Oncology Reviews

, Volume 3, Issue 4, pp 225–235

Breast cancer circulating tumor cells

  • Maria João Carvalho
  • Mafalda Laranjo
  • Margarida Abrantes
  • António S. Cabrita
  • Filomena Botelho
  • Carlos F. de Oliveira


Metastasization of breast cancer involves various mechanisms responsible for progression from invasive lesion to dissemination in distant organs. Regional lymph node metastasization was considered an initial step in this process, but it is now recognized that hematogenous dissemination is a deviation from lymphatic circulation. The detection of circulating tumor cells (CTC) is an aim in several oncology areas. For this purpose, several techniques have been used to detect CTC, including the use of antibodies and techniques with nucleic acids. This study reviews the published studies considering the detection of breast cancer CTC. There are focused the difficulties in identifying a CTC in a heterogeneous population, the handling of the sample, criteria of positivity, analytical techniques, and specific markers. There are systematized various specific markers of breast cancer cells also the problems with false positive results. Finally, we hypothesize clinical applications either as a prognostic marker or as a therapeutic response monitor.


Circulating cells Breast cancer 


  1. 1.
    Wingo PA, Tong T, Bolden S (1995) Cancer statistics. CA Cancer J Clin 45:8–30PubMedCrossRefGoogle Scholar
  2. 2.
    Quinn M, Babb P, Brock A et al (2001) Cancer trends in England and Wales 1950–1999. The stationary office, LondonGoogle Scholar
  3. 3.
    Lacroix M (2006) Significance, detection and markers of disseminated breast cancer cells. Endoc Relat Cancer 13(4):1033–1067CrossRefGoogle Scholar
  4. 4.
    Fisher B, Jeong JH, Anderson S, Bryant J, Fisher ER (2002) Twenty-five year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. N Engl J Med 347:567–575PubMedCrossRefGoogle Scholar
  5. 5.
    Gilbey AM, Burnett D, Coleman RE (2004) The detection of circulating breast cancer cells. J Clin Pathol 57:903–911PubMedCrossRefGoogle Scholar
  6. 6.
    Braun S, Naume B (2005) Circulating and disseminated tumor cells. J Clin Oncol 23:1623–1626PubMedCrossRefGoogle Scholar
  7. 7.
    Zieglschmid V, Hollmann C, Böcher O (2005) Detection of disseminated tumor cells in peripheral blood. Crit Rev Clin Lab Sci 42:155–196PubMedCrossRefGoogle Scholar
  8. 8.
    Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G et al (2000) Cytokeratinpositive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342:525–533PubMedCrossRefGoogle Scholar
  9. 9.
    Pantel K, Müller V, Auer M, Nusser N, Harbeck N, Braun S (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res 9(17):6326–6334PubMedGoogle Scholar
  10. 10.
    Jiang WG, Puntis MC, Hallett MB (1994) Molecular and cellular basis of cancer invasion and metastasis: implications for treatment. Br J Surg 81:1576–1590PubMedCrossRefGoogle Scholar
  11. 11.
    Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Gusterson B, Neville AM (1999) Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group. Lancet 354:896–900PubMedCrossRefGoogle Scholar
  12. 12.
    Braun S, Cevatli BS, Assemi C, Janni W, Kentenich CR, Schindlbeck C, Rjosk D, Hepp F (2001) Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 19:1468–1475PubMedGoogle Scholar
  13. 13.
    Hawes D, Neville AM, Cote RJ (2001) Detection of occult metastasis in patients with breast cancer. Semin Surg Oncol 20:312–318PubMedCrossRefGoogle Scholar
  14. 14.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456PubMedCrossRefGoogle Scholar
  15. 15.
    Gaforio JJ, Serrano MJ, Sanchez-Rovira P, Sirvent A, Delgado-Rodriguez M, Campos M, de la Torre N, Algarra I, Duenas R, Lozano A (2003) Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer 107:984–990PubMedCrossRefGoogle Scholar
  16. 16.
    Pierga JY, Bonneton C, Vincent-Salomon A, de Cremoux P, Nos C, Blin N, Pouillart P, Thiery JP, Magdelénat H (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10:1392–1400PubMedCrossRefGoogle Scholar
  17. 17.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRefGoogle Scholar
  18. 18.
    Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S, Van Marck E, Vermeulen PB, Dirix LY (2006) 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 94:672–680PubMedGoogle Scholar
  19. 19.
    Gilbey AM, Burnett D, Coleman RE, Holen I (2004) The detection of circulating breast cancer cells in blood. J Clin Pathol 57(9):903–911PubMedCrossRefGoogle Scholar
  20. 20.
    Mehes G, Witt A, Kubista E et al (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159:17–20PubMedGoogle Scholar
  21. 21.
    Ross AA, Cooper BW, Lazarus HM et al (1993) Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 82:2605–2610PubMedGoogle Scholar
  22. 22.
    Theirult RL, Hortobagyi GN (1992) Bone metastasis in breast cancer. Anticancer Drugs 3:455–462CrossRefGoogle Scholar
  23. 23.
    Body JJ (1992) Metastatic bone disease: clinical and therapeutic aspects. Bone 13:57–62CrossRefGoogle Scholar
  24. 24.
    Diel IJ, Kaufman M, Goener R et al (1992) Detection of tumour cells in bone marrow of patients with primary breast cancer: prognostic factor for distant metastasis. J Clin Oncol 10:1534–1539PubMedGoogle Scholar
  25. 25.
    Harbeck N, Untch M, Pache L et al (1994) Tumour cell detection in the bone marrow of breast cancer patients at primary therapy: results of a 3-year median follow-up. Br J Cancer 69:566–571PubMedGoogle Scholar
  26. 26.
    Ring A, Smith IE, Dowsett M (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5:79–88PubMedCrossRefGoogle Scholar
  27. 27.
    Braun S, Hepp F, Sommer HL et al (1999) Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 84:1–5PubMedCrossRefGoogle Scholar
  28. 28.
    Silva AL, Diamond MR, Passos-Coelho JL (2001) Cytokeratin 20 is not a reliable molecular marker for occult breast cancer cell detection in haematological tissues. Breast Cancer Res Treat 66:59–66PubMedCrossRefGoogle Scholar
  29. 29.
    Racila E, Euhus D, Weiss AJ et al (1998) Detection and characterisation of carcinoma cells in the blood. Proc Natl Acad Sci USA 95:4589–4594PubMedCrossRefGoogle Scholar
  30. 30.
    Smerage JB, Hayes DF (2006) The measurement and therapeutic implications of circulating tumour cells in breast cancer. Br J Cancer 94:8–12PubMedCrossRefGoogle Scholar
  31. 31.
    Hager G, Cacsire-Castillo Tong D, Schiebel I, Rezniczek GA, Watrowski R, Speiser P, Zeillinger R (2005) The use of a panel of monoclonal antibodies to enrich circulating breast cancer cells facilitates their detection. Gynecol Oncol 98:211–216PubMedCrossRefGoogle Scholar
  32. 32.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRefGoogle Scholar
  33. 33.
    Mayall F, Fairweather S, Wilkins R et al (1999) Microsatellite abnormalities in plasma of patients with breast carcinoma: concordance with the primary tumour. J Clin Pathol 52:363–366PubMedCrossRefGoogle Scholar
  34. 34.
    Chen X, Bonnefoi H, Diebold-Berger S et al (1999) Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin Cancer Res 5:2297–2303PubMedGoogle Scholar
  35. 35.
    Fournie GJ, Courtin JP, Laval F et al (1995) Plasma DNA as a marker of cancerous cell death. Investigations in patients suffering from lung cancer and in nude mice bearing human tumours. Cancer Lett 91:221–227PubMedCrossRefGoogle Scholar
  36. 36.
    Chen XQ, Stroun M, Magnenat JL et al (1996) Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med 2:1033–1035PubMedCrossRefGoogle Scholar
  37. 37.
    Hibi K, Robinson CR, Booker S et al (1998) Molecular detection of genetic alterations in the serum of colorectal cancer patients. Cancer Res 58:1405–1407PubMedGoogle Scholar
  38. 38.
    Gonzalez R, Silva JM, Sanchez A et al (2000) Microsatellite alterations and TP53 mutations in plasma DNA of small-cell lung cancer patients: follow-up study and prognostic significance. Ann Oncol 11:1097–1104PubMedCrossRefGoogle Scholar
  39. 39.
    Silva JM, Dominguez G, Garcia JM et al (1999) Presence of tumor DNA in plasma of breast cancer patients: clinicopathological correlations. Cancer Res 59:3251–3256PubMedGoogle Scholar
  40. 40.
    Kawakami K, Brabender J, Lord RV et al (2000) Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst 92:1805–1811PubMedCrossRefGoogle Scholar
  41. 41.
    Müller V, Pantel K (2005) BM micrometastases and circulating tumor cells in breast cancer patients: where have we been, where are we now and where does the future lie? Cytotherapy 7:478–482PubMedCrossRefGoogle Scholar
  42. 42.
    Fiegl H, Millinger S, Müller-Holzner E, Marth C, Ensinger C, Berger A, Klocker H, Goebel G, Widschwendter M (2005) Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res 65:1141–1145PubMedCrossRefGoogle Scholar
  43. 43.
    Lacroix M, Leclercq G (2004) Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat 83:249–289PubMedCrossRefGoogle Scholar
  44. 44.
    Ring A, Smith IE, Dowsett M (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5:79–88PubMedCrossRefGoogle Scholar
  45. 45.
    Chen XQ, Bonnefoi H, Pelte MF et al (2000) Telomerase RNA as a detection marker in the serum of breast cancer patients. Clin Cancer Res 6:3823–3826PubMedGoogle Scholar
  46. 46.
    Silva JM, Dominguez G, Silva J et al (2001) Detection of epithelial messenger RNA in the plasma of breast cancer patients is associated with poor prognosis tumor characteristics. Clin Cancer Res 7:2821–2825PubMedGoogle Scholar
  47. 47.
    Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N 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. J Clin Oncol 20:3404–3412. Available online http://breast-cancer-research.com/content/8/5/110 Google Scholar
  48. 48.
    Harris LN, Solomon N, Roberts L, Ngo T, Abi Raad R, Gioioso C, Kuter I, Smith B, Iglehart JD, Friedman P et al (2005) Detection and monitoring of circulating tumor cells (CTCs) by CK-19 mRNA in breast cancer patients treated with neoadjuvant chemotherapy: a marker of early recurrence. BreastCancer Res Treat 94(Suppl 1):1021. (Abstract)Google Scholar
  49. 49.
    Weigelt B, Bosma AJ, Hart AA, Rodenhuis S, van ‘t Veer LJ (2003) Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients. Br J Cancer 88:1091–1094PubMedCrossRefGoogle Scholar
  50. 50.
    Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C et al (2004) HER-2 gene amplification can be acquired as breast cancer progresses. PNAS 101:9393–9398PubMedCrossRefGoogle Scholar
  51. 51.
    Müller V, Hayes DF, Pantel K (2006) Recent translational research: circulating tumor cells in breast cancer patients. Breast Cancer Res 8(5):110PubMedCrossRefGoogle Scholar
  52. 52.
    Pantel K, Woelfle U (2005) Detection and molecular characterisation of disseminated tumour cells: implications for anti-cancer therapy. Biochim Biophys Acta 1756:53–64PubMedGoogle Scholar
  53. 53.
    Gray JW (2004) Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell 4:4–6CrossRefGoogle Scholar
  54. 54.
    Ligtenberg MJ, Buijs F, Vos HL, Hilkens J (1992) Suppression of cell aggregation by high levels of episialin. Cancer Res 52:2318–2324PubMedGoogle Scholar
  55. 55.
    Rakha EA, Boyce RW, El-Rehim DA, Kurien T, Green AR, Paish EC, Robertson JF, Ellis IO (2005) Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod Pathol 18:1295–1304PubMedCrossRefGoogle Scholar
  56. 56.
    Silva AL, Diamond J, Silva MR, Passas-Coelho JL (2001) Cytokeratin 20 is not a reliable molecular marker for occult breast cancer cell detection in haematological tissues. Breast Cancer Res Treat 66:59–66PubMedCrossRefGoogle Scholar
  57. 57.
    Watson MA, Fleming TP (1996) Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865PubMedGoogle Scholar
  58. 58.
    Becker RM, Darrow C, Zimonjic DB, Popescu NC, Watson MA, Fleming TP (1998) Identification of mammaglobin B, a novel member of the uteroglobin gene family. Genomics 54:70–78PubMedCrossRefGoogle Scholar
  59. 59.
    Jones C, Damiani S, Wells D, Chaggar R, Lakhani SR, Eusebi V (2001) Molecular cytogenetic comparison of apocrine hyperplasia and apocrine carcinoma of the breast. Am J Pathol 158:207–214PubMedGoogle Scholar
  60. 60.
    Murphy LC, Lee-Wing M, Goldenberg GJ, Shiu RP (1987) Expression of the gene encoding a prolactin-inducible protein by human breast cancers in vivo: correlation with steroid receptor status. Cancer Res 47:4160–4164PubMedGoogle Scholar
  61. 61.
    Gunawardane RN, Sgroi DC, Wrobel CN, Koh E, Daley GQ, Brugge JS (2005) Novel role for PDEF in epithelial cell migration and invasion. Cancer Res 65:11572–11580PubMedCrossRefGoogle Scholar
  62. 62.
    Zehentner BK, Persing DH, Deme A, Toure P, Hawes SE, Brooks L, Feng Q, Hayes DC, Critichlow CW, Houghton RL, Kiviat NB (2004) Mammaglobin as a novel breast cancer biomarker: multigene reverse transcription-pcr assay and sandwich ELISA. Clin Chem 50:2069–2076PubMedCrossRefGoogle Scholar
  63. 63.
    Martin KJ, Kritzman BM, Price LM, Koh B, Kwan CP, Zhang X, Mackay A, O’Hare MJ, Kaelin CM, Mutter GL et al (2000) Linking gene expression patterns to therapeutic groups in breast cancer. Cancer Res 60:2232–2238PubMedGoogle Scholar
  64. 64.
    Umekita Y, Yoshida H (2003) Expression of maspin is up-regulated during the progression of mammary ductal carcinoma. Histopathology 42:541–545PubMedCrossRefGoogle Scholar
  65. 65.
    Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, Goulet R Jr, Badve S, Nakshatri H (2006) CD44+/CD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8:R59PubMedCrossRefGoogle Scholar
  66. 66.
    Fillmore C, Kuperwasser C (2007) Human breast cancer stem cell markers CD44 and CD24: enriching for cells with functional properties in mice or in man? Breast Cancer Res 9:303PubMedCrossRefGoogle Scholar
  67. 67.
    Storci G, Sansone P, Trere D, Tavolari S, Taffurelli M, Ceccarelli C, Guarnieri T, Paterini P, Pariali M, Montanaro L, Santini D, Chieco P, Bonafe M (2008) The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. J Pathol 214:25–37PubMedCrossRefGoogle Scholar
  68. 68.
    Zucchi I, Sanzone S, Astigiano S, Pelucchi P, Scotti M, Valsecchi V, Barbieri O, Bertoli G, Albertini A, Reinbold RA, Dulbecco R (2007) The properties of a mammary gland cancer stem cell. Proc Natl Acad Sci USA 104:10476–10481PubMedCrossRefGoogle Scholar
  69. 69.
    Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615–5621PubMedCrossRefGoogle Scholar
  70. 70.
    Baker M, Gillanders WE, Mikhitarian K et al (2003) The molecular detection of micrometastatic breast cancer. Am J Surg 186:351–358PubMedCrossRefGoogle Scholar
  71. 71.
    Jiang WG, Martin TA, Mansel RE (2002) Molecular detection of micrometastases in breast cancer. Crit Rev Oncol Hematol 43:13–31PubMedCrossRefGoogle Scholar
  72. 72.
    Watson MA, Fleming TP (1996) Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865PubMedGoogle Scholar
  73. 73.
    Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988PubMedCrossRefGoogle Scholar
  74. 74.
    Ko Y, Grunewald E, Totzke G et al (2000) High percentage of false-positive results of cytokeratin 19 RT-PCR in blood: a model for the analysis of illegitimate gene expression. Oncology 59:81–88PubMedCrossRefGoogle Scholar
  75. 75.
    Novaes M, Bendit I, Garicochea B et al (1997) Reverse transcriptase-polymerase chain reaction analysis of cytokeratin 19 expression in the peripheral blood mononuclear cells of normal female blood donors. Mol Pathol 50:209–211PubMedCrossRefGoogle Scholar
  76. 76.
    Savtchenko ES, Schiff TA, Jiang CK et al (1988) Embryonic expression of the human 40-kD keratin: evidence from a processed pseudogene sequence. Am J Hum Genet 43:630–637PubMedGoogle Scholar
  77. 77.
    Ruud P, Fodstad O, Hovig E (1999) Identification of a novel cytokeratin 19 pseudogene that may interfere with reverse transcriptase-polymerase chain reaction assays used to detect micrometastatic tumor cells. Int J Cancer 80:119–125PubMedCrossRefGoogle Scholar
  78. 78.
    Wong IH, Yeo W, Chan AT et al (2001) Quantitative relationship of the circulating tumour burden by reverse transcription-polymerase chain reaction for cytokeratin 19 mRNA in peripheral blood of colorectal cancer patients with Dukes’ stage, serum carcinoembryonic antigen level and tumour progression. Cancer Lett 162:65–73PubMedCrossRefGoogle Scholar
  79. 79.
    Wong IH, Yeo W, Chan AT et al (2001) Quantitative correlation of cytokeratin 19 mRNA level in peripheral blood with disease stage and metastasis in breast cancer patients: potential prognostic implications. Int J Oncol 18:633–638PubMedGoogle Scholar
  80. 80.
    Slade MJ, Smith BM, Sinnett HD et al (1999) Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol 17:870–879PubMedGoogle Scholar
  81. 81.
    Eltahir EM, Mallinson DS, Birnie GD et al (1998) Putative markers for the detection of breast carcinoma cells in blood. Br J Cancer 77:1203–1207PubMedGoogle Scholar
  82. 82.
    Aerts J, Wynendaele W, Paridaens R et al (2001) A real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to detect breast carcinoma cells in peripheral blood. Ann Oncol 12:39–46PubMedCrossRefGoogle Scholar
  83. 83.
    Freeman R, Wheeler J, Robertson H et al (1990) In vitro production of TNF-a in blood samples. Lancet 336:312–313PubMedCrossRefGoogle Scholar
  84. 84.
    Pahl A, Brune K (2002) Gene expression changes in blood after phlebotomy: implications for gene expression profiling. Blood 100:1094–1095PubMedCrossRefGoogle Scholar
  85. 85.
    Leclercq G, Lacroix M, Laïos I, Laurent G (2006) Estrogen receptor alpha: impact of ligands on intracellular shuttling and turnover rate in breast cancer cells. Curr Cancer Drug Targets 6:39–64PubMedCrossRefGoogle Scholar
  86. 86.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374PubMedCrossRefGoogle Scholar
  87. 87.
    Stefansson IM, Foulkes WD, Chappuis PO, Goffin JR, Begin LR, Wong N, Trudel M, Akslen LA (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:1482–1485PubMedGoogle Scholar
  88. 88.
    Weigelt B, Verduijn P, Bosma AJ, Rutgers EJ, Peterse HL, van’t Veer LJ (2004) Detection of metastases in sentinel lymph nodes of breast cancer patients by multiple mRNA markers. Br J Cancer 90:1531–1537PubMedCrossRefGoogle Scholar
  89. 89.
    Loo LW, Grove DI, Williams EM, Neal CL, Cousens LA, Schubert EL, Holcomb IN, Massa HF, Glogovac J, Li CI et al (2004) Array comparative genomic hybridization analysis of genomic alterations in breast cancer subtypes. Cancer Res 64:8541–8549PubMedCrossRefGoogle Scholar
  90. 90.
    Fridlyand J, Snijders AM, Ylstra B, Li H, Olshen A, Segraves R, Dairkee S, Tokuyasu T, Ljung BM, Jain AN et al (2006) Breast tumor copy number aberration phenotypes and genomic instability. BMC Cancer 6:96PubMedCrossRefGoogle Scholar
  91. 91.
    Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Kochli O et al (2004) Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 64:8534–8540PubMedCrossRefGoogle Scholar
  92. 92.
    Liotta LA, Kleinerman J, Saidel GM (1974) Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 34:997–1004PubMedGoogle Scholar
  93. 93.
    Butler TP, Gullino PM (1975) Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res 35:512–516PubMedGoogle Scholar
  94. 94.
    Denis MG, Tessier MH, Dreno B, Lustenberger P (1996) Circulating micrometastases following oncological surgery. Lancet 347:913PubMedCrossRefGoogle Scholar
  95. 95.
    Eschwege P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, Lacour B, Loric S (1995) Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet 346:1528–1530PubMedCrossRefGoogle Scholar
  96. 96.
    Landys K, Persson S, Kovarik J, Hultborn R, Holmberg E (1998) Prognostic value of bone marrow biopsy in operable breast cancer patients at the time of initial diagnosis: results of a 20-year median follow-up. Breast Cancer Res Treat 49:27–33PubMedCrossRefGoogle Scholar
  97. 97.
    Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC (1999) Outcome of primary breast cancer patients with micrometastases: a long-term follow-up study. Lancet 354:197–202PubMedCrossRefGoogle Scholar
  98. 98.
    Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K (2000) 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 18:80–86PubMedGoogle Scholar
  99. 99.
    Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Ch Kouroussis, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N 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. J Clin Oncol 20:3404–3412PubMedCrossRefGoogle Scholar
  100. 100.
    Jotsuka T, Okumura Y, Nakano S, Nitta H, Sato T, Miyachi M, Suzumura K, Yamashita J (2004) 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 135:419–426PubMedCrossRefGoogle Scholar
  101. 101.
    Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen L (2006) 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 12:4218–4224PubMedCrossRefGoogle Scholar
  102. 102.
    Xenidis N, Vlachonikolis I, Mavroudis D, Perraki M, Stathopoulou A, Malamos N, Kouroussis C, Kakolyris S, Apostolaki S, Vardakis N et al (2003) Peripheral blood circulating cytokeratin-19 mRNA-positive cells after the completion of adjuvant chemotherapy in patients with operable breast cancer. Ann Oncol 14:849–855PubMedCrossRefGoogle Scholar
  103. 103.
    Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesl JM, Naume B (2004) Isolated tumor cells in bone marrow three years after diagnosis in disease free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 10:5342–5348PubMedCrossRefGoogle Scholar
  104. 104.
    Bozionellou V, Mavroudis D, Perraki M, Papadopoulos S, Apostolaki S, Stathopoulos E, Stathopoulou A, Lianidou E, Georgoulias V (2004) Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood of patients with breast cancer. Clin Cancer Res 10:8185–8194PubMedCrossRefGoogle Scholar
  105. 105.
    Smith BM, Slade MJ, English J, Graham H, Luchtenborg M, Sinnett HD, Cross NC, Coombes RC (2000) Response of circulating tumor cells to systemic therapy in patients with metastatic breast cancer: comparison of quantitative polymerase chain reaction and immunocytochemical techniques. J Clin Oncol 18:1432–1439PubMedGoogle Scholar
  106. 106.
    Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, Kau SW, Fornage B, Sahin A, Broglio K et al (2005) Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 23:9304–9311PubMedCrossRefGoogle Scholar
  107. 107.
    Campbell MJ, Scott J, Maecker HT, Park JW, Esserman LJ (2005) Immune dysfunction and micrometastases in women with breast cancer. Breast Cancer Res Treat 91:163–171PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Maria João Carvalho
    • 1
  • Mafalda Laranjo
    • 2
  • Margarida Abrantes
    • 2
  • António S. Cabrita
    • 3
  • Filomena Botelho
    • 2
  • Carlos F. de Oliveira
    • 4
  1. 1.Gynaecology ServiceUniversity Hospitals of CoimbraCoimbraPortugal
  2. 2.Biophysics and Biomathematics Institute, IBILIMedicine Faculty of CoimbraCoimbraPortugal
  3. 3.Experimental Pathology InstituteMedicine Faculty of CoimbraCoimbraPortugal
  4. 4.Gynaecology University ClinicMedicine Faculty of CoimbraCoimbraPortugal

Personalised recommendations