Skip to main content

Detection of disseminated tumor cells in the bone marrow and blood of breast cancer patients

  • Chapter
Book cover Metastasis of Breast Cancer

Part of the book series: Cancer Metastasis – Biology and Treatment ((CMBT,volume 11))

  • 1185 Accesses

Abstract

Early tumor cell dissemination can be detected in patients with breast cancer using immunocytochemical and molecular assays based on the use of monoclonal antibodies or PCR. Studies involving more than 4,000 breast cancer patients have demonstrated now that the presence of disseminated tumor cells (DTC) in bone marrow (BM) identified with immuncytochemical assays at primary diagnosis is a strong prognostic factor. The published studies for the detection of disseminated tumor cells in bone marrow fulfill the highest level of evidence as prognostic markers in primary breast cancer. In addition, various assays for the detection of circulating tumor cells in the peripheral blood have been recently developed and some studies suggest a potential clinical relevance of this parameter as prognostic and predictive factor. Advanced methods for molecular characterization of single tumor cells have been developed lately and this approach allows new insights into the metastatic cascade and characterization of targets for therapeutic approaches. These findings provide the basis for the implementation of DTC in BM or blood as markers for stratification and assessment of therapies in prospective clinical trials. The valuable information derived from these trials should help to improve future treatment of breast cancer patients.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
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. 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.

    Article  PubMed  Google Scholar 

  2. Gebauer G, Fehm T, Merkle E, et al. 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 

  3. 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.

    Article  PubMed  CAS  Google Scholar 

  4. 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 

  5. Braun S, Vogl FD, Naume B, et al. International Pooled Analysis of Prognostic Significance of Bone Marrow Micrometastasis in Patients with Stage I, II, or III Breast Cancer. N Engl J Med 2005; 353:793-802.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Braun S, Pantel K, Muller 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Braun S, Pantel K. Micrometastatic bone marrow involvement: detection and prognostic significance. Med Oncol 1999; 16:154-165.

    Article  PubMed  CAS  Google Scholar 

  10. Borgen E, Naume B, Nesland JM, et al. Standardization of the immuno- cytochemical detection of cancer cells in BM and blood: I. establishment of objecive criteria for the evaluation of immunostained cells. Cytometry 1999; 1:377-388.

    CAS  Google Scholar 

  11. Fehm T, Braun S, Müller V, et al. A concept for the standardized detection of disseminated tumor cells in bone marrow of patients with primary breast cancer and its clinical implementation. In press 2006.

    Google Scholar 

  12. Witzig TE, Bossy B, Kimlinger T, et al. Detection of circulating cytokeratin- positive cells in the blood of breast cancer patients using immunomagnetic enrichment and digital microscopy. Clin Cancer Res 2002; 8:1085-1091.

    PubMed  Google Scholar 

  13. Kraeft SK, Ladanyi A, Galiger K, et al. Reliable and sensitive identification of occult tumor cells using the improved rare event imaging system. Clin Cancer Res 2004; 10:3020-3028.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    Article  PubMed  CAS  Google Scholar 

  15. Kraeft SK, 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 

  16. 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 

  17. Mehes G, Luegmayr A, Ambros IM, Ladenstein R, Ambros PF. Combined auto- matic immunological and molecular cytogenetic analysis allows exact identification and quantification of tumor cells in the bone marrow. Clin Cancer Res 2001; 7:1969-1975.

    PubMed  CAS  Google Scholar 

  18. Rosenberg R, Gertler R, Friederichs J, et al. Comparison of two density gradient centrifugation systems for the enrichment of disseminated tumor cells in blood. Cytometry 2002; 49:150-158.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. Woelfle U, Breit E, Zafrakas K, et al. Bi-specific immunomagnetic enrichment of micrometastatic tumour cell clusters from bone marrow of cancer patients. J Immunol Methods 2005; 300:136-145.

    Article  PubMed  CAS  Google Scholar 

  21. Symmans WF, Liu J, Knowles DM, Inghirami G. Breast cancer heterogeneity: evaluation of clonality in primary and metastatic lesions. Hum.Pathol. 1995; 26:210-216.

    Article  PubMed  CAS  Google Scholar 

  22. Braun S, Hepp F, Sommer HL, Pantel K. Tumor-antigen heterogeneity of disse- minated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 1999; 84:1-5.

    Article  PubMed  CAS  Google Scholar 

  23. Datta YH, Adams PT, Drobyski WR, et al. Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction. J Clin Oncol 1994; 12:475-482.

    PubMed  CAS  Google Scholar 

  24. Stathopoulou A, Ntoulia M, Perraki M, et al. 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. Int J Cancer 2006.

    Google Scholar 

  25. Xenidis N, Perraki M, Kafousi M, et al. 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. J Clin Oncol 2006; 24:3756-3762.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  27. Bostick PJ, Chatterjee S, Chi DD, et al. Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. J Clin Oncol 1998; 16:2632-2640.

    PubMed  CAS  Google Scholar 

  28. Jung R, Kruger W, Hosch S, et al. Specificity of reverse transcriptase polymerase chain reaction assays designed for the detection of circulating cancer cells is influenced by cytokines in vivo and in vitro. Br J Cancer 1998; 78:1194-1198.

    PubMed  CAS  Google Scholar 

  29. Klein CA, Blankenstein TJ, Schmidt-Kittler O, et al. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 2002; 360:683-689.

    Article  PubMed  CAS  Google Scholar 

  30. Gangnus R, Langer S, Breit E, Pantel K, Speicher MR. Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clin Cancer Res 2004; 10:3457-3464.

    Article  PubMed  CAS  Google Scholar 

  31. Brandt B, Roetger A, Heidl S, et al. Isolation of blood-borne epithelium-derived c-erbB-2 oncoprotein-positive clustered cells from the peripheral blood of breast cancer patients. Int J Cancer 1998; 76:824-828.

    Article  PubMed  CAS  Google Scholar 

  32. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659-1672.

    Article  PubMed  CAS  Google Scholar 

  33. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673-1684.

    Article  PubMed  CAS  Google Scholar 

  34. Wülfing P, Borchard J, Buerger H, et al. HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res 2006; 12:1715-1720.

    Article  PubMed  Google Scholar 

  35. 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; 61:1890-1895.

    PubMed  CAS  Google Scholar 

  36. 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.

    Article  PubMed  CAS  Google Scholar 

  37. Müller V, Stahmann N, Riethdorf S, et al. Circulating Tumor Cells in Breast Cancer: Correlation to Bone Marrow Micrometastases, Heterogeneous Response to Systemic Therapy and Low Proliferative Activity. Clin Cancer Res 2005; 11: 3678-85.

    Article  PubMed  Google Scholar 

  38. 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 

  39. Bernards R, Weinberg RA. A progression puzzle. Nature 2002; 418:823.

    Article  PubMed  CAS  Google Scholar 

  40. Calaluce R, Miedema BW, Yesus YW. Micrometastasis in colorectal carcinoma: a review. J Surg Oncol 1998; 67:194-202.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  42. Funke I, Schraut W. Meta-analyses of studies on bone marrow micrometastases: an independent prognostic impact remains to be substantiated. J Clin Oncol 1998; 16:557-566.

    PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  Google Scholar 

  44. Braun S, Hepp F, Kentenich CR, 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 

  45. 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; 10:5342-5348.

    Article  PubMed  Google Scholar 

  46. 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; 88:1652-1658.

    Article  PubMed  CAS  Google Scholar 

  47. Mansi JL, Gogas H, Bliss JM, et al. Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet 1999; 354:197-202.

    Article  PubMed  CAS  Google Scholar 

  48. 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 

  49. 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 

  50. 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; 10:1392-1400.

    Article  PubMed  CAS  Google Scholar 

  51. Wiedswang G, Borgen E, Schirmer C, et al. Comparison of the clinical signi- ficance of occult tumor cells in blood and bone marrow in breast cancer. Int J Cancer 2006; 118:2013-2019.

    Article  PubMed  CAS  Google Scholar 

  52. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351:781-791.

    Article  PubMed  CAS  Google Scholar 

  53. Cristofanilli M, Hayes DF, Budd GT, et al. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2005; 23:1420-1430.

    Article  PubMed  Google Scholar 

  54. Meng S, Tripathy D, Shete S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 2004; 101:9393-9398.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer

About this chapter

Cite this chapter

Müller, V., Pantel, K. (2007). Detection of disseminated tumor cells in the bone marrow and blood of breast cancer patients. In: Mansel, R.E., Fodstad, O., Jiang, W.G. (eds) Metastasis of Breast Cancer. Cancer Metastasis – Biology and Treatment, vol 11. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-5867-7_16

Download citation

Publish with us

Policies and ethics