

  44. German Breast Group, GeparQuattro-Trial. English overview: a randomized phase III study exploring the efficacy of capecitabine given concomitantly or in sequence to EC-Doc with or without trastuzumab as neoadjuvant treatment of primary breast cancer [online]. Available from URL: http://www.germanbreastgroup.de/geparquattro/english.html [Accessed 2009 Jun 9]

  45. Pierga JY, Bidard FC, Mathiot C, et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 2008 Nov 1; 14(21): 7004–10

    Article  PubMed  CAS  Google Scholar 

  46. Hayes DF, Walker TM, Singh B, et al. Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer. Int J Oncol 2002 Nov; 21(5): 1111–7

    PubMed  CAS  Google Scholar 

  47. Braun S, Schlimok G, Heumos I, et al. ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients. Cancer Res 2001 Mar 1; 61(5): 1890–5

    PubMed  CAS  Google Scholar 

  48. Fehm T, Becker S, Duerr-Stoerzer S, et al. Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status. Breast Cancer Res 2007; 9(5): R74

    Article  PubMed  Google Scholar 

  49. Bast RC, Ravdin P, Hayes DF, et al. Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001 Mar 15; 19(6): 1865–78

    PubMed  Google Scholar 

  50. Ditsch N, Mayer B, Rolle M, et al. Estrogen receptor expression profile of disseminated epithelial tumor cells in bone marrow of breast cancer patients. Recent Results Cancer Res 2003; 162: 141–7

    Article  PubMed  CAS  Google Scholar 

  51. Fehm T, Krawczyk N, Solomayer EF, et al. ERα-status of disseminated tumor cells in bone marrow of primary breast cancer patients. Breast Cancer Res 2008; 10(5): R76

    Article  PubMed  Google Scholar 

  52. Reuben JM, Lee BN, Li C, et al. Genomic of circulating tumor cells in metastatic breast cancer [abstract no. 1002]. J Clin Oncol 2007; 25 (18S) [online]. Available from URL: http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/1002 [Accessed 2009 Jun 8]

  53. Pantel K, Schlimok G, Kutter D, et al. Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res 1991 Sep 1; 51(17): 4712–5

    PubMed  CAS  Google Scholar 

  54. Pantel K, Schlimok G, Braun S, et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993 Sep 1; 85(17): 1419–24

    Article  PubMed  CAS  Google Scholar 

  55. Italiano A, Saint-Paul MC, Caroli-Bosc FX, et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications. Ann Oncol 2005 Sep; 16(9): 1503–7

    Article  PubMed  CAS  Google Scholar 

  56. Wiedswang G, Borgen E, Schirmer C, et al. Comparison of the clinical significance of occult tumor cells in blood and bone marrow in breast cancer. Int J Cancer 2006 Apr 15; 118(8): 2013–9

    Article  PubMed  CAS  Google Scholar 

  57. Bidard FC, Vincent-Salomon A, Gomme S, et al. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 2008 Nov 1; 14(21): 7004–10

    Article  PubMed  Google Scholar 

  58. Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 2006 Oct 1; 12(19): 5615–21

    Article  PubMed  CAS  Google Scholar 

  59. Theodoropoulos PA, Polioudaki H, Sanidas E, et al. Detection of circulating tumor cells with breast cancer stem cell-like phenotype in blood samples of patients with breast cancer [abstract no. 2008]. 99th Annual Meeting, American Association for Cancer Research; 2008 Apr 12–16; San Diego (CA) [online]. Available from URL: http://aacrmeetingabstracts.org/search.dtl [Accessed 2009 Jun 8]

  60. Abraham BK, Fritz P, McClellan M, et al. Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 2005 Feb 1; 11(3): 1154–9

    PubMed  CAS  Google Scholar 

  61. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007 Nov; 1(5): 555–67

    Article  PubMed  CAS  Google Scholar 

  62. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002 Jun; 2(6): 442–54

    Article  PubMed  CAS  Google Scholar 

  63. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008 Oct; 8(10): 755–68

    Article  PubMed  CAS  Google Scholar 

  64. Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004 Aug 6; 118(3): 277–9

    Article  PubMed  CAS  Google Scholar 

  65. Watson MA, Ylagan LR, Trinkaus KM, et al. Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clin Cancer Res 2007 Sep 1; 13(17): 5001–9

    Article  PubMed  CAS  Google Scholar 

  66. Aktas B, Tewes M, Fehm T, et al. Stem cell and epithelial-mesenchymal transition markers are frequently expressed in metastatic breast cancer patients with circulating tumor cells. Breast Cancer Res. In press

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this article. The author has no conflicts of interest that are directly relevant to the content of the article.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sabine Kasimir-Bauer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kasimir-Bauer, S. Circulating Tumor Cells as Markers for Cancer Risk Assessment and Treatment Monitoring. Mol Diag Ther 13, 209–215 (2009). https://doi.org/10.1007/BF03256327

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256327

Keywords

Navigation