Skip to main content
SpringerLink
Log in

Isolierte Tumorzellen in Knochenmark und Blut von Patientinnen mit primärem Mammakarzinom – Klinische Relevanz

The clinical relevance of the demonstration of isolated cancer cells in bone marrow and blood from patients with primary breast cancer

  • Leitthema
  • Published:
Der Gynäkologe Aims and scope

Zusammenfassung

Trotz wesentlicher Fortschritte in der systemischen Therapie des Mammkarzinoms sind Rezidive nach oft langer Latenzzeit charakteristisch. Ausgangspunkt für eine Fernmetastasierung sind in der Regel isolierte Tumorzellen, die bereits früh im Verlauf der Erkrankung hämatogen disseminieren. Der Nachweis dieser minimalen Tumorresiduen („minimal residual disease“, MRD) ist mit konventionellen bildgebenden Verfahren nicht möglich; die dafür am besten etablierte Methode ist der immunzytochemische Nachweis isolierter Tumorzellen im Knochenmark (KM). Die daraus gewonnenen Informationen über Prävalenz und Phänotyp der Tumorzellen lassen Rückschlüsse auf Tumorbiologie und individuelle Prognose zu und könnten in der adjuvanten Situation eine Therapieoptimierung ermöglichen. Die immunzytochemische KM-Untersuchung könnte die Antwort auf die Frage nach dem individuellen Erfolg adjuvanter Therapien erleichtern und Grundlage für die Einleitung einer sekundär-adjuvanten Therapie sein. Außerhalb klinischer Studien sollte der Nachweis isolierter Tumorzellen derzeit nicht als alleinige Grundlage für eine Therapieentscheidung herangezogen werden.

Abstract

Data is emerging on the prognostic relevance of occult metastatic cells in the bone marrow of patients with various solid tumors. There is increasing evidence that validated anti-cytokeratin antibodies represent the present standard for the detection of isolated tumor cells. This immunocytochemical assay allows the identification of patients with occult tumor cell dissemination that cannot be identified by conventional screening methods in tumor staging. According to recent studies, these patients are at higher risk for the subsequent development of distant metastases and might therefore benefit from early systemic therapy. Therapeutic monitoring and cell cycle independent antibody-based therapy are among the possible implications of this new, promising diagnostic tool. The present review also focuses on the state of the art in reliable detection methods of occult metastatic cells in the bone marrow of breast cancer patients and on the prognostic relevance of these cells at different stages of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. DeVita VTJ (1989) Breast cancer therapy: exercising all our options. N Eng J Med 320: 527–529

    Article  Google Scholar 

  2. Rosner D, Lane WW (1993) Predicting recurrence in axillary-node negative breast cancer patients. Breast Cancer Res Treat 25: 127–139

    Article  PubMed  CAS  Google Scholar 

  3. Braun S, Pantel K, Muller P et al. (2000) 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

    Article  PubMed  CAS  Google Scholar 

  4. Cote RJ, Rosen PP, Lesser ML et al. (1991) Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol 9: 1749–1756

    PubMed  CAS  Google Scholar 

  5. Diel IJ, Kaufmann M, Costa SD et al. (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

    Article  PubMed  CAS  Google Scholar 

  6. Gebauer G, Fehm T, Merkle E et al. (2001) Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol 19: 3669–3674

    PubMed  CAS  Google Scholar 

  7. Gerber B, Krause A, Muller H et al. (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

    PubMed  CAS  Google Scholar 

  8. 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

    PubMed  CAS  Google Scholar 

  9. Landys K, Persson S, Kovarik J et al. (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

    Article  PubMed  CAS  Google Scholar 

  10. Mansi JL, Gogas H, Bliss JM et al. (1999) Outcome of primary-breast-cancer patients with micrometastases: a long-term follow-up study. Lancet 354: 197–202

    Article  PubMed  CAS  Google Scholar 

  11. Harbeck N, Kates RE, Gauger K et al. (2004) Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. Thromb Haemost 91: 450–456

    PubMed  CAS  Google Scholar 

  12. Hayes DF, Bast RC, Desch CE et al. (1996) Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 88: 1456–1466

    Article  PubMed  CAS  Google Scholar 

  13. Beiske K, Myklebust AT, Aamdal S et al. (1992) Detection of bone marrow metastases in small cell lung cancer patients. Comparison of immunologic and morphologic methods. Am J Pathol 141: 531–538

    PubMed  CAS  Google Scholar 

  14. Ellis G, Ferguson M, Yamanaka E et al. (1989) Monoclonal antibodies for detection of occult carcinoma cells in bone marrow of breast cancer patients. Cancer 63: 2509–2514

    Article  PubMed  CAS  Google Scholar 

  15. Funke I, Fries S, Rolle M et al. (1996) Comparative analyses of bone marrow micrometastases in breast and gastric cancer. Int J Cancer 65: 755–761

    Article  PubMed  CAS  Google Scholar 

  16. Braun S, Pantel K (1999) Micrometastatic bone marrow involvement: detection and prognostic significance. Med Oncol 16: 154–165

    Article  PubMed  CAS  Google Scholar 

  17. Braun S, Pantel K (1996) Biological characteristics of micrometastatic carcinoma cells in bone marrow. Curr Top Microbiol Immunol 213: 163–177

    PubMed  Google Scholar 

  18. Braun S, Pantel K (1998) Prognostic significance of micrometastatic bone marrow involvement. Breast Cancer Res Treat 52: 201–216

    Article  PubMed  CAS  Google Scholar 

  19. Braun S, Muller M, Hepp F et al. (1998) 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

    Article  PubMed  CAS  Google Scholar 

  20. Braun S, Hepp F, Kentenich CR et al. (1999) 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

    PubMed  CAS  Google Scholar 

  21. Braun S, Kentenich C, Janni W et al. (2000) 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

    PubMed  CAS  Google Scholar 

  22. Cote RJ, Beattie EJ, Chaiwun B et al. (1995) Detection of occult bone marrow micrometastases in patients with operable lung carcinoma. Ann Surg 222: 415–423

    Article  PubMed  CAS  Google Scholar 

  23. Dearnaley DP, Sloane JP, Ormerod MG et al. (1981) Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. Br J Cancer 44: 85–90

    PubMed  CAS  Google Scholar 

  24. Janni W, Gastroph S, Hepp F et al. (2000) Incidence and prognostic significance of an increased number of tumor cells in bone marrow of patients with first recurrence of breast cancer. Cancer 88: 2252–2259

    Article  PubMed  CAS  Google Scholar 

  25. Mansi JL, Easton D, Berger U et al. (1991) Bone marrow micrometastases in primary breast cancer: prognostic significance after 6 years‘ follow-up. Eur J Cancer 27: 1552–1555

    PubMed  CAS  Google Scholar 

  26. Myklebust AT, Pharo A, Fodstad O (1993) Effective removal of SCLC cells from human bone marrow. Use of four monoclonal antibodies and immunomagnetic beads. Br J Cancer 67: 1331–1336

    PubMed  CAS  Google Scholar 

  27. Osborne MP, Rosen PP (1994) Detection and management of bone marrow micrometastases in breast cancer. Oncology Huntingt 8: 25–31

    PubMed  CAS  Google Scholar 

  28. Pantel K, Izbicki J, Passlick B et al. (1996) Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 347: 649–653

    Article  PubMed  CAS  Google Scholar 

  29. Rye PD, Hoifodt HK, Overli GE, Fodstad O (1997) Immunobead filtration: a novel approach for the isolation and propagation of tumor cells. Am J Pathol 150: 99–106

    PubMed  CAS  Google Scholar 

  30. Schlimok G, Funke I, Holzmann B et al. (1987) Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17–1A monoclonal antibodies. Proc Natl Acad Sci U S A 84: 8672–8676

    Article  PubMed  CAS  Google Scholar 

  31. Wiedswang G, Borgen E, Karesen R et al. (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 21: 3469–3478

    Article  PubMed  CAS  Google Scholar 

  32. Doglioni C, Dell’Orto P, Zanetti G et al. (1990) Cytokeratin-immunoreactive cells of human lymph nodes and spleen in normal and pathological conditions. An immunocytochemical study. Virchows Arch A Pathol Anat Histopathol 416: 479–490

    Article  PubMed  CAS  Google Scholar 

  33. Pantel K, Muller V, Auer M et al. (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res 9: 6326–6334

    PubMed  CAS  Google Scholar 

  34. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4: 448–456

    Article  PubMed  CAS  Google Scholar 

  35. Hermanek P, Hutter RV, Sobin LH, Wittekind C (1999) International Union Against Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 86: 2668–2673

    Article  PubMed  CAS  Google Scholar 

  36. Brugger W, Buhring HJ, Grunebach F et al. (1999) Expression of MUC-1 epitopes on normal bone marrow: implications for the detection of micrometastatic tumor cells. J Clin Oncol 17: 1535–1544

    PubMed  CAS  Google Scholar 

  37. Bostick PJ, Chatterjee S, Chi DD et al. (1998) Limitations of specific reverse-transcriptase polymerase chain reaction markers in the detection of metastases in the lymph nodes and blood of breast cancer patients. J Clin Oncol 16: 2632–2640

    PubMed  CAS  Google Scholar 

  38. Krismann M, Todt B, Schroder J et al. (1995) Low specificity of cytokeratin 19 reverse transcriptase-polymerase chain reaction analyses for detection of hematogenous lung cancer dissemination. J Clin Oncol 13: 2769–2775

    PubMed  CAS  Google Scholar 

  39. Ruud P, Fodstad O, Hovig E (1999) Identification of a novel cytokeratin 19 pseudogene that may interfere with reverse transcriptase-polymerase chain reaction assays used to detect micrometastatic tumor cells. Int J Cancer 80: 119–125

    Article  PubMed  CAS  Google Scholar 

  40. Traweek ST, Liu J, Battifora H (1993) Keratin gene expression in non-epithelial tissues. Detection with polymerase chain reaction. Am J Pathol 142: 1111–1118

    PubMed  CAS  Google Scholar 

  41. Zippelius A, Kufer P, Honold G et al. (1997) Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J Clin Oncol 15: 2701–2708

    PubMed  CAS  Google Scholar 

  42. Cote RJ, Rosen PP, Hakes TB et al. (1988) Monoclonal antibodies detect occult breast carcinoma metastases in the bone marrow of patients with early stage disease. Am J Surg Pathol 12: 333–340

    Article  PubMed  CAS  Google Scholar 

  43. Pantel K, Schlimok G, Angstwurm M et al. (1994) Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 3: 165–173

    PubMed  CAS  Google Scholar 

  44. Klein CA, Schmidt KO, Schardt JA et al. (1999) Comparative genomic hybridization, loss of heterozygosity, and DNA sequence analysis of single cells. Proc Natl Acad Sci U S A 96: 4494–4499

    Article  PubMed  CAS  Google Scholar 

  45. Klein CA, Blankenstein TJ, Schmidt-Kittler O et al. (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360: 683–689

    Article  PubMed  CAS  Google Scholar 

  46. Mueller P, Carroll P, Bowers E et al. (1998) Low frequency epithelial cells in bone marrow aspirates from prostate carcinoma patients are cytogenetically aberrant. Cancer 83: 538–546

    Article  PubMed  CAS  Google Scholar 

  47. Pantel K, Felber E, Schlimok G (1994) Detection and characterization of residual disease in breast cancer. J Hematother 3: 315–322

    PubMed  CAS  Google Scholar 

  48. Borgen E, Beiske K, Trachsel S et al. (1998) Immunocytochemical detection of isolated epithelial cells in bone marrow: non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase. J Pathol 185: 427–434

    Article  PubMed  CAS  Google Scholar 

  49. Naume B, Borgen E, Nesland JM et al. (1998) 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

    Article  PubMed  CAS  Google Scholar 

  50. Cote RJ, Shi SR, Beattie EJ et al. (1997) Automated detection of occult bone marrow micrometastases in patients with operable lung carcinoma. Proc ASCO 16: 458a-

    Google Scholar 

  51. Makarewicz B, McDuffie L, Shi SR et al. (1997) Immunohistochemical detection of occult micrometastases using an automated intelligent microscopy system. Proc Am Assoc Cancer 38: 269-

    Google Scholar 

  52. Osborne MP, Wong GY, Asina S et al. (1991) Sensitivity of immunocytochemical detection of breast cancer cells in human bone marrow. Cancer Res 51: 2706–2709

    PubMed  CAS  Google Scholar 

  53. Martin VM, Siewert C, Scharl A et al. (1998) Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol 26: 252–264

    PubMed  CAS  Google Scholar 

  54. Naume B, Borgen E, Beiske K et al. (1997) Immunomagnetic techniques for the enrichment and detection of isolated breast carcinoma cells in bone marrow and peripheral blood. J Hematother 6: 103–114

    PubMed  CAS  Google Scholar 

  55. Naume B, Borgen E, Nesland JM et al. (1998) 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

    Article  PubMed  CAS  Google Scholar 

  56. Racila E, Euhus D, Weiss AJ et al. (1998) Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A 95: 4589–4594

    Article  PubMed  CAS  Google Scholar 

  57. Otte M, Deppert K, Ebel S et al. (2000) Immunomagnetic enrichment of disseminated tumor cells from bone marrow of carcinoma patients. Proc Am Assoc Cancer 41: 390-

    Google Scholar 

  58. Bos JL (1989) Ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689

    PubMed  CAS  Google Scholar 

  59. Gribben JG, Freedman AS, Neuberg D et al. (1991) Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325: 1525–1533

    Article  PubMed  CAS  Google Scholar 

  60. Harris CC, Hollstein M (1993) Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329: 1318–1327

    Article  PubMed  CAS  Google Scholar 

  61. Hayashi N, Arakawa H, Nagase H et al. (1994) Genetic diagnosis identifies occult lymph node metastases undetectable by the histopathological method. Cancer Res 54: 3853–3856

    PubMed  CAS  Google Scholar 

  62. Riethmuller G, Schneider GE, Schlimok G et al. (1994) Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes‘ C colorectal carcinoma. German Cancer Aid 17–1A Study Group. Lancet 343: 1177–1183

    Article  PubMed  CAS  Google Scholar 

  63. Bostick PJ, Hoon DS, Cote RJ (1998) Detection of carcinoembryonic antigen messenger RNA in lymph nodes from patients with colorectal cancer. N Engl J Med 339: 1643–1644

    PubMed  CAS  Google Scholar 

  64. Slade MJ, Smith BM, Sinnett HD et al. (1999) Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol 17: 870–879

    PubMed  CAS  Google Scholar 

  65. Gerhard M, Juhl H, Kalthoff H et al. (1994) Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Oncol 12: 725–729

    PubMed  CAS  Google Scholar 

  66. Ciudad J, San Miguel JF, Lopez-Berges MC et al. (1998) Prognostic value of immunophenotypic detection of minimal residual disease in acute lymphoblastic leukemia. J Clin Oncol 16: 3774–3781

    PubMed  CAS  Google Scholar 

  67. Jennings CD, Foon KA (1997) Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy. Blood 90: 2863–2892

    PubMed  CAS  Google Scholar 

  68. Gross HJ, Verwer B, Houck D et al. (1995) Model study detecting breast cancer cells in peripheral blood mononuclear cells at frequencies as low as 10(-7). Proc Natl Acad Sci U S A 92: 537–541

    Article  PubMed  CAS  Google Scholar 

  69. Molino A, Pelosi G, Turazza M et al. (1997) Bone marrow micrometastases in 109 breast cancer patients: correlations with clinical and pathological features and prognosis. Breast Cancer Res Treat 42: 23–30

    Article  PubMed  CAS  Google Scholar 

  70. Vredenburgh JJ, Silva O, Tyer C et al. (1996) A comparison of immunohistochemistry, two-color immunofluorescence, and flow cytometry with cell sorting for the detection of micrometastatic breast cancer in the bone marrow. J Hematother 5: 57–62

    PubMed  CAS  Google Scholar 

  71. Wingren S, Guerrieri C, Franlund B, Stal O (1995) Loss of cytokeratins in breast cancer cells using multiparameter DNA flow cytometry is related to both cellular factors and preparation procedure. Anal Cell Pathol 9: 229–233

    PubMed  CAS  Google Scholar 

  72. Ridell B, Landys K (1979) Incidence and histopathology of metastases of mammary carcinoma in biopsies from the posterior iliac crest. Cancer 44: 1782–1788

    Article  PubMed  CAS  Google Scholar 

  73. Braun S, Pantel K (1998) Prognostic significance of micrometastatic bone marrow involvement. Breast Cancer Res Treat 52: 201–216

    Article  PubMed  CAS  Google Scholar 

  74. Pantel K, Felber E, Schlimok G (1994) Detection and characterization of residual disease in breast cancer. J Hematother 3: 315–322

    PubMed  CAS  Google Scholar 

  75. Borgen E, Naume B, Nesland JM et al. (2001) Use of automated microscopy for the detection of disseminated tumor cells in bone marrow samples. Cytometry 46: 215–221

    Article  PubMed  CAS  Google Scholar 

  76. Borgen E, Beiske K, Trachsel S et al. (1998) Immunocytochemical detection of isolated epithelial cells in bone marrow: non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase. J Pathol 185: 427–434

    Article  PubMed  CAS  Google Scholar 

  77. Pantel K, Schlimok G, Braun S et al. (1993) Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 85: 1419–1424

    Article  PubMed  CAS  Google Scholar 

  78. Putz E, Witter K, Offner S et al. (1999) Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res 59: 241–248

    PubMed  CAS  Google Scholar 

  79. Schmidt-Kittler O, Ragg T, Daskalakis A et al. (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 100: 7737–7742

    Article  PubMed  CAS  Google Scholar 

  80. Weckermann D, Muller P, Wawroschek F et al. (1999) Micrometastases of bone marrow in localized prostate cancer: correlation with established risk factors. J Clin Oncol 17: 3438–3443

    PubMed  CAS  Google Scholar 

  81. Meng S, Tripathy D, Shete S et al. (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 101: 9393–9398

    Article  PubMed  CAS  Google Scholar 

  82. Solakoglu O, Maierhofer C, Lahr G et al. (2002) Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci U S A 99: 2246–2251

    Article  PubMed  CAS  Google Scholar 

  83. Braun S, Vogl F, Schlimok G et al. (2003) Pooled analysis of prognostic impact of bone marrow micrometastases: 10 year survival 4199 breast cancer patients. Breast Cancer Res Treat 67

  84. Diel IJ, Solomayer EF, Costa SD et al. (1998) Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357–363

    Article  PubMed  CAS  Google Scholar 

  85. Fields KK, Elfenbein GJ, Trudeau WL et al. (1996) 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 14: 1868–1876

    PubMed  CAS  Google Scholar 

  86. Datta YH, Adams PT, Drobyski WR et al. (1994) Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction. J Clin Oncol 12: 475–482

    PubMed  CAS  Google Scholar 

  87. Vannucchi AM, Bosi A, Glinz S et al. (1998) Evaluation of breast tumour cell contamination in the bone marrow and leukapheresis collections by RT-PCR for cytokeratin-19 mRNA. Br J Haematol 103: 610–617

    Article  PubMed  CAS  Google Scholar 

  88. Courtemanche DJ, Worth AJ, Coupland RW, MacFarlane JK (1991) Detection of micrometastases from primary breast cancer. Can J Surg 34: 15–19

    PubMed  CAS  Google Scholar 

  89. Porro G, Menard S, Tagliabue E et al. (1988) Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients. Cancer 61: 2407–2411

    Article  PubMed  CAS  Google Scholar 

  90. Salvadori B, Squicciarini P, Rovini D et al. (1990) Use of monoclonal antibody MBr1 to detect micrometastases in bone marrow specimens of breast cancer patients. Eur J Cancer 26: 865–867

    PubMed  CAS  Google Scholar 

  91. Untch M, Kahlert S, Funke I et al. (1999) Detection of cytokeratin (CK) 18 positive cells in the bone marrow (BM) of breast cancer patients - no prediction of bad outcome. Proc ASCO 18: 693a-

    Google Scholar 

  92. Mathieu MC, Friedman S, Bosq J et al. (1990) Immunohistochemical staining of bone marrow biopsies for detection of occult metastasis in breast cancer. Breast Cancer Res Treat 15: 21–26

    Article  PubMed  CAS  Google Scholar 

  93. Singletary SE, Larry L, Tucker SL, Spitzer G (1991) Detection of micrometastatic tumor cells in bone marrow of breast carcinoma patients. J Surg Oncol 47: 32–36

    Article  PubMed  CAS  Google Scholar 

  94. Funke I, Schraut W (1998) Meta-analyses of studies on bone marrow micrometastases: an independent prognostic impact remains to be substantiated. J Clin Oncol 16: 557–566

    PubMed  CAS  Google Scholar 

  95. Braun S, Vogl FD, Naume B et al. (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353: 793–802

    Article  PubMed  CAS  Google Scholar 

  96. Braun S, Schindlbeck C, Hepp F et al. (2001) Occult tumor cells in bone marrow of patients with locoregionally restricted ovarian cancer predict early distant metastatic relapse. J Clin Oncol 19: 368–375

    PubMed  CAS  Google Scholar 

  97. Marth C, Kisic J, Kaern J et al. (2002) Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer 94: 707–712

    Article  PubMed  Google Scholar 

  98. Janni W, Hepp F, Strobl B et al. (2003) Patterns of relapse influenced by hematogenous tumor cell dissemination in patients with cervical carcinoma of the uterus. Cancer 97: 405–411

    Article  PubMed  Google Scholar 

  99. Scheungraber C, Muller B, Kohler C et al. (2002) Detection of disseminated tumor cells in patients with cervical cancer. J Cancer Res Clin Oncol 128: 329–335

    Article  PubMed  Google Scholar 

  100. Goldhirsch A, Glick JH, Gelber RD et al. (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16: 1569–1583

    Article  PubMed  CAS  Google Scholar 

  101. Janni W, Rack B, Schindlbeck C et al. (2004) Association of persistence of isolated tumor cells (ITC) in bone marrow (BM) of breast cancer patients with risk for relapse. Proc ASCO

  102. Wiedswang G, Borgen E, Karesen R et al. (2003) The presence of isolated tumor cells in the bone marrow three years after diagnosis in disease free breast cancer patients predicts an unfavorable outcome. Breast Cancer Res Treat 67:

  103. Janni W, Wiedswang G, Fehm T et al. (2006) Persistence of disseminated tumor cells (DTC) in bone marrow (BM) during Follow-up predicts increased risk for relapse – Up-date of the pooled European data. Breast Cancer Res Treat 70:

  104. Coombes RC, Berger U, Mansi J et al. (1986) Prognostic significance of micrometastases in bone marrow in patients with primary breast cancer. NCI Monogr 1: 51–53

    PubMed  Google Scholar 

  105. Kirk SJ, Cooper GG, Hoper M et al. (1990) The prognostic significance of marrow micrometastases in women with early breast cancer. Eur J Surg Oncol 16: 481–485

    PubMed  CAS  Google Scholar 

  106. Dearnaley DP, Ormerod MG, Sloane JP (1991) Micrometastases in breast cancer: long-term follow-up of the first patient cohort. Eur J Cancer 27: 236–239

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der Autor hat Drittmittelfinanzierungen der Firmen Veridex, Chromovision, Applied Imaging und Roche erhalten.

Author information

Authors and Affiliations

  1. Universitätsfrauenklinik Innenstadt LMU, Maistraße 11, 80337, München, Deutschland

    W. Janni, B. Rack, H. Sommer, C. Schindlbeck, J. Jückstock & K. Friese

  2. Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg-Eppendorf, Deutschland

    V. Müller

  3. Universitätsfrauenklinik Tübingen, Tübingen, Deutschland

    T. Fehm & E. Solomayer

  4. Institut für Tumorbiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland

    K. Pantel

Authors
  1. W. Janni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Fehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Rack
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Solomayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Pantel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Sommer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Schindlbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Jückstock
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K. Friese
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W. Janni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janni, W., Fehm, T., Rack, B. et al. Isolierte Tumorzellen in Knochenmark und Blut von Patientinnen mit primärem Mammakarzinom – Klinische Relevanz. Gynäkologe 40, 431–439 (2007). https://doi.org/10.1007/s00129-007-1993-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00129-007-1993-8

Schlüsselwörter

Keywords

Search

Navigation