Cancer and Metastasis Reviews

, Volume 31, Issue 3–4, pp 663–671 | Cite as

Molecular characterization of circulating tumor cells in breast cancer: challenges and promises for individualized cancer treatment

Article

Abstract

Blood testing using Circulating Tumor Cells (CTCs) has emerged as one of the hottest fields in cancer diagnosis. Research on CTCs present nowadays a challenge, as these cells are well defined targets for understanding tumour biology and improving cancer treatment. The presence of tumor cells in patient’s bone marrow or peripheral blood is an early indicator of metastasis and may signal tumor spread sooner than clinical symptoms appear and imaging results confirm a poor prognosis. CTC enumeration can serve as a “liquid biopsy” and an early marker to assess response to systemic therapy. Definition of biomarkers based on comprehensive characterization of CTCs has a strong potential to be translated to individualized targeted treatments and spare breast cancer patients unnecessary and ineffective therapies but also to reduce the costs for the health system and to downsize the extent and length of clinical studies. In this review, we briefly summarize recent studies on the molecular characterization of circulating tumor cells in breast cancer and discuss challenges and promises of CTCs for individualized cancer treatment.

Keywords

Breast cancer Cancer treatment CTC Molecular characterization Individualized treatment Liquid biopsy 

Notes

Acknowledgments

The present work was funded by SYNERGASIA 2009 PROGRAMME. This program is co-funded by the European Regional Development Fund and National Resources (project code: ONCOSEED diagnostics).

Conflict of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Pantel, K., Alix-Panabières, C., & Riethdorf, S. (2009). Cancer micrometastases. Nature Reviews Clinical Oncology, 6, 339–351.PubMedCrossRefGoogle Scholar
  2. 2.
    Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., Pantel, K., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. The New England Journal of Medicine, 353, 793–802.PubMedCrossRefGoogle Scholar
  3. 3.
    Stathopoulou, A., Vlachonikolis, I., Mavroudis, D., Perraki, M., Georgoulias, V., et al. (2002). Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. Journal of Clinical Oncology, 20, 3404–3412.PubMedCrossRefGoogle Scholar
  4. 4.
    Xenidis, N., Vlachonikolis, I., Mavroudis, D., Perraki, M., Stathopoulou, A., Lianidou, E., Georgoulias, V., et al. (2003). Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer. Annals of Oncology, 14, 849–855.PubMedCrossRefGoogle Scholar
  5. 5.
    Xenidis, N., Perraki, M., Kafousi, M., Apostolaki, S., Lianidou, E. S., Georgoulias, V., Mavroudis, D., et al. (2006). Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients. Journal of Clinical Oncology, 24, 3756–3762.PubMedCrossRefGoogle Scholar
  6. 6.
    Ignatiadis, M., Kallergi, G., Ntoulia, M., Lianidou, E., Georgoulias, V., Mavroudis, D., et al. (2008). Prognostic value of the molecular detection of circulating tumor cells using a multimarker reverse transcription-PCR assay for cytokeratin 19, mammaglobin A, and HER2 in early breast cancer. Clinical Cancer Research, 14, 2593–2600.PubMedCrossRefGoogle Scholar
  7. 7.
    Ignatiadis, M., Xenidis, N., Perraki, M., Lianidou, E., Sotiriou, C., Georgoulias, V., Mavroudis, D., et al. (2007). Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer. Journal of Clinical Oncology, 25, 5194–5202.PubMedCrossRefGoogle Scholar
  8. 8.
    Cristofanilli, M., Budd, G. T., Ellis, M. J., Allard, W. J., Terstappen, L. W., Hayes, D. F., et al. (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England Journal of Medicine, 351, 781–791.PubMedCrossRefGoogle Scholar
  9. 9.
    Xenidis, N., Ignatiadis, M., Apostolaki, S., Perraki, M., Georgoulias, V., Mavroudis, D., et al. (2009). Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. Journal of Clinical Oncology, 27, 2177–2184.PubMedCrossRefGoogle Scholar
  10. 10.
    de Bono, J. S., Scher, H. I., Montgomery, R. B., Doyle, G. V., Terstappen, L. W., Pienta, K. J., Raghavan, D., et al. (2008). Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clinical Cancer Research, 14, 6302–6309.PubMedCrossRefGoogle Scholar
  11. 11.
    Scher, H. I., Jia, X., de Bono, J. S., Fleisher, M., Pienta, K. J., Raghavan, D., & Heller, G. (2009). Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer. A reanalysis of IMMC38 trial data. The Lancet Oncology, 10, 233–239.PubMedCrossRefGoogle Scholar
  12. 12.
    Diamandis, E. P., Pantel, K., Scher, H. I., Terstappen, L., & Lianidou, E. (2011). Circulating cancer cells and their clinical applications. Clinical Chemistry, 57, 1478–1484.PubMedCrossRefGoogle Scholar
  13. 13.
    Meng, S., Tripathy, D., Shete, S., Ashfaq, R., Haley, B., Uhr, J., et al. (2004). HER-2 gene amplification can be acquired as breast cancer progresses. Proceedings of the National Academy of Sciences of the United States of America, 101, 9393–9398.PubMedCrossRefGoogle Scholar
  14. 14.
    Bozionellou, V., Mavroudis, D., Perraki, M., Stathopoulou, A., Lianidou, E., Georgoulias, V., et al. (2004). Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clinical Cancer Research, 10, 8185–8194.PubMedCrossRefGoogle Scholar
  15. 15.
    Korkaya, H., & Wicha, M. S. (2009). HER-2, notch, and breast cancer stem cells: targeting an axis of evil. Clinical Cancer Research, 15, 1845–1847.PubMedCrossRefGoogle Scholar
  16. 16.
    Maheswaran, S., Sequist, L. V., Nagrath, S., et al. (2008). Detection of mutations in EGFR in circulating lung-cancer cells. The New England Journal of Medicine, 359, 366–377.PubMedCrossRefGoogle Scholar
  17. 17.
    Fehm, T., Braun, S., Muller, V., Janni, W., Naume, B., Pantel, K., Solomayer, E., et al. (2006). A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer, 107, 885–892.PubMedCrossRefGoogle Scholar
  18. 18.
    Ring, A. E., Zabaglo, L., Ormerod, M. G., Smith, I. E., & Dowsett, M. (2005). Detection of circulating epithelial cells in the blood of patients with breast cancer. Comparison of three techniques. British Journal of Cancer, 92, 906–912.PubMedCrossRefGoogle Scholar
  19. 19.
    Reinholz, M. M., Nibbe, A., Jonart, L. M., Houghton, R., Zehentner, B., Roche, P. C., Lingle, W. L., et al. (2005). Evaluation of a panel of tumor markers for molecular detection of circulating cancer cells in women with suspected breast cancer. Clinical Cancer Research, 11, 3722–3732.PubMedCrossRefGoogle Scholar
  20. 20.
    Stathopoulou, A., Gizi, A., Perraki, M., Apostolaki, S., Georgoulias, V., Lianidou, E. S., et al. (2003). Real-time quantification of CK-19 mRNA-positive cells in peripheral blood of breast cancer patients using the Lightcycler system. Clinical Cancer Research, 9, 5145–5151.PubMedGoogle Scholar
  21. 21.
    Stathopoulou, A., Ntoulia, M., Perraki, M., Malamos, N., Georgoulias, V., Lianidou, E. S., et al. (2006). A highly specific real-time RT-PCR method for the quantitative determination of CK-19 mRNA positive cells in peripheral blood of patients with operable breast cancer. International Journal of Cancer, 119, 1654–1659.CrossRefGoogle Scholar
  22. 22.
    Raynor, M. P., Stephenson, S. A., Pittman, K. B., Walsh, D. C., Henderson, M. A., & Dobrovic, A. (2009). Identification of circulating tumour cells in early stage breast cancer patients using multi marker immunobead RT-PCR. Journal of Hematology & Oncology, 2, 24–35.CrossRefGoogle Scholar
  23. 23.
    Riethdorf, S., Fritsche, H., Müller, V., Cristofanilli, M., Pantel, K., et al. (2007). Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer. A validation study of the Cell Search system. Clinical Cancer Research, 13, 920–928.PubMedCrossRefGoogle Scholar
  24. 24.
    Kallergi, G., Markomanolaki, H., Strati, A., Lianidou, E. S., Georgoulias, V., Mavroudis, D., Agelaki, S., et al. (2009). Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Research, 11, R84.PubMedCrossRefGoogle Scholar
  25. 25.
    Zheng, S., Lin, H., Liu, J. Q., Balic, M., Datar, R., Cote, R. J., & Tai, Y. C. (2007). Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. Journal of Chromatography. A, 1162, 154–161.PubMedCrossRefGoogle Scholar
  26. 26.
    Nagrath, S., Sequist, L. V., Maheswaran, S., Kwak, E. L., Toner, M., et al. (2007). Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature, 450, 1235–1239.PubMedCrossRefGoogle Scholar
  27. 27.
    Lianidou, E. S., & Markou, A. (2011). Circulating tumor cells (CTC) in breast cancer: detection systems, molecular characterization and future challenges. Clinical Chemistry, 57, 1242–1255.PubMedCrossRefGoogle Scholar
  28. 28.
    Lianidou, E. S., & Markou, A. (2011). Circulating tumor cells as emerging tumor biomarkers in breast cancer. Clinical Chemistry and Laboratory Medicine, 49, 1579–1590.PubMedCrossRefGoogle Scholar
  29. 29.
    Cao, S., Li, Y., Li, J., Li, C. F., Zhang, W., Yang, Z. Q., et al. (2010). Quantitative determination of HER2 expression by confocal microscopy assay in CTCs of breast cancer. Oncology Reports, 23, 423–428.PubMedGoogle Scholar
  30. 30.
    Fehm, T., Hoffmann, O., Aktas, B., Becker, S., Solomayer, E. F., Wallwiener, D., et al. (2009). Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Research, 11, R59.PubMedCrossRefGoogle Scholar
  31. 31.
    Fehm, T., Müller, V., Aktas, B., Janni, W., Schneeweiss, A., Stickeler, E., et al. (2010). HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Research and Treatment, 124, 403–412.PubMedCrossRefGoogle Scholar
  32. 32.
    Tewes, M., Aktas, B., Welt, A., Mueller, S., Hauch, S., Kimmig, R., et al. (2009). 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 Research and Treatment, 115, 581–590.PubMedCrossRefGoogle Scholar
  33. 33.
    Riethdorf, S., Müller, V., Zhang, L., Rau, T., Loibl, S., Komor, M., et al. (2010). Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clinical Cancer Research, 16(9), 2634–2645.PubMedCrossRefGoogle Scholar
  34. 34.
    Ignatiadis, M., Rothé, F., Chaboteaux, C., Durbecq, V., Rouas, G., Criscitiello, C., et al. (2011). HER2-positive circulating tumor cells in breast cancer. PloS One, 6, e15624.PubMedCrossRefGoogle Scholar
  35. 35.
    Flores, L. M., Kindelberger, D. W., Ligon, A. H., Capelletti, M., Fiorentino, M., Loda, M., et al. (2010). Improving the yield of circulating tumour cells facilitates molecular characterisation and recognition of discordant HER2 amplification in breast cancer. British Journal of Cancer, 102, 1495–1502.PubMedCrossRefGoogle Scholar
  36. 36.
    Pestrin, M., Bessi, S., Galardi, F., Truglia, M., Biggeri, A., Biagioni, C., Cappadona, S., Biganzoli, L., Giannini, A., & Di Leo, A. (2009). Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Research and Treatment, 118(3), 523–530.PubMedCrossRefGoogle Scholar
  37. 37.
    Sieuwerts, A. M., Mostert, B., Bolt-de Vries, J., Peeters, D., de Jongh, F. E., Stouthard, J. M., Dirix, L. Y., van Dam, P. A., Van Galen, A., de Weerd, V., Kraan, J., van der Spoel, P., Ramírez-Moreno, R., van Deurzen, C. H., Smid, M., Yu, J. X., Jiang, J., Wang, Y., Gratama, J. W., Sleijfer, S., Foekens, J. A., & Martens, J. W. (2011). mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clinical Cancer Research, 17(11), 3600–3618.PubMedCrossRefGoogle Scholar
  38. 38.
    Punnoose, E. A., Atwal, S. K., Spoerke, J. M., Savage, H., Pandita, A., Yeh, R. F., Pirzkall, A., Fine, B. M., Amler, L. C., Chen, D. S., Lackner, MR. (2010). Molecular biomarker analyses using circulating tumor cells. PLoS One, 5(9).Google Scholar
  39. 39.
    Aktas, B., Müller, V., Tewes, M., Zeitz, J., Kasimir-Bauer, S., Loehberg, C. R., Rack, B., Schneeweiss, A., & Fehm, T. (2011). Comparison of estrogen and progesterone receptor status of circulating tumor cells and the primary tumor in metastatic breast cancer patients. Gynecologic Oncology, 122(2), 356–360.PubMedCrossRefGoogle Scholar
  40. 40.
    Banys, M., Krawczyk, N., Becker, S., Jakubowska, J., Staebler, A., Wallwiener, D., Fehm, T., & Rothmund, R. (2011). The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. Breast Cancer Research and Treatment, 132, 121–129.PubMedCrossRefGoogle Scholar
  41. 41.
    Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial–mesenchymal transition. The Journal of Clinical Investigation, 119(6), 1420–1428.PubMedCrossRefGoogle Scholar
  42. 42.
    Sleeman, J. P., & Thiery, J. P. (2011). SnapShot: the epithelial–mesenchymal transition. Cell, 145(1), 162.PubMedCrossRefGoogle Scholar
  43. 43.
    Bonnomet, A., Brysse, A., Tachsidis, A., Waltham, M., Thompson, E. W., Polette, M., et al. (2010). Epithelial-to-mesenchymal transitions and circulating tumor cells. Journal of Mammary Gland Biology and Neoplasia, 15, 261–273.PubMedCrossRefGoogle Scholar
  44. 44.
    Balic, M., Williams, A., Dandachi, N., & Cote, R. J. (2011). Micrometastasis: detection methods and clinical importance. Cancer Biomarkers, 9(1–6), 397–419.Google Scholar
  45. 45.
    Balic, M., Lin, H., Young, L., Hawes, D., Giuliano, A., McNamara, G., et al. (2006). Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clinical Cancer Research, 12, 5615–5621.PubMedCrossRefGoogle Scholar
  46. 46.
    Aktas, B., Tewes, M., Fehm, T., Hauch, S., Kimmig, R., & Kasimir-Bauer, S. (2009). Stem cell and epithelial–mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Research, 11(4), R46.PubMedCrossRefGoogle Scholar
  47. 47.
    Theodoropoulos, P. A., Polioudaki, H., Agelaki, S., Kallergi, G., Saridaki, Z., Mavroudis, D., & Georgoulias, V. (2010). Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Letters, 288(1), 99–106.PubMedCrossRefGoogle Scholar
  48. 48.
    Raimondi, C., Gradilone, A., Naso, G., Vincenzi, B., Petracca, A., Nicolazzo, C., Palazzo, A., Saltarelli, R., Spremberg, F., Cortesi, E., & Gazzaniga, P. (2011). Epithelial–mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Research and Treatment, 130(2), 449–455.PubMedCrossRefGoogle Scholar
  49. 49.
    Gradilone, A., Raimondi, C., Nicolazzo, C., Petracca, A., Gandini, O., Vincenzi, B., Naso, G., Aglianò, A. M., Cortesi, E., & Gazzaniga, P. (2011). Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. Journal of Cellular and Molecular Medicine, 15(5), 1066–1070.PubMedCrossRefGoogle Scholar
  50. 50.
    Armstrong, A. J., Marengo, M. S., Oltean, S., Kemeny, G., Bitting, R. L., Turnbull, J. D., Herold, C. I., Marcom, P. K., George, D. J., & Garcia-Blanco, M. A. (2011). Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Molecular Cancer Research, 9(8), 997–1007.PubMedCrossRefGoogle Scholar
  51. 51.
    Strati, A., Markou, A., Parisi, C., Politaki, E., Mavroudis, D., Georgoulias, V., & Lianidou, E. (2011). Gene expression profile of circulating tumor cells in breast cancer by RT-qPCR. BMC Cancer, 11, 422.PubMedCrossRefGoogle Scholar
  52. 52.
    Markou, A., Strati, A., Malamos, N., Georgoulias, V., & Lianidou, E. S. (2011). Molecular characterization of circulating tumor cells in breast cancer by a liquid bead array hybridization assay. Clinical Chemistry, 57(3), 421–430.PubMedCrossRefGoogle Scholar
  53. 53.
    Kallergi, G., Papadaki, M. A., Politaki, E., Mavroudis, D., Georgoulias, V., & Agelaki, S. (2011). Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Research, 13(3), R59.PubMedCrossRefGoogle Scholar
  54. 54.
    Payne, R. E., Yagüe, E., Slade, M. J., Apostolopoulos, C., Jiao, L. R., Ward, B., Coombes, R. C., & Stebbing, J. (2009). Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients. Pharmacogenomics, 10(1), 51–57.PubMedCrossRefGoogle Scholar
  55. 55.
    Liu, Z., Fusi, A., Schmittel, A., Tinhofer, I., Schneider, A., & Keilholz, U. (2010). Eradication of EGFR-positive circulating tumor cells and objective tumor response with lapatinib and capecitabine. Cancer Biology & Therapy, 10(9), 860–864.CrossRefGoogle Scholar
  56. 56.
    Kallergi, G., Mavroudis, D., Georgoulias, V., & Stournaras, C. (2007). Phosphorylation of FAK, PI-3K, and impaired actin organization in CK-positive micrometastatic breast cancer cells. Molecular Medicine, 13(1-2), 79–88.PubMedCrossRefGoogle Scholar
  57. 57.
    Kallergi, G., Agelaki, S., Kalykaki, A., Stournaras, C., Mavroudis, D., & Georgoulias, V. (2008). Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients. Breast Cancer Research, 10(5), R80.PubMedCrossRefGoogle Scholar
  58. 58.
    Kasimir-Bauer, S., Hoffmann, O., Wallwiener, D., Kimmig, R., & Fehm, T. (2012). Expression of stem cell and epithelial–mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Research, 14(1), R15.PubMedCrossRefGoogle Scholar
  59. 59.
    Ntoulia, M., Stathopoulou, A., Ignatiadis, M., Malamos, N., Mavroudis, D., Georgoulias, V., et al. (2006). Detection of mammaglobin A-mRNA-positive circulating tumor cells in peripheral blood of patients with operable breast cancer with nested RT-PCR. Clinical Biochemistry, 39, 879–887.PubMedCrossRefGoogle Scholar
  60. 60.
    Zehentner, B. K., Secrist, H., Hayes, D. C., Zhang, X., Ostenson, R. C., Loop, S., Goodman, G., Houghton, R. L., & Persing, D. H. (2006). Detection of circulating tumor cells in peripheral blood of breast cancer patients during or after therapy using a multigene real-time RT-PCR assay. Molecular Diagnosis & Therapy, 10(1), 41–47.CrossRefGoogle Scholar
  61. 61.
    Roncella, S., Ferro, P., Bacigalupo, B., Pronzato, P., Tognoni, A., Falco, E., Gianquinto, D., Ansaldo, V., Dessanti, P., Fais, F., Rosai, J., & Fedeli, F. (2005). Human mammaglobin mRNA is a reliable molecular marker for detecting occult breast cancer cells in peripheral blood. Journal of Experimental & Clinical Cancer Research, 24(2), 265–271.Google Scholar
  62. 62.
    Marques, A. R., Teixeira, E., Diamond, J., Correia, H., Santos, S., Neto, L., Ribeiro, M., Miranda, A., & Passos-Coelho, J. L. (2009). Detection of human mammaglobin mRNA in serial peripheral blood samples from patients with non-metastatic breast cancer is not predictive of disease recurrence. Breast Cancer Research and Treatment, 114(2), 223–232.PubMedCrossRefGoogle Scholar
  63. 63.
    Reinholz, M. M., Kitzmann, K. A., Tenner, K., Hillman, D., Dueck, A. C., Hobday, T. J., Northfelt, D. W., Moreno-Aspitia, A., Roy, V., Laplant, B., Allred, J. B., Stella, P. J., Lingle, W. L., & Perez, E. A. (2011). Cytokeratin-19 and mammaglobin gene expression in circulating tumor cells from metastatic breast cancer patients enrolled in north central cancer treatment group trials, n0234/336/436/437. Clinical Cancer Research, 17(22), 7183–7193.PubMedCrossRefGoogle Scholar
  64. 64.
    Chimonidou, M., Strati, A., Tzitzira, A., Sotiropoulou, G., Malamos, N., Georgoulias, V., & Lianidou, E. S. (2011). DNA methylation of tumor suppressor and metastasis suppressor genes in circulating tumor cells. Clinical Chemistry, 57(8), 1169–1177.PubMedCrossRefGoogle Scholar
  65. 65.
    Sotiropoulou, G., Anisowicz, A., & Sager, R. (1997). Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer. Journal of Biological Chemistry, 272, 903–910.PubMedCrossRefGoogle Scholar
  66. 66.
    Kioulafa, M., Balkouranidou, I., Sotiropoulou, G., Kaklamanis, L., Mavroudis, D., Georgoulias, V., & Lianidou, E. (2009). Methylation of cystatin M promoter is associated with unfavorable prognosis in operable breast cancer. International Journal of Cancer, 125, 2887–2892.CrossRefGoogle Scholar
  67. 67.
    Phadke, P. A., Vaidya, K. S., Nash, K. T., Hurst, D. R., & Welch, D. R. (2008). BRMS1 suppresses breast cancer experimental metastasis to multiple organs by inhibiting several steps of the metastatic process. American Journal of Pathology, 172, 809–817.PubMedCrossRefGoogle Scholar
  68. 68.
    Hurst, D. R., Edmonds, M. D., Scott, G. K., Benz, C. C., Vaidya, K. S., & Welch, D. R. (2009). Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Research, 69, 1279–1283.PubMedCrossRefGoogle Scholar
  69. 69.
    Du, Y. C., Oshima, H., Oguma, K., Kitamura, T., Itadani, H., Fujimura, T., et al. (2009). Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology, 137, 1346–1357.PubMedCrossRefGoogle Scholar
  70. 70.
    Gazzaniga, P., Naso, G., Gradilone, A., Cortesi, E., Gandini, O., Gianni, W., et al. (2010). Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors. International Journal of Cancer, 126, 2437–2447.Google Scholar
  71. 71.
    Gradilone, A., Naso, G., Raimondi, C., Cortesi, E., Gandini, O., Vincenzi, B., et al. (2011). Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): prognosis, drug resistance and phenotypic characterization. Annals of Oncology, 22, 86–92.PubMedCrossRefGoogle Scholar
  72. 72.
    Nakamura, S., Yagata, H., Ohno, S., Yamaguchi, H., Iwata, H., Tsunoda, N., et al. (2010). Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Br Cancer, 17, 199–204.CrossRefGoogle Scholar
  73. 73.
    Serrano, M. J., Sánchez-Rovira, P., Delgado-Rodriguez, M., & Gaforio, J. J. (2009). Detection of circulating tumor cells in the context of treatment: prognostic value in breast cancer. Cancer Biology & Therapy, 8, 671–675.CrossRefGoogle Scholar
  74. 74.
    Georgoulias, V. et al. (2012). Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study. Annals of Oncology. doi: 10.1093/annonc/mds020.
  75. 75.
    Pachmann, K., Camara, O., Kroll, T., Gajda, M., Gellner, A. K., Wotschadlo, J., & Runnebaum, I. B. (2011). Efficacy control of therapy using circulating epithelial tumor cells (CETC) as “liquid biopsy”: trastuzumab in HER2/neu-positive breast carcinoma. Journal of Cancer Research and Clinical Oncology, 137(9), 1317–1327.PubMedCrossRefGoogle Scholar
  76. 76.
    Hayashi, N., Nakamura, S., Tokuda, Y., Shimoda, Y., Yagata, H., Yoshida, A., Ota, H., Hortobagyi, G. N., Cristofanilli, M., & Ueno, N. T. (2011). Prognostic value of HER2-positive circulating tumor cells in patients with metastatic breast cancer. International Journal of Clinical Oncology, 17, 96–104.PubMedCrossRefGoogle Scholar
  77. 77.
    Fehm, T., Müller, V., Alix-Panabières, C., & Pantel, K. (2008). Micrometastatic spread in breast cancer: detection, molecular characterization and clinical relevance. Breast Cancer Research, 10(Suppl 1), S1.PubMedCrossRefGoogle Scholar
  78. 78.
    Kim, M. Y., Oskarsson, T., Acharyya, S., Nguyen, D. X., Zhang, X. H., Norton, L., et al. (2009). Tumor self-seeding by circulating cancer cells. Cell, 139, 1315–1326.PubMedCrossRefGoogle Scholar
  79. 79.
    Mego, M., Mani, S. A., & Cristofanilli, M. (2010). Molecular mechanisms of metastasis in breast cancer—clinical applications. Nature Reviews. Clinical Oncology, 7, 693–701.PubMedCrossRefGoogle Scholar
  80. 80.
    Riethdorf, S., & Pantel, K. (2010). Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. Annals of the New York Academy of Sciences, 1210, 66–77.PubMedCrossRefGoogle Scholar
  81. 81.
    Kasimir-Bauer, S. (2009). Circulating tumor cells as markers for cancer risk assessment and treatment monitoring. Molecular Diagnosis & Therapy, 13, 209–215.CrossRefGoogle Scholar
  82. 82.
    Lianidou, E. S. (2012). Circulating tumor cells—new challenges ahead (editorial). Clinical Chemistry, 58, 5.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Analysis of Circulating Tumor Cells Lab, Laboratory of Analytical Chemistry, Department of ChemistryUniversity of AthensAthensGreece

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