Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Circulating Tumour Cells

Prognostic significance of the detection of tumour cells in peripheral blood stem cell collections in stage II and III breast cancer patients treated with high-dose therapy

Summary:

The purpose of this study was to evaluate the incidence and extent of tumour cell contamination in bone marrow specimens and stem cell collections from 34 breast cancer patients undergoing high-dose therapy as adjuvant treatment, and to determine the prognostic significance for the clinical outcome. Tumour cell contamination was evaluated by flow cytometry using a double-colour test and an anti- Pan cytokeratin (CK) antibody. Two out of 34 (6%) baseline bone marrow specimens, none of seven marrow harvests and nine out of 32 aphereses (28%) mobilised from seven out of 27 patients (26%) contained CK+ cells. Tumour contamination was more frequent in patients with 10 or more involved lymph nodes and in those who received a shorter course of adjuvant chemotherapy before mobilisation. At a median follow-up of 43 months, 24 patients are in complete remission, whereas 10 patients experienced recurrence. Out of the 10 patients who relapsed, five (50%) had CK+ peripheral blood stem cell (PBSC) collections, whereas disease recurrence was seen in only two out of 24 (8%) patients who received CK− products (P=0.02). Moreover, CK+ PBSC collections were associated with a significantly shorter event-free survival and overall survival. CK+ collection is an unfavourable prognostic factor for patients treated with high-dose therapy. Whether the negative impact on clinical outcome depends on reinfusion of tumour cells or whether it simply indicates a larger disease extension is still unclear.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Henderson BE, Ross RK, Pike MC . Toward the primary prevention of cancer. Science 1991; 254: 1131–1137.

    Article  CAS  PubMed  Google Scholar 

  2. Bonadonna G, Valagussa P, Moliterni A et al. Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-positive breast carcinoma. N Engl J Med 1995; 332: 901–906.

    Article  CAS  PubMed  Google Scholar 

  3. Peters WP, Rossner G, Vredenburgh J et al. A prospective randomised comparison of two doses of combination alkylating agents as consolidation after CAF in high risk primary breast cancer involving ten or more axillary lymphnodes: preliminary results of CALGB 9082. Proc Am Soc Clin Oncol 1999; 18: 2a.

    Google Scholar 

  4. The Scandinavian Breast Cancer Study Group 9401. Results from a randomized adjuvant breast cancer study with high-dose chemotherapy with CTCb supported by autologous bone marrow stem cells vs dose escalated and tailored FEC therapy. Proc Am Soc Clin Oncol 1999; 18: 3a.

    Google Scholar 

  5. Rodenhuis S, Richel DJ, van der Wall et al. Randomized trial of high dose chemotherapy and hematopoietic progenitors-cell support in operable breast cancer with extensive axillary lymphnode involvement. Lancet 1998; 2325: 515–521.

    Article  Google Scholar 

  6. Hortobagy GN, Buzar AU, Champlin R, Gajewski J . Lack of efficacy of adjuvant high dose tandem combination chemotherapy for high-risk primary breast cancer – a randomized trial. Proc Am Soc Clin Oncol 1998; 17: 471.

    Google Scholar 

  7. Gluck S, Stewart D . High-dose therapy in breast cancer: out of favour but not out of promise. Bone Marrow Transplant 2000; 1017–1019.

  8. Redding WH, Coombes RC, Monaghan P et al. Detection of micrometastases in patients with primary breast cancer. Lancet 1983; 2: 271–274.

    Google Scholar 

  9. Berger U, Bettelheim R, Mansi JL et al. The relationship between micrometastases in the bone marrow, histopathologic features of the primary tumour in breast cancer and prognosis. Am J Clin Pathol 1988; 90: 1–6.

    Article  CAS  PubMed  Google Scholar 

  10. Dearnaley DP, Ormerod MG, Sloane JP . Micrometastases in breast cancer: long term follow-up of a first patient cohort. Eur J Cancer 1991; 27: 236–239.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. Harbeck N, Untch M, Pache L . Tumour 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Funke I, Schraut W . Meta-analyses of studies on bone marrow micrometastases: an independent prognostic impact remains to be substantiated. J Clin Oncol 1998; 2: 557–566.

    Article  Google Scholar 

  15. Gianni AM, Siena S, Bregni M et al. Efficacy, toxicity and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five year results. J Clin Oncol 1997; 6: 2312–2321.

    Article  Google Scholar 

  16. Vannucchi AM, Bosi A, Glinnz 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.

    Article  CAS  PubMed  Google Scholar 

  17. Fields KK, Elfenbein GJ, Trudeau WL et al. Clinical significance of bone marrow metastases as detected using the polymerase chain reaction in patients with breast cancer undergoing high-dose chemotherapy and autologous bone marrow transplantation. J Clin Oncol 1996; 6: 1868–1876.

    Article  Google Scholar 

  18. Shulze R, Schulze M, Wischnik A et al. Tumour contamination of peripheral blood stem cell transplants and bone marrow in high-risk breast cancer patients. Bone Marrow Transplant 1997; 19: 1223–1228.

    Article  Google Scholar 

  19. Franklin WA, Glapsy J, Pflaumer SM et al. Incidence of tumour-cell contamination in leukapheresis products of breast cancer patients mobilized with stem factor and granulocyte colony-stimulating factor (G-CSF) or with G-CSF alone. Transplantation 1999; 94: 340–347.

    CAS  Google Scholar 

  20. Lalle M, De Rosa L, Marzetti L et al. Detection of breast cancer cells in the bone marrow or peripheral blood: methods and prognostic significance. Tumori 2000; 86: 183–190.

    Article  CAS  PubMed  Google Scholar 

  21. Vredenburgh JJ, Silva O, Tyer C et al. A comparison of immunohistochemistry, two colour- immunofluorescence and flow cytometry with cell sorting for the detection of micrometastatic breast cancer in the bone marrow. J Haemather 1996; 5: 57–62.

    Article  CAS  Google Scholar 

  22. Gluck S, Ross A, Layton TJ et al. Detection in tumour cell contamination and progenitor yield in leukapheresis products after consecutive cycles of chemotherapy for breast cancer patients. Biol Blood Marrow Transplant 1999; 6: 316–323.

    Google Scholar 

  23. Moreb J, Cooper B, Wingard JR et al. The prognostic value of immunocytochemical analysis on bone marrow taken from patients with stage II/III breast cancer undergoing autologous transplant therapy. Blood 1997; 90: 1703a.

    Google Scholar 

  24. Moss TJ, Umiel T, Herzig RM et al. The presence of clonogenic breast cancer cells in peripheral blood stem cell (PBSC) products correlates with an extremely poor prognosis for patients with stage IV disease. Proc Am Soc Clin Oncol 1998; 17: 409a.

    Google Scholar 

  25. Myers SE, Mick R, Williams SF . High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved marrow: a role for peripheral blood progenitor transplant. Bone Marrow Transplant 1994; 13: 449–454.

    CAS  PubMed  Google Scholar 

  26. Umiel T, Moss TJ, Cooper B et al. The prognostic value of bone marrow micrometastases in stage II/III breast cancer patients undergoing autologous transplant therapy. Proc Am Soc Clin Onc 1998; 17: 306a.

    Google Scholar 

  27. Ross AA, Copper BW, Lazarus HM et al. Detection and viability of tumour cells in peripheral blood stem cell collections from breast cancer patients using an immunocytochemical and clonogenic assay techniques. Blood 1993; 9: 2605–2610.

    Google Scholar 

  28. Shpall EJ, Jones RB . Release of tumour cells from bone marrow. Blood 1994; 3: 623–625.

    Google Scholar 

  29. Brugger W, Bross KJ, Glatt M et al. Mobilization of tumor cells and haematopoietic progenitors cells into peripheral blood in patients with solid tumours. Blood 1994; 3: 636–640.

    Google Scholar 

  30. Passos-Coelho JL, Ross AA, Moss TJ et al. Absence of breast cancer cells in a single-day peripheral blood progenitor cell collection after priming with cyclophosphamide and granulocyte-macrophage colony-stimulating factor. Blood 1995; 4: 1138–1143.

    Google Scholar 

  31. Weaver CH, Moss T, Schwartzberg LS et al. High-dose chemotherapy in patients with breast cancer: evaluation of infusing peripheral blood stem cells containing occult tumor cells. Bone Marrow Transplant 1998; 21: 1117–1124.

    Article  CAS  PubMed  Google Scholar 

  32. Cooper B, Moss JT, Ross AA et al. Occult tumour contamination of haemopoietic stem-cell products does not affect clinical outcome of autologous transplantation in patients with metastatic breast cancer. J Clin Oncol 1998; 11: 3509–3517.

    Article  Google Scholar 

  33. Sphall EJ, Jones RB, Bearman SI et al. Transplantation of enriched CD34 positive autologous marrow into breast cancer patients following high-dose chemotherapy: influence of CD 34 positive peripheral blood progenitors and growth factors on engrafment. J Clin Oncol 1994; 1: 28–36.

    Google Scholar 

  34. Mapara MY, Korner IJ, Hillebrandt et al. Monitoring of tumour cell purging after highly efficient immunomagnetic selection of CD 34 cells from leukapheresis products in breast cancer patients: comparison of immunocytochemical tumour staining and reverse transcriptase-polymerase chain reaction. Blood 1997; 1: 337–344.

    Google Scholar 

  35. Yanovich S, Mitsky P, Cornetta K et al. Transplantation of CD34+ peripheral blood cells selected using a fully automated immunomagnetic system in patients with high-risk breast cancer: results of a prospective randomized multicenter clinical trial. Bone Marrow Transplant 2000; 11: 1165–1174.

    Article  Google Scholar 

  36. Preti RA, Lazarus HM, Winter J et al. Tumour cell depletion of peripheral blood progenitor cells using positive and positive/negative selection in metastatic breast cancer. Cytotherapy 2001; 2: 85–95.

    Article  Google Scholar 

  37. Burgess J, Mills B, Griffith M et al. Reduction of breast cancer cell in peripheral blood stem cell product by positive selection of CD34+ cells. J Hematother 1998; 7: 285.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patriarca, F., Sacco, C., Sperotto, A. et al. Prognostic significance of the detection of tumour cells in peripheral blood stem cell collections in stage II and III breast cancer patients treated with high-dose therapy. Bone Marrow Transplant 31, 789–794 (2003). https://doi.org/10.1038/sj.bmt.1703929

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1703929

Keywords

This article is cited by

Search

Quick links