Abstract
In breast cancer, about 35% of patients without any clinical signs of overt distant metastases already have disseminated tumor cells in bone marrow aspirates at the time of primary therapy. A significant prognostic impact of these disseminated tumor cells has been shown by many international studies: patients with tumor cells in their bone marrow have a significantly worse prognosis than those without them. Even in malignancies where the skeletal system is not a preferred location for distant metastasis, such as ovarian cancer, early presence of minimal residual disease (MRD) is correlated with poor patient outcome. Thus, besides analysis of the primary tumor, detection of MRD can be used for assessment of patient prognosis and for prediction or monitoring of response to systemic therapy. Disseminated tumor cells are also the targets for novel tumor biological therapy approaches such as specific antibody-based therapies against target cell-surface antigens such as HER2, EpCAM (17–1A), and uPA-R. In breast cancer, a first antibody-based tumor therapy against HER2 (Herceptin) has already been approved for clinical use in recurrent disease. However, patient selection for such tumor biological therapies becomes rather difficult due to phenotype changes, which may manifest themselves as differences between primary lesion and disseminated tumor cells. Therefore, not only identification of disseminated tumor cells but even more so their characterization at the protein and gene levels have become increasingly important. In conclusion, characterization of tumor biological properties of disseminated tumor cells allows identification of patients with breast cancer or gynecological malignancies at risk for relapse who are likely to benefit from systemic treatment and/or novel tumor biological therapy approaches.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Allgayer H, Heiss MM, Riesenberg R, Babic R, Jauch KW, Schildberg FW (1997) Immunocytochemical phenotyping of disseminated tumor cells in bone marrow by uPA receptor and CK18: investigation of sensitivity and specificity of an immunogold/alkaline phos-phatase double staining protocol. J Histochem Cytochem 45:203–212
Borgen E, Naume B, Nesland JM, Kvalheim G, Beiske K, Fodstad O, Diel I, Solomayer EF, Theocharous P, Coombes RC, Smith BM, Wunder E, Marolleau JP, Garcia J, Pantel K (1999) Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy 1:377–388
Braun S, Pantel K (1998) Prognostic significance of micrometastatic bone marrow involve-ment. Breast Cancer Res Treat 52:201–216
Braun S, Hepp F, Kentenich CR, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer HL (1999a) 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
Braun S, Hepp F, Sommer HL, Pantel K (1999b) Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer 84:1–5
Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K (2000a) 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
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000b) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342:525–533
Braun S, Cevatli BS, Assemi C, Janni W, Kentenich CR, Schindlbeck C, Rjosk D, Hepp F (2001a) Comparative analysis of micrometastasis to the bone marrow and lymph nodes of node-negative breast cancer patients receiving no adjuvant therapy. J Clin Oncol 19:1468–1475
Braun S, Schindlbeck C, Hepp F, Janni W, Kentenich C, Riethmüller G, Pantel K (2001b) Oc-cult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic relapse. J Clin Oncol 19:368–375
Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmüller G, Pantel K (2001c) ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients. Cancer Res 61:1890–1895
Braun S, Nusser N, Harbeck N, Pantel K (2002) Occult metastatic cancer cells in the bone marrow: a clinical marker for tumor staging and decision making in primary breast cancer. Clin Cancer Res (in press)
Brugger W, Bühring HJ, Grünebach F, Vogel W, Kaul S, Müller R, Brümmendorf TH, Ziegler BL, Rappold I, Brossart P, Scheding S, Kanz L (1999) Expression of MUC-1 epitopes on normal bone marrow: implications for the detection. J Clin Oncol 17: 1535–1544
Cain JM, Ellis GK, Collins C, Greer BE, Tamimi HK, Figge DC, Gown AM, Livingston RB (1990) Bone marrow involvement in epithelial ovarian cancer by immunocytochemical assessment. Gynecol Oncol 38:442–445
Coombes RC, Dearnaley DP, Redding WH, Ormerod MG, Skilton RA, Sloane JP, Imrie S, Edwards AW, Monaghan P, Neville AM (1983) Micrometastases in breast cancer. In: Peeters H (ed) Protides of the biological fluids. Pergamon, Oxford, pp 317–323
Cote RJ, Rosen PP, Lesser ML, Old LJ, Osborne MP (1991) Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol 9:1749–1756
Czegledy J, Iosif C, Hansson BG, Evander M, Gergely L, Wadell G (1995) Can a test for E6/E7 transcripts of human papillomavirus type 16 serve as a diagnostic tool for the detection of micrometastasis in cervical cancer? Int J Cancer 64:211–215
Dearnaley DP, Sloane JP, Ormerod MG, Steele K, Coombes RC, Clink HM, Powles TJ, Ford HT, Gazet JC, Neville AM (1981) Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. Br J Cancer 44:85–90
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 status. J Natl Cancer Inst 88:1652–1658
Diel IJ, Kaufmann M, Goerner R, Costa SD, Kaul S, Bastert G (1992) Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis. J Clin Oncol 10:1534–1539
Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G (1998) Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:357–363
Fishman A, Klein A, Zemer R, Zimlichman S, Bernheim J, Cohen I, Altaras MM (2000) Detection of micrometastasis by cytokeratin-20 (reverse transcription polymerase chain reaction) in lymph nodes of patients with endometrial cancer. Gynecol Oncol 77:399–404
Funke I, Schraut W, Jauch KW, Untch M, Schildberg FW (2001) Prospective study on minimal residual disease in breast cancer. Proceedings of 1st International Congress on Molecular staging of cancer. Munich, p 25
Gabriel M, Obrebowska A, Spaczynski M (2000) Nachweis von Epithelzellen im Knochenmark von Patientinnen mit Ovarialkarzinomen unter Anwendung von immunhistochemischen Methoden. Gynakol Geburtshilfliche Rundsch 40:140–144
Gebauer G, Fehm T, Merkle E, Beck EP, Lang N, Jager W (2001) Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during longterm follow-up. J Clin Oncol 19:3669–3674
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 factors. J Clin Oncol 19:960–971
Harbeck N, Untch M, Pache L, Eiermann W (1994) 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
Hayes DF, Bast RC, Desch CE, Fritsche HJr, Kemeny NE, Jessup JM, Locker GY, Macdonald JS, Mennel RG, Norton L, Ravdin P, Taube S, Winn RJ (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 88:1456–1466
Heiss MM, Allgayer H, Gruetzner KU, Funke I, Babic R, Jauch KW, Schildberg FW (1995) In-dividual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med 1:1035–1039
Hempel D, Müller P, Oruzio D, Ehnle S, Schlimok G (1997) Adoptive immunotherapy with the monoclonal antibody (moab) 17/1A to reduce minimal residual disease in breast cancer patients after high dose chemotherapy (HDC) (abstract). Blood 90[Suppl 1]:379b
Hepp F, Kentenich C, Janni W, Kindermann G, Braun S (2000) Prognostische Bedeutung Cytokeratin (CK)-positiver Knochenmark-Mikrometastasen (KMM) bei Patientinnen mit Zervixkarzinom (CC) im Stadium FIGO I-II. Geburtsh Frauenheilk 60: S37
Heyderman E, Strudley I, Powell G, Richardson TC, Cordell JL, Mason DY (1985) A new monoclonal antibody to epithelial membrane antigen (EMA)-E29. A comparison of its immunocytochemical reactivity with polyclonal anti-EMA antibodies and with another monoclonal antibody, HMFG-2. Br J Cancer 52:355–361
Hohaus S, Funk L, Brehm M, Abdallah A, Murea S, Kaul S, Haas R (1996) Persistence of isolated tumor cells in patients with breast cancer after sequential high-dose therapy with peripheral blood stem cell transplantation (PBSC) (abstract). Blood 88[Suppl 10]:128a
Horn LC, Fischer U, Hockel M (2001) Occult tumor cells in surgical specimens from cases of early cervical cancer treated by liposuction-assisted nerve-sparing radical hysterectomy. Int J Gynecol Cancer 11:159–163
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 recurrence. Cancer 92:46–53
Klein A, Fishman A, Zemer R, Zimlichman S, Altaras MM (2000) Detection of tumor circulat-ing cells by cytokeratin 20 in the blood of patients with endometrial carcinoma. Gynecol Oncol 78:352–355
Kowolik JH, Kuhn W, Nahrig J, Werner M, Obst T, Avril N, Schmitt M, Graeff H (2000) Detection of micrometastases in sentinel lymph nodes of the breast applying monoclonal anti-bodies AE1/AE3 to pancytokeratins. Oncol Rep 7:745–749
Kriiger WH, Kroger N, Togel F, Renges H, Badbaran A, Hornung R, Jung R, Gutensohn K, Gieseking F, Janicke F, Zander AR (2001) Disseminated breast cancer cells prior to and after high-dose therapy. J Hematother Stem Cell Res 10:681–689
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-up. Breast Cancer Res Treat 49:27–33
Mansi JL, Berger U, McDonnell T, Pople A, Rayter Z, Gazet JC, Coombes RC (1989) The fate of bone marrow micrometastases in patients with primary breast cancer. J Clin Oncol 7:445–449
Mansi JL, Gogas H, Bliss JM, Gazet JC, Berger U, Coombes RC (1999) Outcome of primaryreast-cancer patients with micrometastases: a long-term follow-up study. Lancet 354:197–202
Marth C, Hoifodt H, Walberg L, Kaern J, Andresen M, Hovland B, Mathiesen O, Trope C (1999) Carcinoma cells in bone marrow and peripheral blood of ovarian cancer patients (abstract). 2nd International Symposium on Minimal Residual Cancer, Berlin, Germany
McGuire W (1991) Breast cancer prognostic factors: Evaluation guidelines. J Natl Cancer Inst 83:154–155
McGuire WL, Clark GM (1992) Prognostic factors and treatment decisions in axillary-node-negative breast cancer. N Engl J Med 326:1756–1761
Molino A, Colombatti M, Bonetti F, Zardini M, Pasini F, Perini A, Pelosi G, Tridente G, Veneri D, Cetto GL (1991) A comparative analysis of three different techniques for the detection of breast cancer cells in bone marrow Cancer 67:1033–1036
Molino A, Pelosi G, Micciolo R, Turazza M, Nortilli R, Pavanel F, Cetto GL (1999) Bone marrow micrometastases in breast cancer patients. Breast Cancer Res Treat 58:123–130
Noack F, Schmitt M, Bauer J, Helmecke D, Kruger W, Thorban S, Sandherr M, Kuhn W, Graeff H, Harbeck N (2000) A new approach to phenotyping disseminated tumor cells: methodological advances and clinical implications. Int J Biol Markers 15:100–104
Osborne MP, Wong GY, Asina S, Old LJ, Cote RJ, Rosen PP (1991) Sensitivity of immunocytochemical detection of breast cancer cells in human bone marrow. Cancer Res 51:2706–2709
Otte M, Deppert K, Ebel S, Hosch S, Janicke F, Izbicki JR, Pantel K (2000) Immunomagnetic enrichment of disseminated tumor cells from bone marrow of carcinoma patients (abstract 2475). Proc AACR687
Pantel K, Felber E, Schlimok G (1994) Detection and characterization of residual disease in breast cancer. J Hematother 3:315–322
Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmüller G (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85:1419–1424
Pantel K, Schlimok G, Kutter D, Schaller G, Genz T, Wiebecke B, Backmann R, Funke I, Riethmuller G (1991) Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res 51:4712–4715
Rappold I, Brossart P, Scheding S, Kanz L (1999) Expression of MUC-1 epitopes on normal bone marrow: implications for the detection of occult bone marrow micrometastases. J Clin Oncol 17:1535–1544
Redding WH, Coombes RC, Monaghan P, Clink HM, Imrie SF, Dearnaley DP, Ormerod MG, Sloane JP, Gazet JC, Powles TJ (1983) Detection of micrometastases in patients with primary breast cancer. Lancet 2:1271–1274
Ridell B, Landys K (1979) Incidence and histopathology of metastases of mammary carcinoma in biopsies from the posterior iliac crest. Cancer 44:1782–1788
Riethmüller G, Holz E, Schlimok G, Schmiegel W, Raab R, Höffken K, Gruber R, Funke I, Pichlmaier H, Hirche H, Buggisch P, Witte J, Pichlmayr R (1998) Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: seven-year outcome of a multicenter randomized trial. J Clin Oncol 16:1788–1794
Roggel F, Späthe K, Sinz S, Braun S, Hocke S, Rutke S, Bosl M, Schmalfeldt B, Sandherr M, Werner M, Kuhn W, Schmitt M, Harbeck N (2001) Characterization of disseminated tumor cells in bone marrow of patients with ovarian carcinoma (abstract 62). 3rd International Symposium on Minimal Residual Cancer, Hamburg, Germany
Ross AA, Miller GW, Moss TJ, Kahn DG, Warner NE, Sweet DL, Louie KG, Schneidermann E, Pecora AL, Meagher RC (1995) Immunocytochemical detection of tumor cells in bone marrow and peripheral blood stem cell collections from patients with ovarian cancer. Bone Marrow Transplant 15:929–933
Ross JS, Fletcher JA (1998) The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Oncologist 3:237–252
Salvadori B, Squicciarini P, Rovini D, Orefice S, Andreola S, Rilke F, Barletta L, Menard S, Colnaghi MI (1990) Use of monoclonal antibody MBrl to detect micrometastases in bone marrow specimens of breast cancer patients. Eur J Cancer 26:865–867
Schlimok G, Funke I, Holzmann B, Gottlinger G, Schmidt G, Hauser H, Swierkot S, Warnecke HH, Schneider B, Koprowski H (1987) Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-lA monoclonal antibodies. Proc Natl Acad Sci USA 84:8672–8676
Schlimok G, Riethmuller G (1990) Detection, characterization and tumorigenicity of disseminated tumor cells in human bone marrow. Semin Cancer Biol 1:207–215
Sinz S, Rutke S, Späthe K, Hocke S, Roggel F, Sandherr M, Werner M, Braun S, Kuhn W, Schmitt M, Harbeck N (2001) Phenotyping of disseminated tumor cells in bone marrow aspirates of breast cancer patients (abstract 63). 3rd International Symposium on Minimal Residual Cancer, Hamburg, Germany
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792
Tögel F, Datta C, Badbaran A, Kröger N, Renges H, Gieseking F, Jänicke F, Zander AR, Krüger W (2001) Urokinase-like plasminogen activator receptor expression on disseminated breast cancer cells. J Hematother Stem Cell Res 10:141–145
Wilex AG MG (2001) Wilex starts phase I trial with anti-metastatic urokinase inhibitor drug. Press release 21–09-2001 http://www.wilex.de
Wong SL, Chao C, Edwards MJ, Simpson D, McMasters KM (2001) The use of cytokeratin staining in sentinel lymph node biopsy for breast cancer. Am J Surg 182:330–334
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2003 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Roggel, F. et al. (2003). Minimal Residual Disease in Breast Cancer and Gynecological Malignancies: Phenotype and Clinical Relevance. In: Allgayer, H., Heiss, M.M., Schildberg, F.W. (eds) Molecular Staging of Cancer. Recent Results in Cancer Research, vol 162. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59349-9_8
Download citation
DOI: https://doi.org/10.1007/978-3-642-59349-9_8
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-63945-6
Online ISBN: 978-3-642-59349-9
eBook Packages: Springer Book Archive