Abstract
We studied cytokeratin-positive (CK+) cells in the bone marrow (BM) and tumor markers (TM) in the blood of 128 patients with primary breast cancer in order to obtain an early diagnosis of residual disease. CK+ cells of two BM aspirations were detected by immunocytochemistry (IC). To evaluate the usefulness of immunomagnetic separation (IMS) for tumor cell enrichment in clinical samples, IMS was performed prior to IC and compared with the results for IC alone. The overall CK+ rate was 34% (44/128 patients), 29% (15/51) for patients with T1 tumors, 33% (28/84) for N0 patients and 31% (26/82) for patients with G1-2 breast carcinoma. Interestingly, 67% of CK+ patients were only positive in one of the two aspirates studied. A comparison between IC alone and IMS/IC could be performed in 70/128 patients (28/70 CK+). In 6/28 patients, CK+ cells were detected by both methods, in 16/28 patients only by IC and in 6/28 patients only by IMS. At least one TM, including carcinoembryonic antigen, carbohydrate antigen 15-3 and tissue polypeptide antigen, was increased in 58/128 (45%) patients [21/58 (36%) were CK+ in the BM]. Surprisingly, levels for the extracellular domain of Her-2/neu in serum samples were within the normal range in every patient studied. After a 2-year follow-up, 7/128 patients relapsed (3/7 CK+/TM−; 2/7 CK−/TM+; 2/7 CK−/TM−). We conclude that studying two BM aspirates for CK+ cells by IC in combination with TM determination is useful for identifying patients with a higher risk for relapse, however, tumor cell enrichment techniques will have to be improved for clinical use.
Similar content being viewed by others
References
Veronesi U, Luini A, Galimberti V, Marchini S, Sacchini V, Rilke F: Extent of metastatic axillary involvement in 1446 cases of breast cancer. Eur J Surg Oncol 16: 127-133, 1990
Pectasides D, Pavlidis N, Gogou L, Antoniou F, Nicolaides C, Tsikalakis D, Fountzilas G: Clinical value of CA 15-3, mucin-like carcinoma-associated antigen, tumor polypeptide antigen, and carcinoembryonic antigen in monitoring early breast cancer patients. Am J Clin Oncol 19: 459-464, 1996
Nicolini A, Carpi A, Ferrari P, Anselmi L: Clinical use of tumour markers in the postoperative management of breast cancer patients: new concepts. Int J BiolMarkers 12: 181-186, 1997
Nicolini A, Ferrari P, Sagripanti A, Carpi A: The role of tumour markers in predicting skeletal metastases in breast cancer patients with equivocal bone scintigraphy. Br J Cancer 79: 1443-1447, 1999
Findeisen R, Albrecht S, Richter B, Deutschmann K, Distler W: Comparison of tissue polypeptide antigen (TPA) with cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) in follow-up of breast cancer. Clin Chem Lab Med 36: 841-846, 1998
Barrenetxea G, Schneider J, Llorente MF: Use of serum tumor markers for the diagnosis and follow-up of breast cancer. Oncology 55: 447-449, 1998
Leitzel K, Teramoto Y, Konrad K, Chinchilli VM, Volas G, Grossberg H, Harvey H, Demers L, Lipton A: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13: 1129-1135, 1995
Yamauchi H, O'Neill A, Gelman R, Carney WP, Tenney DY, Hösch S, Hayes DF: Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol 15: 2518-2525, 1997
Vargas-Roig LM, Gago, FE, Tello O, Martin de Civetta MT, Ciocca DR: c-erbB-2 (HER-2/neu) protein and drug resistance in breast cancer patients treated with induction chemotherapy. Int J Cancer 84: 129-134, 1999
Diel IJ, Kaufmann M, Costa SD, Holle R, Von Minckwitz G, Solomayer EF, Kaul S, Bastert G: Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 88: 1652-1664, 1996
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 90: 1-6, 1988
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 9: 1749-1756, 1991
Dearnaley DP, Ormerod MG, Sloane JP: Micrometastases in breast cancer: long-term follow-up of the first patient cohort. Eur J Cancer 27: 236-239, 1991
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 69: 566-571, 1994
Molino A, Pelosi G, Turazza M, Sperotto L, Bonetti A, Nortilli R, Fattovich G, Alaimo C, Piubello Q, Pavanel F, Micciolo R, Cetto GL: Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features and prognosis. Breast Cancer Res Treat: 42: 23-30, 1997
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 study. Lancet 354: 197-202, 1999
Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki R, Riethmüller G: Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85: 1419-1424, 1993
Braun S, Hepp F, Sommer HL, Pantel K: Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 84: 1-5, 1999
Braun S, Kentenich C, Janni W, Hepp F, DeWaal J, Willgeroth F, Sommer HL, Pantel K: 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: 80-86, 2000
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklar in NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L: Phase II study of weekly intravenous recombinant humanized antip185-HER2 monoclonal antibody in patients with HER2/neu overexpressing metastatic breast cancer. J Clin Oncol 14: 737-744, 1996
Braun S, Hepp F, Kentenich CRM, Janni W, Pantel K, Riethmüller G, Willgeroth F, Sommer HL: Monoclonal antibody therapy with Edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res 5: 3999-4004, 1999
Pantel K, Cote RJ, Fodstad O: Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 91: 1113-1124, 1999
Griwatz C, Brandt B, Assmann G, Zänker KS: An immunological enrichment method for epithelial cells from peripheral blood. J Immunol Methods 183: 251-265, 1995
Naume B, Borgen E, Beiske K, Herstad T, Ravnas G, Renolen A, Thrane-Stehen K, Trachsel S, Funderud S, Kvalheim G: Detection of isolated breast carcinoma cells in peripheral blood or bone marrow by immunomagnetic techniques. J Hematother 6: 103-113, 1997
Naume B, Borgen E, Nesland JM, Beiske K, Gilen E, Renolen A, Ravnas G, Qvist H, Karesen R, Kvalheim G: 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 78: 556-560, 1998
Martin VM, Siewert C, Scharl A, Harms T, Heinze R, Öhl S, Radbruch A, Miltenyi S, Schmitz J: Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol 26: 252-264, 1998
Nekarda H, Geß C, Stark M, Mueller JD, Fink U, Schenck U, Siewert JR: Immunocytochemically detected free peritoneal tumour cells (FPTC) are a strong prognostic factor in gastric carcinoma. Br J Cancer 79: 611-619, 1999
Braun S, Pantel K, Müller P, Janni W, Hepp F, Kentenich CRM, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmüller G, Schlimok G: Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. New Engl J Med 342: 525-533, 2000
Cote RJ, Peterson HF, Chaiwun B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Gusterson B, Neville AM, for the International Breast Cancer Study Group: Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. Lancet 354: 896-900, 1999
Hermanek P: pTNM and residual tumor classifications: problems of assessment and prognostic significance. World J Surg 19: 184-190, 1995
Braun S, Müller P, 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 90: 1099-1101, 1998
Hohaus S, Funk L, Brehm M, Abdallah A, Murea S, Kaul S, Haas R: Persistence of isolated tumor cells in patients with breast cancer after sequential high-dose therapy with peripheral blood stem cell transplantation (abstr 501). Blood 88: 128a (suppl 1), 1996
Hempel D, Müller P, Oruzio D, Ehnle S, Schlimok G: Adoptive immunotherapy with the monoclonal antibody 17-1A to reduce minimal residual disease in breast cancer patients after high-dose chemotherapy (abstr 4454). Blood 90: 379b (suppl 1), 1997
Kasimir-Bauer S, Mayer S, Bojko P, Borquez D, Neumann R, Seeber S: Survival of tumor cells in stem cell pre parations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy. Clin Cancer Res 7: 1582-1589, 2001
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kasimir-Bauer, S., Oberhoff, C., Sliwinska, K. et al. Evaluation of different methods for the detection of minimal residual disease in blood and bone marrow of patients with primary breast cancer: importance for clinical use?. Breast Cancer Res Treat 69, 123–132 (2001). https://doi.org/10.1023/A:1012288201969
Issue Date:
DOI: https://doi.org/10.1023/A:1012288201969