Summary
The presence of cytokeratin-positive cells in the bone marrow of breast cancer patients has been proven to be an independent prognostic factor. Their fate in primary breast cancer patients undergoing adjuvant therapy is of particular interest. We investigated the bone marrow status of 112 patients undergoing postoperative adjuvant treatment before and after therapy. A total of 373 patients with histologically confirmed primary breast cancer underwent bone marrow aspiration at the time of primary surgery. All patients were informed of their bone marrow status and offered repeat aspiration after 12 months. All patients were then treated with adjuvant chemotherapy, endocrine therapy or both based on current treatment recommendations. About 112 patients returned for a second bone marrow aspiration after a mean interval of 12 months following the initiation of adjuvant treatment. In 93 of 112 patients (83%) disseminated tumor cells had been found in the bone marrow before initiation of systemic chemo/endocrine therapy. At the time of follow-up sampling, after surgery and completion of adjuvant chemotherapy, the positivity rate dropped to 24%. Positive bone marrow status during follow-up was only associated with grading (p=0.020). Adjuvant treatment regimens are not able to completely eliminate cytokeratin-positive cells from the bone marrow. Prospective studies need to evaluate, whether these cells could become targets for additional adjuvant therapy.
Similar content being viewed by others
References
Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B. (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancerJ Clin Oncol 21:3469–3478
Solomayer EF, Diel IJ, Salanti G, Hahn M, Gollan C, Schutz F, Bastert G. (2001) Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patientsClin Cancer Res 7:4102–4108
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 studyLancet 354:197–202
Diel IJ, Kaufmann M, Costa SD, Holle R, von Minckwitz G, Solomayer EF, Kaul S, Bastert G. (1996) Micrometastatic breast cancer cells in bone marrow at primary surgery – prognostic value in comparison with nodal statusJ Natl Cancer Inst 88:1652–1658
French Adjuvant Study Group 2001 Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19:602–611
Becker S, Becker-Pergola G, Fehm T, Wallwiener D, Solomayer EF, (2005) Her2-expression on disseminated tumor cells from bone marrow – correlation with the primary tumorAnticancer Res 25:2171–2175
Fehm T, Sagalowsky A, Clifford E, Beitsch P, Saboorian H, Euhus D, Meng S, Morrison L, Tucker T, Lane N, Ghadimi BM, Heselmeyer-Haddad K, Ried T, Rao C, Uhr J. (2002) Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignantClin Cancer Res 8:2073–2084
Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel, IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancerN Engl J Med 353(8):793–802
Jamshidi K, Swaim WR (1971) Bone marrow biopsy with unaltered architecture: a new biopsy deviceJ Lab Clin Med 77: 335–342
Kahlert S, von Koch F, Ditsch N, Untch M. (2004) Adjuvant treatment of breast cancer in 2004. A review of the 8th consensus conference of St. Gallen and new study results. Gynakol Geburtsh Rundsch 44:102–112
Becker S, Becker-Pergola G, Fehm T, Emig R, Wallwiener D, Solomayer EF. (2005) Image analysis systems for the detection of disseminated breast cancer cells on bone marrow cytospinsJ Clin Lab Anal 19:115–119
Borgen E, Naume B, Nesland JM, Kvalheim G, Beiske K, Fodstad O, et al. (1999) Standardization of the immunological detection of cancer cells in bone marrow and blood: Establishment of objective criteria for the evaluation of immunostained cellsCytotherapy 5:377–388
American Cancer Society. (2004) Cancer Facts & Figures American Cancer Society, Inc., Atlanta
Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, Aguilar M, Marubini E. (2002) Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancerN Engl J Med 347:1227–1232
Veronesi U, Banfi A, Saccozzi R, et al. (1977) Conservative treatment of breast cancer: a trial in progress at the Cancer Institute in MilanCancer 39:2822–2826
Bonadonna G, Brusamolino E, Valagussa P Rossi A, Brugnatelli L, Brambilla C, et al. (1976) Combination chemotherapy as an adjuvant treatment in operable breast cancerN Engl J Med 294:405–410
Early Breast Cancer Trialists’ Collaborative Group. (1995) Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trialsN Engl J Med 333:1444–1455
van Dongen JA, Voogd AC, Fentiman IS, Legrand C, Sylvester RJ, Tong D, van der Schueren E, Helle PA, van Zijl K, Bartelink H. (2000) Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trialJ Natl Cancer Inst 92:1143–1150
Fisher B, Jeong J-H, Anderson S, Bryant J, Fisher ER, Wolmark N. (2002) Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiationN Engl J Med 347:567–575
Klein CA, Schmidt-Kittler O, Schardt JA, Pantel K, Speicher MR, Riethmuller G. (1999) Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cellsProc Natl Acad Sci 96:4494–4499
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-upBreast Cancer Res Treat 49:27–33
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G. (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancerN Engl J Med. 342:525–33 Erratum in: N Engl J Med 343:308 2000
Gerber B, Krause A, Muller H, Richter D, Reimer T, Makovitzky J, Herrnring C, Jeschke U, Kundt G, Friese K. (2001) Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factorsJ Clin Oncol 19:960–971
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 therapyJ Clin Oncol 19:1468–1475
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 patientsJ Clin Oncol 18:80–86
Schlimok G, Pantel K, Loibner H, Fackler-Schwalbe I, Riethmuller G. (1995) Reduction of metastatic carcinoma cells in bone marrow by intravenously administered monoclonal antibody: towards a novel surrogate test to monitor adjuvant therapies of solid tumoursEur J Cancer 31A:1799–1803
Hohaus S: Persistence of isolated tumor cells in patients with breast cancer after sequential high dose therapy with peripheral blood stem cell transplantation. Blood 88, 128A (Abstract 501)
Janni W, Hepp F, Rjosk D, Kentenich C, Strobl B, Schindlbeck C, Hantschmann P, Sommer H, Pantel K, Braun S. (2001) The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrenceCancer 92:46–53
Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesland JM, Naume B. (2004) Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcomeClin Cancer Res 10:5342–5348
Slade MJ, Singh A, Smith BM, Tripuraneni G, Hall E, Peckitt C, Fox S, Graham H, Luchtenborg M, Sinnett HD, Cross NC, Coombes RC. (2004) Persistence of bone marrow micrometastases in patients receiving adjuvant therapy for breast cancer: results at 4 yearsInt J Cancer 114:94–100
Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G. (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cellsJ Natl Cancer Inst 85:1419–1424
Slamon JD, Leyland-Jones B, Shak S, et al (1998) Addition of HerceptinTM (humanized anti-HER2 antibody) to first-line chemotherapy for HER2 overexpressing metastatic breast cancer markedly increases anti-cancer activity: a randomized, multinational controlled phase III trialProc Natl Acad Sci USA 17:98 (abstr 377)
Solomayer E-F, Diel IJ, Wallwiener D, Bode S, Meyberg G, Sillem M, Gollan C, Kramer MD, Krainick U, Bastert G. (1997) Prognostic relevance of urokinase plasminogen activator in micrometastatic cells in the bone marrow of patients with primary breast cancerBr J Cancer 76: 812–818
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Becker, S., Becker-Pergola, G., Wallwiener, D. et al. Detection of cytokeratin-positive cells in the bone marrow of breast cancer patients undergoing adjuvant therapy. Breast Cancer Res Treat 97, 91–96 (2006). https://doi.org/10.1007/s10549-005-9095-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-005-9095-6