Breast cancer is the most frequent neoplastic disease in populations of developed countries. It will affect 1 of every 6 or 7 women during their lifetime. The disease eventually evolves to a metastatic stage, and currently appears to be not curable at that stage. Thus, understanding mechanisms that result in the establishment of tumor at sites distant from the primary location is of the utmost importance. Equally important is the definition of a metastatic state, especially in regard to the detection of micrometastases. Finally, the presence of circulating tumor cells in the peripheral blood of patients who undergo progenitor mobilization, collection and reinfusion may be of clinical significance in the setting of high-dose chemotherapy for breast cancer.

Keywords:
Breast cancer, High-dose chemotherapy, Hematopoietic stem cells, Autologous transplantation
1.
Braun S, Pantel K, Müller P, Janni W, Hepp F, Kentenchi 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. N Engl J Med 2000;342:525–533.
2.
Simpson SJ, Vachula M, Kennedy MJ, Kaizer H, Coon JS, Ghalie R, Williams S, Van Epps D: Detection of tumor cells in the bone marrow, peripheral blood, and apheresis products of breast cancer patients using flow cytometry. Exp Hematol 1995;23:1062–1068.
3.
Mapara M, Körner IJ, Hildebrandt M, Bergou R, Krahl D, Reichardt P, Dörken B: 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.
4.
Ross AA, Cooper BW, Lazarus HM, Mackay W, Moss TJ, Ciobanu N, Tallman MS, Kennedy MJ, Davidson NE, Sweet D, Winter C, Adard L, Janse J, Copelan E, Meagher RC, Herzig RH, Klumpp TR, Kanh DG, Warner NE: Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 1993;82:2605–2610.
5.
Mozziconacci MJ, Arnoulet C, Novakovitch G, Chabannon C, Viens P, Gravis G, Faucher C, Blaise D, Maraninchi D, Sainty D: Contamination des cytaphérèses par des cellules tumorales: À propos de 39 cas de cancer du sein. Bull Cancer 1996;83:649–653.
6.
Chabannon C, Cornetta K, Lotz JP, Rosenfeld C, Shlomchik M, Yanovitch S, Marolleau JP, Sledge G, Novakovitch G, Srour EF, Burtness B, Camerlo J, Gravis G, Lee-Fischer J, Faucher C, Chabbert I, Krause D, Maraninchi D, Mills B, Kunkel L, Oldham F, Blaise D, Viens P: High-dose chemotherapy followed by reinfusion of selected CD34+ peripheral blood cells in patients with poor-prognosis breast cancer: A randomized multicenter study. Br J 1998;78:913–921.
7.
Weaver CH, Moss T, Schwartzberg LS, Zhen B, West J, Rhinehart S, Campos L, Beeker T, Lautersztain L, Messino M, Buckner CD: 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.
8.
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 1998;78:556–560.
9.
Brugger W, Bross KJ, Glatt MG, Weber F, Mertelsmann R, Kanz L: Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 1994;83:636–640.
10.
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.
11.
Vredenburgh JJ, Peters WP, Rosner G, DeSombre K, Johnston WW, Kamel A, Wu K, Bast RC Jr: Detection of tumor cells in the bone marrow of stage IV breast cancer patients receiving high-dose chemotherapy: The role of induction chemotherapy. Bone Marrow Transplant 1995;16:815–821.
12.
Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, 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 2000;18:80–86.
13.
Schlimok G, Pantel K, Loibner H, Fackler-Schwalbe I, Riethmuller 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.
14.
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L: Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 1996;14:737–744.
15.
Mansi JL, Easton D, Berger U, Gazet JC, Ford HT, Dearnaley D, Coombes RC: Bone marrow micrometastases in primary breast cancer: Prognostic significance after 6 years’ follow-up. Eur J Cancer 1991;27:1552–1555.
16.
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.
17.
Diel IJ, Kaufmann M, Goerner R, Costa SD, Kaul S, Bastert G: Detection of tumor cells in bone marrow of patients with primary breast cancer: A prognostic factor for distant metastasis. J Clin Oncol 1992;10:1534–1539.
18.
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.
19.
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 1996;88:1652–1658.
20.
Fields KK, Elfenbein GJ, Trudeau WL, Perkins JB, Janssen WE, Mascinski LC: 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;14:1868–1876.
21.
Braun S, Muller M, Hepp F, Schlimok G, Riethmuller 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;90:1099–1101.
22.
Fagnou C, Michon J, Peter M, Bernous A, Oberlin O, Zucker JM, Magdelenat H, Delattre O, and for the Société Française d’Oncologie Pédiatrique: Presence of tumor cells in bone marrow but not in blood is associated with adverse prognosis in patients with Ewing’s tumor. J Clin Oncol 1998;16:1707–1711.
23.
Gribben JG, Neuberg D, Barber M, Moore J, Pesek KW, Freedman AS, Nadler LM: Detection of residual lymphoma cells by polymerase chain reaction in peripheral blood is significantly less predictive for relapse than detection in bone marrow. Blood 1994;83:3800–3807.
24.
Cooper BW, Moss TJ, Ross AA, Ybanez J, Lazarus HM: Occult tumor contamination of hematopoietic stem-cell products does not affect clinical outcome of autologous transplantation in patients with metastatic breast cancer. J Clin Oncol 1998;16:3509–3517.
25.
Philip T, Guglielmi C, Hagenbeek A, Somers R, Van Der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F, Chauvin F: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995;333:1540–1545.
26.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91–97.
27.
Gratwohl A, Passweg J, Baldomero H, Hermans J: Blood and marrow transplantation activity in Europe 1997. European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transpl 1999;24:231–245.
28.
Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winer E, Kurzberg J, Bast RC Jr, Jones R, Shpall E, Wu K, Rosner G, Gilbert C, Mathias B, Coniglio D, Petros W, Craig Henderson I, Norton L, Weiss RB, Budman D, Hurd D: High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 1993;11:1132–1143.
29.
Antman, K, Ayash L, Elias A, Wheeler C, Hunt M, Eder JP, Teicher BA, Critchlow J, Bibbo J, Schnipper LE, et al: A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy [see comments]. J Clin Oncol 1992;10:102–110.
30.
Ayash LJ, Wheeler C, Fairclough D, Schwartz G, Reich E, Warren D, Schnipper L, Antman K, Frei E 3rd, Elias A: Prognostic factors for prolonged progression-free survival with high-dose chemotherapy with autologous stem-cell support for advanced breast cancer. J Clin Oncol 1995;13:2043–2049.
31.
Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 1996;13:2483–2489.
32.
Gisselbrecht C, Extra JM, Lotz JP, Devaux Y, Janvier M, Peny AM, Guillevin L, Bremond D, Delain M, Herbrecht R, Lepage E, Maraninchi D: Cyclophosphamide/mitoxantrone/melphalan (CMA) regimen prior to autologous bone marrow transplantation (ABMT) in metastatic breast cancer. Bone Marrow Transplant 1996;18:857–863.
33.
Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CC, Peterse JL, Borger JH, Nooijen WJ, Bakx R, Dalesio O, Rutgers E: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 1998;352:515–521.
34.
Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med 2000;342:1069–1076.
35.
Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000;92:225–233.
36.
Brenner MK, Rill DR, Moen RC, Krance RA, Mirro J, Anderseon WF, Ihle JN: Gene-marking to trace origin of relapse after autologous bone marrow transplantation. Lancet 1993;341:85–86.
37.
Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF, Hester J, Korbling M, Durett A, Moen R, Berenson R, Heimfeld S, Hamer H, Calvert L, Tibbits P, Talpaz M, Kantarjian H, Champlin R, Reading R: Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow in CML. Blood 1994;83:3068–3076.
38.
Berenson RJ, Bensinger WI, Hill RS, Andrews RG, Garcia-Lopez J, Kalamasz DF, Still BS, Spitzer G, Buckner CD, Bernstein ID, Thomas ED: Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. Blood 1991;77:1717–1722.
39.
Shpall E, Jones R, Bearman SI, Franklin WA, Archer PG, Curiel T, Bitter M, Clarr HN, Stemmer SM, Purdy M, Meyers SE, Hami L, Taffs S, Heimfeld S, Hallagan J, Berenson RJ: Transplantation of enriched CD34-positive autologous marrow into breast cancer patients following high-dose chemotherapy: Influence of CD34-positive peripheral blood progenitors and growth factors on engraftment. J Clin Oncol 1994;12:28–36.
40.
Richel DJ, Johnsen HE, Canon J, Guillaume T, Schaafsma MR, Schenkeveld C, Hansen SW, McNiece I, Gringeri AJ, Briddell R, Ewen C, Davies R, Freeman J, Miltenyi S, Symann M: Highly purified CD34+ cells isolated using magnetically activated cell selection provide rapid engraftment following high-dose chemotherapy in breast cancer patients. Bone Marrow Transplant 2000;25:243–249.
41.
Marolleau JP, Dal Cortivo L, Mills B, Fermand JP, Miclea JM, Lotz JP, Gisselbrecht C, Benbunan M: Enrichment of peripheral blood CD34+ cells for transplantation using a fully automated immunomagnetic cell selection system and a novel octapeptide releasing agent. Bone Marrow Transplant 1999;23:819–826.
42.
Yanovich S, Mitsky P, Cornetta K, Maziarz RT, Rosenfeld C, Krause DS, Lotz JP, Bitran JD, Williams S, Preti R, Somlo G, Burtness B, Mills B: 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;25:1165–1174.
43.
Shpall E, LeMaistre CF, Holland K, Ball E, Jones RB, Saral R, Jacobs C, Heimfeld S, Berenson R, Champlin R: A prospective randomized trial of buffy-coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients receiving high dose chemotherapy. Blood 1997;90:4313–4320.
44.
Cornetta K, Yanovich S, Rosenfeld C, Chabannon C, Burtness B, Lotz JP, Maziarz R, Williams S, Somlo G, Mills B: High dose chemotherapy and stem cell transplant in breast cancer: A randomized multicenter study of CD34 selection. American Society for Bone Marrow Transplantation Tandem BMT Meeting. Anaheim, 2000.
45.
Gribben JG, Freedman AS, Neuberg D, Roy DC, Blake KW, Woo SD, Grossbard ML, Rabinowe SN, Coral F, Freeman GJ, Ritz J, Nadler LM: Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 1991;325:1525–1533.
46.
Shpall EJ, Jones RB, Bast RC, Rosner GL, Vandermark R, Ross M, Affonti M, Johnston C, Eggleston S, Tepperburg M, Coniglio D, Peters WP: 4-Hydroperoxycyclophosphamide purging of breast cancer from bone marrow for autologous transplantation. J Clin Oncol 1991;9:85–93.
47.
Williams CD, Goldstone AH, Pearce AM, Philip T, Hartmann O, Colombat P, Santini G, Foulard F, Gorin NC: Purging of bone marrow in autologous bone marrow transplantation for non-Hodgkin’s lymphoma: A case-matched comparison with unpurged cases by the European Blood and Marrow Transplant Lymphoma Registry. J Clin Oncol 1996;14:2454–2464.
© 2001 S. Karger AG, Basel
2001
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.