Skip to main content
SpringerLink
Log in

Occult Metastatic Cells in Breast Cancer Patients

State of the Art, Pitfalls, and Promises

  • Chapter
Biomarkers in Breast Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 725 Accesses

Abstract

Blood-borne distant metastasis is the leading cause of cancer-related death in patients with breast cancer. The onset of this fundamental process can now be assessed in cancer patients using immunocytochemical and molecular assays able to detect even single metastatic cells. However, careful validation of technically confounding variables, including choice of detection antibody, preparation of cellular samples, and size of analyzed sample volumes, is mandatory for reproducible and comparable results. In studies with validated assays, analyses of bone marrow samples show that disseminated cells are present in 20–40% of primary breast cancer patients without any clinical or histopathological signs of metastasis. The common homing of circulating breast cancer cells in bone marrow is indicative of systemic tumor cell spread and growth of overt metastases in relevant organ sites such as bone, lung, or liver. Recent clinical studies involving more than 3000 breast cancer patients demonstrated that presence of tumor cells in bone marrow at primary diagnosis is an independent prognostic factor for unfavorable clinical outcome. To date, sampling of bone marrow, however, is not a routine procedure in clinical management of breast cancer patients. In this chapter, we review the existing tumor cell assays and discuss their current clinical relevance and perspectives for the clinical management of breast cancer patients.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Senn HJ. Meeting highlights: international consensus panel on the treatment of primary breast cancer. J Clin Oncol 2001;19:3817–3827.

    PubMed  CAS  Google Scholar 

  2. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn H-J. Meeting highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer. J Clin Oncol 2003;21:3357–3365.

    PubMed  Google Scholar 

  3. Woelfle U, Cloos J, Sauter G, et al. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 2003;63:5679–5684.

    PubMed  CAS  Google Scholar 

  4. Braun S, Cevatli BS, Assemi C, et al. Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 2001;19:1468–1475.

    PubMed  CAS  Google Scholar 

  5. Gerber B, Krause A, Muller H, et al. Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. J Clin Oncol 2001;19:960–971.

    PubMed  CAS  Google Scholar 

  6. Ridell B, Landys K. Incidence and histopathology of metastases of mammary carcinoma in biopsies from the posterior iliac crest. Cancer 1979;44:1782–1788.

    PubMed  CAS  Google Scholar 

  7. Schlimok G, Funke I, Holzmann B, et al. Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1A monoclonal antibodies. Proc Natl Acad Sci USA 1987;84:8672–8676.

    PubMed  CAS  Google Scholar 

  8. Gebauer G, Fehm T, Merkle E, Beck EP, Lang N, Jager W. Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol 2001;19:3669–3674.

    PubMed  CAS  Google Scholar 

  9. Braun S, Pantel K, Müller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II or III breast cancer. N Engl J Med 2000;342:525–533.

    PubMed  CAS  Google Scholar 

  10. Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC. Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up. Lancet 1999;354:197–202.

    PubMed  CAS  Google Scholar 

  11. Landys K, Persson S, Kovarik J, Hultborn R, Holmberg E. 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 1998;49:27–33.

    PubMed  CAS  Google Scholar 

  12. Diel IJ, Kaufmann M, Costa SD, et al. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1996;88:1652–1664.

    PubMed  CAS  Google Scholar 

  13. Harbeck N, Untch M, Pache L, Eiermann W. 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 1994;69:566–571.

    PubMed  CAS  Google Scholar 

  14. Cote RJ, Rosen PP, Lesser ML, Old LJ, Osborne MP. Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol 1991;9:1749–1756.

    PubMed  CAS  Google Scholar 

  15. Untch M, Kahlert S, Funke I, et al. Detection of cytokeratin 18-positive cells in bone marrow of breast cancer patients: no prediction of bad outcome. Proc ASCO 1999;18:639a (Abstr 2472).

    Google Scholar 

  16. Molino A, pelosi G, Turazza M, et al. Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features. Breast Cancer Res Treat 1997;42:23–30.

    PubMed  CAS  Google Scholar 

  17. Funke I, Fries S, Rolle M, et al. Comparative analyses of bone marrow micrometastases in breast and gastric cancer. Int J Cancer 1996;65:755–761.

    PubMed  CAS  Google Scholar 

  18. Courtemanche DJ, Worth AJ, Coupland RW, Rowell JL, MacFarlane JK. Monoclonal antibody LICR-LON-M8 does not predict the outcome of operable breast cancer. Can J Surg 1991;34:21–26.

    PubMed  CAS  Google Scholar 

  19. Singletary SE, Larry L, Trucker SL, Spitzer G. Detection of micrometastatic tumor cells in bone marrow of breast carcinoma patients. J Surg Oncol 1991;47:32–36.

    PubMed  CAS  Google Scholar 

  20. Mathieu MC, Friedman S, Bosq J, et al. Immunohistochemical staining of bone marrow biopsies for detection of occult metastasis in breast cancer. Breast Cancer Res Treat 1990;15:21–26.

    PubMed  CAS  Google Scholar 

  21. Salvadori B, Squicciarini P, Rovini D, et al. Use of monoclonal antibody MBr1 to detect micrometastases in bone marrow specimens of breast cancer patients. Eur J Cancer 1990;26:865–867.

    PubMed  CAS  Google Scholar 

  22. Porro G, Menard S, Tagliabue E, et al. Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients. Cancer 1988;61:2407–2411.

    PubMed  CAS  Google Scholar 

  23. Wiedswang G, Borgen E, Karesen R, et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 2003;21:3469–3478.

    PubMed  CAS  Google Scholar 

  24. Pantel K, Schlimok G, Angstwurm M, et al. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 1994;3:165–173.

    PubMed  CAS  Google Scholar 

  25. Schaller G, Fuchs I, Pritze W, et al. Elevated keratin 18 protein expression indicates a favorable prognosis in patients with breast cancer. Clin Cancer Res 1996;2:1879–1885.

    PubMed  CAS  Google Scholar 

  26. Zajchowski DA, Bartholdi MF, Gong Y, et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 2001;61:5168–5178.

    PubMed  CAS  Google Scholar 

  27. Borgen E, Naume B, Nesland JM, et al. Standardisation of the immunocytochemi-cal detection of cancer cells in bone marrow and blood: I. Establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy 1999;1:377–388.

    Google Scholar 

  28. Borgen E, Beiske K, Trachsel S, et al. Immunocytochemical detection of isolated epithelial cells in bone marrow: non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase. J Pathol 1998;185:427–434.

    PubMed  CAS  Google Scholar 

  29. Braun S, Müller M, Hepp F, Schlimok G, Riethmüller G, Pantel K. Re: Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1998;90:1099–1100.

    PubMed  CAS  Google Scholar 

  30. Putz E, Witter K, Offner S, et al. Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res 1999;59:241–248.

    PubMed  CAS  Google Scholar 

  31. Pantel K, Dickmanns A, Zippelius A, et al. Establishment of micrometastatic carcinoma cell lines: a novel source of tumor cell vaccines. J Natl Cancer Inst 1995;87:1162–1168.

    PubMed  CAS  Google Scholar 

  32. Pantel K, Schlimok G, Braun S, et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993;85:1419–1424.

    PubMed  CAS  Google Scholar 

  33. Pantel K, Izbicki JR, Angstwurm M, et al. Immunocytochemical detection of bone marrow micrometastasis in operable non-small cell lung cancer. Cancer Res 1993;53:1027–1031.

    PubMed  CAS  Google Scholar 

  34. Müller P, Carroll P, Bowers E, et al. Low frequency epithelial cells in bone marrow from prostate carcinoma patients are cytogenetically aberrant. Cancer 1998;83:538–546.

    Google Scholar 

  35. Dietmaier W, Hartmann A, Wallinger S, et al. Multiple mutation analyses in single tumor cells with improved whole genome amplification. Am J Pathol 1999;154:83–95.

    PubMed  CAS  Google Scholar 

  36. Schmidt-Kittler O, Ragg T, Daskalakis A, et al. From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA 2003;100:7737–7742.

    PubMed  CAS  Google Scholar 

  37. Klein CA, Seidl S, Petat-Dutter K, et al. Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotech 2002;20:387–392.

    CAS  Google Scholar 

  38. Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmüller G. Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci USA 1999;96:4494–4499.

    PubMed  CAS  Google Scholar 

  39. Lugo TG, Braun S, Cote RJ, Pantel K, Rusch V. Detection and measurement of occult disease for the prognosis of solid tumors. J Clin Oncol 2003;21:2609–2615.

    PubMed  Google Scholar 

  40. Borgen E, Naume B, Nesland JM, et al. Use of automated microscopy for the detection of disseminated tumor cells in bone marrow samples. Cytometry 2001;46:215–221.

    PubMed  CAS  Google Scholar 

  41. Kraeft S-K, Sutherland R, Gravelin L, et al. Detection and analysis of cancer cells in blood and bone marrow using a rare event imaging system. Clin Cancer Res 2000;6:434–442.

    PubMed  CAS  Google Scholar 

  42. Bauer KD, de la Torre-Bueno J, Diel IJ, et al. Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res 2000;6:3552–3559.

    PubMed  CAS  Google Scholar 

  43. Zeidman I. The fate of circulating tumors cells. I. Passage of cells through capillaries. Cancer Res 1961;21:38–39.

    PubMed  CAS  Google Scholar 

  44. Fidler IJ. Quantitative analysis of distribution and fate of tumor emboli labeled with 125I-5-iodo-2′-desoxyuridine. J Natl Cancer Inst 1970;145:773–782.

    Google Scholar 

  45. Hansen E, Wolff N, Knuechel R, Ruschoff J, Hofstaedter F, Taeger K. Tumor cells in blood shed from the surgical field. Arch Surg 1995;130:387–393.

    PubMed  CAS  Google Scholar 

  46. Denis MG, Lipart C, Leborgne J, et al. Detection of disseminated tumor cells in peripheral blood of colorectal cancer patients. Int J Cancer 1997;74:540–544.

    PubMed  CAS  Google Scholar 

  47. Eschwege P, Dumas F, Blanchet P, et al. Haematogenous dissemination of pros-tatic epithelial cells during radical prostatectomy. Lancet 1995;346:1528–1530.

    PubMed  CAS  Google Scholar 

  48. Weitz J, Kienle P, Magener A, et al. Detection of disseminated colorectal cancer cells in lymph nodes, blood and bone marrow. Clin Cancer Res 1999;5:1830–1836.

    PubMed  CAS  Google Scholar 

  49. Weitz J, Kienle P, Lacroix J, et al. Dissemination of tumour cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res 1998;4:343–348.

    PubMed  CAS  Google Scholar 

  50. Uchikura K, Takao S, Nakajo A, et al. Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis. Ann Surg Oncol 2002;9:364–370.

    PubMed  Google Scholar 

  51. Engel H, Kleespies C, Friedrich J, et al. Detection of circulating tumour cells in patients with breast or ovarian cancer by molecular cytogenetics. Br J Cancer 1999;81:1165–1173.

    PubMed  CAS  Google Scholar 

  52. Fehm T, Sagalowsky A, Clifford E, et al. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 2002;8:2073–2084.

    PubMed  CAS  Google Scholar 

  53. Liotta LA, Kleinerman J, Saidel GM. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res 1974;34:997–1004.

    PubMed  CAS  Google Scholar 

  54. Butler TP, Gullino PM. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res 1975;35:512–516.

    PubMed  CAS  Google Scholar 

  55. Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LLM. osaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci USA 2000;97:14608–14613.

    PubMed  CAS  Google Scholar 

  56. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2:563–572.

    PubMed  CAS  Google Scholar 

  57. 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;20:3404–3412.

    PubMed  CAS  Google Scholar 

  58. Terstappen LW, Rao C, Gross S, Weiss AJ. Peripheral blood tumor cell load reflects the clinical activity of the disease in patients with carcinoma of the breast. Int J Oncol 2000;17:573–578.

    PubMed  CAS  Google Scholar 

  59. Smith BM, Slade MJ, English J, et al. 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 2000;18:1432–1439.

    PubMed  CAS  Google Scholar 

  60. Ghossein RA, Rosai J, Scher HI, et al. Prognostic significance of detection of prostate-specific antigen transcripts in the peripheral blood of patients with metastatic androgen-independent prostatic carcinoma. Urology 1997;50:100–105.

    PubMed  CAS  Google Scholar 

  61. Thorban S, Rosenberg R, Busch R, Roder RJ. Epithelial cells in bone marrow of oesophageal cancer patients: a significant prognostic factor in multivariate analysis. Br J Cancer 2000;83:35–39.

    PubMed  CAS  Google Scholar 

  62. Hoon DSB, Wang Y, Dale PS, et al. Detection of occult melanoma cells in blood with a multiple-marker polymerase chain reaction assay. J Clin Oncol 1995;13:2109–2116.

    PubMed  CAS  Google Scholar 

  63. Hoon DSB, Bostick P, Kuo C, et al. Molecular markers in blood as surrogate prognostic indicators of melanoma recurrence. Cancer Res 2000;60:2253–2257.

    PubMed  CAS  Google Scholar 

  64. de la Taille A, Olsson CA, Buttyan R, et al. Blood-based reverse transcriptase polymerase chain reaction assays for prostatic specific antigen: long term follow-up confirms the potential utility of this assay in identifying patients more likely to have biochemical recurrence (rising PSA) following radical prostatectomy. Int J Cancer 1999;84:360–364.

    PubMed  Google Scholar 

  65. Ellis WJ, Pfitzenmaier J, Colli J, Arfman E, Lange PH, Vessella RLU-hwscsaB-X-a. Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology 2003;61:277–281.

    PubMed  Google Scholar 

  66. Bilkenroth U, Taubert H, Riemann D, Rebmann U, Heynemann H, Meye A. Detection and enrichment of disseminated renal carcinoma cells from peripheral blood by immunomagnetic cell separation. Int J Cancer 2001;92:577–582.

    PubMed  CAS  Google Scholar 

  67. Flatmark K, Bjornland K, Johannessen HO, et al. Immunomagnetic detection of micrometastatic cells in bone marrow of colorectal cancer patients. Clin Cancer Res 2002;8:444–449.

    PubMed  Google Scholar 

  68. Naume B, Borgen E, Beiske K, et al. Immunomagnetic techniques for the enrichment and detection of isolated breast carcinoma cells in bone marrow and peripheral blood. J Hematother 1997;6:103–114.

    PubMed  CAS  Google Scholar 

  69. Martin VM, Siewert C, Scharl A, et al. Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol 1998;26:252–264.

    PubMed  CAS  Google Scholar 

  70. Naume B, Borgen E, Nesland JM, et al. Increased sensitivity for detection of micrometastases in bone marrow/peripheral-blood stem-cell products from breast cancer patients by negative immunomagnetic separation. Int J Cancer 1998;78:556–560.

    PubMed  CAS  Google Scholar 

  71. Racila E, Euhus D, Weiss AJ, et al. Detection and characterization of carcinoma cells in the blood. PNAS 1998;95:4589–4594.

    PubMed  CAS  Google Scholar 

  72. Kruger WH, Kroger N, Togel F, et al. Disseminated breast cancer cells prior to and after high-dose therapy. J Hematother Stem Cell Res 2001;10:681–689.

    PubMed  CAS  Google Scholar 

  73. Rye PD, Hoifodt HK, Overli GE, Fodstad O. Immunobead filtration: a novel approach for the isolation and propagation of tumor cells. Am J Pathol 1997;150:99–106.

    PubMed  CAS  Google Scholar 

  74. Zippelius A, Lutterbuse R, Riethmuller G, Pantel K. Analytical variables of reverse transcription-polymerase chain reaction-based detection of disseminated prostate cancer cells. Clin Cancer Res 2000;6:2741–2750.

    PubMed  CAS  Google Scholar 

  75. Zippelius A, Kufer P, Honold G, et al. Limitations of reverse transcriptase-poly-merase chain reaction for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol 1997;15:2701–2708.

    PubMed  CAS  Google Scholar 

  76. Bosma AJ, Weigelt B, Lambrechts AC, et al. Detection of circulating breast tumor cells by differential expression of marker genes. Clin Cancer Res 2002;8:1871–1877.

    PubMed  CAS  Google Scholar 

  77. Taback B, Chan AD, Kuo CT, et al. Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease. Cancer Res 2001;61:8845–8850.

    PubMed  CAS  Google Scholar 

  78. Slade MJ, Smith BM, Sinnett HD, Cross NCP, Coombes RC. Quantitative poly-merase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol 1999;17:870–879.

    PubMed  CAS  Google Scholar 

  79. Zach O, Kasparu H, Krieger O, Hehenwarter W, Girschikofsky M, Lutz D. Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA. J Clin Oncol 1999;17:2015–2019.

    PubMed  CAS  Google Scholar 

  80. Vannucchi AM, Bosi A, Glinz S, et al. Evaluation of breast tumour cell contamination in the bone marrow and leukapheresis collections by RT-PCR for cytokeratin-19 mRNA. Br J Haematol 1998;103:610–617.

    PubMed  CAS  Google Scholar 

  81. Fields KK, Elfenbein GJ, Trudeau WL, Perlinss JB, Jansen WE, Moscinski LC. Clinical significance of bone marrow metastases as detected using polymerase chain reaction in patients with breast cancer undergoing high-dose chemotherapy and autologous bone marrow transplantation. J Clin Oncol 1996;14:1868–1876.

    PubMed  CAS  Google Scholar 

  82. Datta YH, Adams PT, Drobyski WR. Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain re action. J Clin Oncol 1994;12:475–482.

    PubMed  CAS  Google Scholar 

  83. Auer M, Fiegl H, Riha K, Daxenbichler G, Braun S, Marth C. Parallel immuno-magnetic enrichment and cytokeratin-19 reverse transcriptase PCR for occult metastatic tumor cell detection in bone marrow of breast and ovarian cancer patients. Proc AACR 2003;44:782–783 (Abstr 3424).

    Google Scholar 

  84. Grunewald K, Haun M, Urbanek M, et al. Mammaglobin gene expression: a superior marker of breast cancer cells in peripheral blood in comparison to epidermal-growth-factor receptor and cytokeratin-19. Lab Invest 2000;80:1071–1077.

    PubMed  CAS  Google Scholar 

  85. Lambrechts AC, Bosma AJ, Klaver SG, et al. Comparison of immunocytochem-istry, reverse transcriptase polymerase chain reaction, and nucleic acid sequence-based amplification for the detection of circulating breast cancer cells. Breast Cancer Res Treat 1999;56:219–231.

    PubMed  CAS  Google Scholar 

  86. Mapara MY, Körner IJ, Hildebrandt M, et al. Monitoring of tumor cell purging after highly efficient immunomagnetic selection of CD34 cells from leukapheresis products in breast cancer patients: comparison of immunocytochemical tumor cell staining and reverse transcriptase-polymerase chain reaction. Blood 1997;89:337–344.

    PubMed  CAS  Google Scholar 

  87. Krismann M, Todt B, Schröder J, et al. Low specificity of cytokeratin 19 reverse transcriptase-polymerase chain reaction analyses for detection of hematogenous lung cancer dissemination. J Clin Oncol 1995;13:2769–2775.

    PubMed  CAS  Google Scholar 

  88. van Trappen PO, Gyselman VG, Lowe DG, et al. Molecular quantification and mapping of lymph-node micrometastases in cervical cancer. Lancet 2001;357:15–20.

    PubMed  Google Scholar 

  89. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–428.

    PubMed  CAS  Google Scholar 

  90. Widschwendter M, Jones PA. DNA methylation and breast carcinogenesis. Oncogene 2002;21:5462–5482.

    PubMed  CAS  Google Scholar 

  91. Laird PW. Early detection: the power and the promise of DNA methylation markers. Nat Rev Cancer 2003;3:253–266.

    PubMed  CAS  Google Scholar 

  92. Muller HM, Widschwendter A, Fiegl H, et al. DNA Methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res 2003;63:7641–7645.

    PubMed  Google Scholar 

  93. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment. Blood 2002;100:2957–2964.

    PubMed  CAS  Google Scholar 

  94. Berger U, Bettelheim R, Mansi JL, Easton D, Coombes RC, Neville AM. The relationship between micrometastases in the bone marrow, histopathologic features of the primary tumor in breast cancer and prognosis. Am J Clin Pathol 1988;90:1–6.

    PubMed  CAS  Google Scholar 

  95. Cote RJ, Rosen PP, Hakes TB, et al. Monoclonal antibodies detect occult breast carcinoma metastases in the bone marrow of patients with early stage disease. Am J Surg Pathol 1988;12:333–340.

    PubMed  CAS  Google Scholar 

  96. Mansi JL, Easton D, Berger U, et al. Bone marrow micrometastases in primary breast cancer: prognostic significance after 6 years’ follow-up. Eur J Cancer 1991;27:1552–1555.

    PubMed  CAS  Google Scholar 

  97. Hermanek P, Hutter RV, Sobin LH, Wittekind C. Classification of isolated tumor cells and micrometastases. Cancer 1999;86:2668–2673.

    PubMed  CAS  Google Scholar 

  98. Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer Staging System for Breast Cancer. J Clin Oncol 2002;20:3628–3636.

    PubMed  Google Scholar 

  99. Thurm H, Ebel S, Kentenich C, et al. Rare expression of epithelial cell adhesion molecule on residual micrometastatic breast cancer cells after adjuvant chemotherapy. Clin Cancer Res 2003;9:2598–2604.

    PubMed  CAS  Google Scholar 

  100. Braun S, Kentenich CRM, 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;18:80–86.

    PubMed  CAS  Google Scholar 

  101. Braun S, Hepp F, Kentenich CRM, et al. Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res 1999;5:3999–4004.

    PubMed  CAS  Google Scholar 

  102. Pantel K, Enzmann T, Köllermann J, Caprano J, Riethmüller G, Köllermann MW. Immunocytochemical monitoring of micrometastatic disease: reduction of prostate cancer cells in bone marrow by androgen deprivation. Int J Cancer 1997;71:521–525.

    PubMed  CAS  Google Scholar 

  103. Schlimok G, Pantel K, Loibner H, Fackler-Schwalbe I, Riethmüller G. Reduction of metastatic carcinoma cells in bone marrow by intravenously administered monoclonal antibody: towards a novel surrogate test to monitor adjuvant therapies of solid tumours. Eur J Cancer 1995;31A:1799–1803.

    PubMed  CAS  Google Scholar 

  104. Janni W, Hepp F, Rjosk D, et al. The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence. Cancer 2001;92:46–53.

    PubMed  CAS  Google Scholar 

  105. Wiedswang G, Borgen E, Kåresen R, et al. Isolated tumor cells in bone marrow three years after diagnosis in disease free breast cancer patients predict unfavourable clinical outcome. Breast Cancer Res Treat 2003;82:S8 (Abstr 8).

    Google Scholar 

  106. Witzig TE, Bossy B, Kimlinger T, et al. Detection of circulating cytokeratin-positive cells in blood of breast cancerpatients using immunomagnetic enrichment and digital microscopy. Clin Cancer Res 2001;8:1085–1091.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Breast Center Tirol, Department of Obstetrics and Gynecology, University Hospital, Innsbruck, Austria

    Stephan Braun MD, Julia Seeber MD & Christian Marth MD

Authors
  1. Stephan Braun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Seeber MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian Marth MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Medical Oncology, “San Filippo Neri” Hospital, Rome, Italy

    Giampietro Gasparini MD

  2. Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI

    Daniel F. Hayes MD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Braun, S., Seeber, J., Marth, C. (2006). Occult Metastatic Cells in Breast Cancer Patients. In: Gasparini, G., Hayes, D.F. (eds) Biomarkers in Breast Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1385/1-59259-915-X:213

Download citation

Publish with us

Policies and ethics

Search

Navigation