TumorDiagnostik & Therapie 2006; 27(1): 21-26
DOI: 10.1055/s-2006-926527
Thieme Onkologie aktuell

Georg Thieme Verlag KG Stuttgart · New York

Tumorzelldissemination und Mikrometastasierung bei Mammakarzinom

Bedeutung und Stand der WissenschaftTumor Cell Dissemination and Micrometastases in Breast CancerS. Becker1 , T. Fehm1 , G. Becker-Pergola1 , D. Wallwiener1 , E. Solomayer1
  • 1Universitäts-Frauenklinik Tübingen
Further Information

Publication History

11.4.2005 · Eingang revidiertes Manuskript: 20.10.2005

angenommen: 2.11.2005

Publication Date:
14 February 2006 (online)

Zusammenfassung

Trotz primär kurativer Therapie durch Operation, Chemotherapie/Hormontherapie und Strahlentherapie erleiden 20 - 40 % der an Brustkrebs erkrankten Frauen innerhalb von 5 - 10 Jahren ein nicht mehr heilbares systemisches Rezidiv. Nach dem heutigen Kenntnisstand muss eine Tumorzelldissemination von bisher nur wenig verstandenen Subpopulationen des Primärtumors zum Zeitpunkt der Primärtherapie bereits erfolgt sein. Die Untersuchung dieser mikrodisseminierten Zellen hat in den letzten Jahren wichtige Fortschritte gemacht. Ziel dieses Artikels ist, eine Übersicht über den aktuellen Stand der Forschung zu geben sowie die Rationale für weitere Untersuchungen auf diesem Gebiet. Durch Phänotypisierung und Genotypisierung könnten wichtige Erkenntnisse über das tumorbiologische Verhalten disseminierter Tumorzellen gewonnen werden.

Abstract

Despite primary curative therapy by surgery, chemo/hormone therapy and radiation therapy 20 - 40 % of women diagnosed with breast cancer will suffer from a systemic recurrence of their disease within five to ten years, which is incurable. Current interpretation of research data supports the theory that tumor cell dissemination of subpopulations of the primary tumor must have occurred already at the time of primary therapy. Knowledge about these microdisseminated cells has significantly increased over the past few years. The aim of this article is to provide an overview of the latest advances of research in this area, as well as to provide a rationale for further studies. Phenotyping and genotyping could yield important insights into the biologic characteristics of disseminated tumor cells.

Literatur

  • 1 Schmidt-Matthiesen H, Bastert G, Wallwiener D. Gynäkologische Onkologie. 7. Auflage. Stuttgart; Schattauer Verlag 2002
  • 2 Rodenhuis S, Bontenbal M, Beex L, van der Wall E, Richel D, Nooij M, Voest E, Hupperets P, Westermann A, Dalesio O, de Vries E. Randomized Phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes.  Proc Am Soc Clin Oncol. 2000;  27 74 a
  • 3 Ellis L D, Jensen J N, Westerman M F. Needle biopsy of bone marrow: An experience with 1,445 biopsies.  Arch Intern Med. 1964;  27 213-214
  • 4 Jamshidi K, Swaim W R. Bone marrow biopsy with unaltered architecture: a new biopsy device.  J Lab Clin Med. 1971;  27 335-342
  • 5 Diel I J, Kaufmann M, Goerner R, Costa S D, 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;  27 1534-1539
  • 6 Solomayer E F, Diel I J, Salanti G, Hahn M, Gollan C, Schutz F, Bastert G. Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.  Clin Cancer Res. 2001;  27 4102-4108
  • 7 Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland J M, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer.  J Clin Oncol. 2003;  27 3469-3478
  • 8 Borgen E, Naume B, Nesland J M, Kvalheim G, Beiske K, Fodstad O. et al . Standardization of the immunological detection of cancer cells in bone marrow and blood: Establishment of objective criteria for the evaluation of immunostained cells.  Cytotherapy. 1999;  27 377-388
  • 9 Funke I, Schraut W. Meta-analyses of studies on bone marrow micrometastases: an independent prognostic impact remains to be substantiated.  J Clin Oncol. 1998;  27 557-566
  • 10 Borgen E, Naume B, Nesland J M. et al . The European ISHAGE Working Group for Standardization of Tumor Cell Detection: Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. establishment of objective criteria for the evaluation of immunostained cells.  Cytotherapy. 1999;  27 377-388
  • 11 Diel I J, Cote R J. Bone marrow and lymph node assessment for minimal residual disease in patients with breast cancer.  Cancer Treat Rev. 2000;  27 53-65
  • 12 Pantel K, Cote R J, Fodstad O. Detection and clinical importance of micrometastatic disease.  J Natl Cancer Inst. 1999;  27 1113-1124
  • 13 Solomayer E-F, Diel I J, Meyberg G C, Gollan C, Bode S, Wallwiener D, Bastert G. Prognostic relevance of cathepsin d detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.  Breast Cancer Res Treat. 1998;  27 145-154
  • 14 Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich C R, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller 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;  27 525-533
  • 15 Solomayer E-F, Diel I J, Salanti G, Hahn M, Gollan C, Schutz F, Bastert G. Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.  Clin Cancer Res. 2001;  27 4102-4108
  • 16 Mansi J L, Gogas H, Bliss J M, Gazet J C, Berger U, Coombes R C. Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study.  Lancet. 1999;  27 197-202
  • 17 Diel I J, Kaufmann M, Costa S D, Holle R, von Minckwitz G, Solomayer E-F, 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;  27 1652-1658
  • 18 Braun S, Vogl F, Schlimok G, Diel I, Janni W, Gerber B, Gebauer G, Coombes R C, Pierga J-Y, Naume B, Pantel K. Pooled analysis of prognostic impact of bone marrow micrometastases: 10 year survival 4199 breast cancer patients.  Breast Cancer Res Treat. 2003;  27 Abstract SABCS; No.7
  • 19 Krag D N, Ashikaga T, Moss T J, Kusminsky R E, Feldman S, Carp N Z, Moffat F L, Beitsch P D, Frazier T G, Gaskin T A, Shook J W, Harlow S P, Weaver D L. Breast cancer cells in the blood: a pilot study.  Breast J. 1999;  27 354-358
  • 20 Fehm T, Sagalowsky A, Clifford E, Beitsch P, Saboorian H, Euhus D, Meng S, Morrison L, Tucker T, Lane N, Ghadimi B M, Heselmeyer-Haddad K, Ried T, Rao C, Uhr J. Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant.  Clin Cancer Res. 2002;  27 2073-2084
  • 21 Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmuller G, Pantel K. ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I - III breast cancer patients.  Cancer Res. 1999;  27 1890-1895
  • 22 Solomayer E-F, Diel I J, Wallwiener D, Bode S, Meyberg G, Sillem M, Gollan C, Kramer M D, Krainick U, Bastert G. Prognostic relevance of urokinase plasminogen activator in micrometastatic cells in the bone marrow of patients with primary breast cancer.  Br J Cancer. 1997;  27 812-818
  • 23 Solomayer E-F, Wallwiener D, Fehm T, Schauf B, Bastert G, Diel I, Meyberg G. Tumorzelldissemination unter neoadjuvanter Chemotherapie bei Patientinnen mit primärem Mammakarzinom.  Geburtsh Frauenheilk. 2003;  27 1267-1273
  • 24 Janni W, Hepp F, Rjosk D, Kentenich C, Strobl B, Schindlbeck C, Hantschmann P, Sommer H, Pantel K, Braun S. The fate and prognostic value of occult metastatic cells in the bone marrow of patients with breast carcinoma between primary treatment and recurrence.  Cancer. 2001;  27 46-53
  • 25 Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki J R, Riethmuller G. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells.  J Natl Cancer Inst. 1993;  27 1419-1424
  • 26 Becker S, Pergola G, Fehm T, Aydeniz B, Huober J, Wallwiener D, Solomayer E-F. The fate of disseminated tumor cells in bone marrow of primary breast cancer patients after adjuvant systemic therapy.  Cancer Res Clin Oncol. 2004;  27 46
  • 27 Diel I J, Solomayer E-F, Costa S D, Gollan Ch, Goerner R, Wallwiener D, Kaufmann M, Bastert G. Reduction in new metastases in breast cancer with adjuvant clodronate treatment.  N Engl J Med. 1998;  27 357-363
  • 28 Elomaa I, Saarto T. Use of clodronate in the adjuvant treatment of breast cancer is questionable for the time being.  Duodecim. 2001;  27 1021-1022
  • 29 Powles T, Paterson S, Kanis J A, McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S, Pajunen M, Nevantaus A, Mannisto E, Suovuori A, Atula S, Nevalainen J, Pylkkanen L. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.  J Clin Oncol. 2002;  27 3219-3224
  • 30 Krämer B, Solomayer E-F, Wallwiener D. Einfluss von Zoledronsäure auf die Tumorzelldissemination beim primären Mammakarzinom.  Archives of Gynecology and Obstetrics. 2004;  27 20
  • 31 Janni W, Rack B, Sommer H, Rjosk D, Thieleke W, Schindlbeck C, Gerber B, Friese K. Der Einfluss von Zoledronat auf den Verlauf persistierender isolierter Tumorzellen im Knochenmark von rezidivfreien Brustkrebspatientinnen.  Archives of Gynecology and Obstetrics. 2004;  27 56
  • 32 Rack K, Janni W, Schoberth A, Schindlbeck C, Strobl B, Blankenstein T, Rjosk D, Heinrigs M, Sommer H, Friese K. Effect of zoledronate on persisting isolated tumor cells (ITC) in the bone marrow (BM) of patients without recurrence of early breast cancer.  ASCO Annual Meeting Proceedings J Clin Oncol. 2004;  27 14
  • 33 Vehmanen L, Saarto T, Elomaa I, Makela P, Valimaki M, Blomqvist C. Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.  Eur J Cancer. 2001;  27 2373-2378
  • 34 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;  27 80-86
  • 35 Becker S, Becker-Pergola G, Fehm T, Wallwiener D, Solomayer E-F. Time is an important factor when processing samples for the detection of disseminated tumor cells in blood/bone marrow by reverse transcription-PCR.  Clin Chem. 2004;  27 785-786
  • 36 Becker S, Pergola G, Fehm T, Wallwiener D, Dürr-Störzer S, Solomayer E-F. Detection of disseminated tumor cells in the peripheral circulation - difficulties of method and principle;.  Cancer Res Clin Oncol. 2004;  27 55
  • 37 Cristofanilli M, Budd G T, Ellis M J, Stopeck A, Matera J, Miller M C, Reuben J M, Doyle G V, Allard W J, Terstappen L W, Hayes D F. Circulating tumor cells, disease progression, and survival in metastatic breast cancer.  N Engl J Med. 2004;  27 781-791
  • 38 Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmüller G, Pantel K. ErbB2 overexpression on occult metastatic cell in bone marrow predicts poor clinical outcome of stage I - III breast cancer patients.  Cancer Res. 2001;  27 1890-1895
  • 39 Becker S, Becker-Pergola G, Fehm T, Wallwiener D, Solomayer E-F. Her2-expression on disseminated tumor cells from bone marrow of breast cancer patients.  Anticancer Res. 2005;  27 2171-2175

Dr. med. Sven Becker

Universitäts-Frauenklinik

Calwer Straße 7

72076 Tübingen

Email: sven.becker@med.uni-tuebingen.de

    >