Konsensusempfehlungen zu methodischen Aspekten und zur klinischen Relevanz des Nachweises disseminierter Tumorzellen (DTZ) im Knochenmark (KM) von Patientinnen mit primärem Mammakarzinom

T. Fehm; V. Müller; W. Janni; S. Braun; G. Gebauer; C. Marth; C. Schindlbeck; D. Wallwiener; E. Borgen; K. Pantel; E. Solomayer

doi:10.1055/s-2007-960739

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2007; 4(2): 85-91
DOI: 10.1055/s-2007-960739

Wissenschaftliche Arbeit

Konsensusempfehlungen zu methodischen Aspekten und zur klinischen Relevanz des Nachweises disseminierter Tumorzellen (DTZ) im Knochenmark (KM) von Patientinnen mit primärem Mammakarzinom

Ergebnisse des Konsensustreffens im Rahmen der Dreiländertagung Senologie, Stuttgart, September 2005Consensus Recommendations on Methodical Aspects and Clinical Relevance of the Evidence of Disseminated Tumor Cells in the Bone Marrow of Patients with Primary Breast CancerT. Fehm¹ ^, ⁸ , V. Müller² ^, ⁸ , W. Janni³ ^, ⁸ , S. Braun⁴ ^, ⁸ , G. Gebauer⁵ ^, ⁸ , C. Marth⁴ ^, ⁸ , C. Schindlbeck³ ^, ⁸ , D. Wallwiener¹ ^, ⁸ , E. Borgen⁶ ^, ⁹ , K. Pantel⁷ ^, ⁸ ^, ⁹ , E. Solomayer¹ ^, ⁸

¹Universitätsfrauenklinik Tübingen, Calwer Straße 7, 72076 Tübingen
²Universitätsfrauenklinik Hamburg, Martinistraße 52, 20246 Hamburg
³Universitätsfrauenklinik LMU, Maistraße 11, 80337 München
⁴Universitätsfrauenklinik Innsbruck, Anichstraße 35, 6020 Innsbruck, Österreich
⁵Universitätsfrauenklinik Heidelberg, Vossstraße 9, 69115 Heidelberg
⁶Institut für Pathologie, Radium Hospital, Ullernchausseen 70, 0310 Oslo, Norwegen
⁷Institut für Tumorbiologie, Martinistraße52, 20246 Hamburg
⁸stellvertetend für die Kommission Tumorzelldissemination der Senologie
⁹stellvertretend für DISMAL (Disseminated Malignancies) Projekt Konsortium (unterstützt durch das European Community's Framework programme, LSHC‐CT-2005-018911)

Abstract

Zusammenfassung

Das Gebiet der Tumorzelldissemination beim Mammakarzinom hat in den letzten Jahren immer mehr an Bedeutung gewonnen. Durch den Nachweis disseminierter Tumorzellen im Knochenmark und Blut wurde bewiesen, dass das Mammakarzinom eine systemische Erkrankung ist. Disseminierte Tumorzellen können bei 20 - 40 % aller Mammakarzinompatientinnen detektiert werden. Die Daten der Pooled Analysis der Collaborative Bone Marrow Micrometastasis Group bestätigten den Tumorzellnachweis im Knochenmark als unabhängigen prognostischen Marker. Darüber hinaus ist die Prognose für Frauen mit Tumorzellpersistenz nach adjuvanter systemischer Therapie im Vergleich zu den Patientinnen ohne Tumorzellnachweis deutlich schlechter. In zukünftigen Studien müssen nun Therapieansätze evaluiert werden, die die Eliminierung disseminierter Tumorzellen zum Ziel haben. Eine entscheidende Voraussetzung für die Durchführung von solchen (Multizenter-)Studien ist, dass ein standardisiertes Vorgehen zum Nachweis von disseminierten Tumorzellen im Knochenmark definiert wird. Im Rahmen der Dreiländertagung der Gesellschaften für Senologie traf sich daher ein internationales Expertenpanel aus Deutschland, der Schweiz und aus Österreich, um die bestehenden Methoden zum Tumorzellnachweis im Knochenmark zu evaluieren sowie einen Konsensus für den standardisierten Nachweis sowie die klinische Implementierung festzulegen.

Abstract

The presence of disseminated tumor cells in blood and bone marrow (BM) has confirmed the hypothesis of breast cancer as a systemic disease. Disseminated tumor cells (DTC) are already present in 20 - 40 % of primary breast cancer patients without clinical evidence of metastatic disease. A large pooled analysis has recently shown that the presence of disseminated tumor cells in the bone marrow (BM) of primary breast cancer patients (stages I - III) is associated with poor prognosis. Moreover, tumor cell persistence after completion of adjuvant therapy identifies patients at a high risk for recurrence. To date, sampling of BM and assessment of DTC is not considered a routine procedure in the clinical management of breast cancer patients, but emerging data suggests a future role for risk stratification and monitoring of therapeutic efficacy. Since these clinical options need to be evaluated in clinical trials, agreement on the standardized detection of DTC is mandatory. Therefore, the German, Austrian and Swiss Societies for Senology recently initiated an international consensus meeting to define a consensus for the standardized detection of DTC and to explore the options for its clinical implementation.

Schlüsselwörter

Mammakarzinom - Tumorzelldissemination - Konsensustreffen - Prognose

Key words

Breast cancer - tumor cell dissemination - consensus meeting - prognosis

Full Text

References

Literatur

1 Coombes R C, Berger U, Mansi J, Redding H, Powles T J, Neville A M, McKinna A, Nash A G, Gazet J C, Ford H T. Prognostic significance of micrometastases in bone marrow in patients with primary breast cancer. NCI. 1986; 1 51-53
2 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; 7 4102-4108
3 Porro G, Menard S, Tagliabue E, Orefice S, Salvadori B, Squicciarini P, Andreola S, Rilke F, Colnaghi M I. Monoclonal antibody detection of carcinoma cells in bone marrow biopsy specimens from breast cancer patients. Cancer. 1988; 61 2407-2411
4 Salvadori B, Squicciarini P, Rovini D, Orefice S, Andreola S, Rilke F, Barletta L, Menard S, Colnaghi M I. Use of monoclonal antibody MBr 1 to detect micrometastases in bone marrow specimens of breast cancer patients. Eur J Cancer. 1990; 26 865-867
5 Mathieu M C, Friedman S, Bosq J, Caillou B, Spielmann M, Travagli J P, Contesso G. Immunohistochemical staining of bone marrow biopsies for detection of occult metastasis in breast cancer. Breast Cancer Res Treat. 1990; 15 21-26
6 Dearnaley D P, Ormerod M G, Sloane J P. Micrometastases in breast cancer: long-term follow-up of the first patient cohort. Eur J Cancer. 1991; 27 236-239
7 Cote R J, Rosen P P, Lesser M L, Old L J, Osborne M P. Prediction of early relapse in patients with operable breast cancer by detection of occult bone marrow micrometastases. J Clin Oncol. 1991; 9 1749-1756
8 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; 21 3469-3478
9 Harbeck N, Untch M, Pache L, Eiermann W. Tumor cell detection in the bone marrow of breast cancer patients at primary therapy: Results of a 3-year median follow-up. British J Cancer. 1994; 69 566-571
10 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. 1998; 90 1099-1101
11 Funke I, Fries S, Rolle M, Heiss M M, Untch M, Bohmert H, Schildberg F W, Jauch K W. Comparative analyses of bone marrow micrometastases in breast and gastric cancer. Int J Cancer. 1996; 65 755-761
12 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; 354 197-202
13 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; 342 525-533
14 Gerber B, Krause A, Muller H, Richter D, Reimer T, Makovitzky J, Herrnring C, Jeschke U, Kundt G, Friese K. 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. 2001; 19 960-971
15 Gebauer G, Fehm T, Merkle E, Beck E P, Lang N, Jager W. Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol. 2001; 19 3669-3674
16 Pantel K, Brakenhoff R H. Dissecting the metastatic cascade. Nat Rev Cancer. 2004; 4 448-456
17 Braun S, Vogl F D, Naume B, Janni W, Osborne M P, Coombes R C, Schlimok G, Diel I J, Gerber B, Gebauer G, Pierga J Y, Marth C, Oruzio D, Wiedswang G, Solomayer E F, Kundt G, Strobl B, Fehm T, Wong G Y, Bliss J, Vincent-Salomon A, Pantel K. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005; 353 793-802
18 Wiedswang G, Borgen E, Karesen R, Qvist H, Janbu J, Kvalheim G, Nesland J M, Naume B. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res. 2004; 10 5342-5348
19 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
20 Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K. The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer. 2005; 103 884-891
21 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; 92 46-53
22 Naume B, Borgen E, Kvalheim G, Karesen R, Qvist H, Sauer T, Kumar T, Nesland J M. Detection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: Comparison with preoperative clinical parameters and primary tumor characteristics. Clin Cancer Res. 2001; 7 4122-4129
23 Bauer K D, de la Torre-Bueno J, Diel I J, Hawes D, Decker W J, Priddy C, Bossy B, Ludmann S, Yamamoto K, Masih A S, Espinoza F P, Harrington D S. Reliable and sensitive analysis of occult bone marrow metastases using automated cellular imaging. Clin Cancer Res. 2000; 6 3552-3559
24 Wiedswang G, Borgen E, Karesen R, Naume B. Detection of isolated tumor cells in BM from breast-cancer patients: significance of anterior and posterior iliac crest aspirations and the number of mononuclear cells analyzed. Cytotherapy. 2003; 5 40-45
25 Borgen E, Naume B, Nesland J M, Kvalheim G, Beiske K, Fodstad O, Diel I J, Solomayer E-F, Theocharous P, Coombes R C, Smith B M, Wunder E, Marolleau J-P, Garcia J, Pantel K. (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; 5 377-388
26 Pierga J Y, Bonneton C, Vincent-Salomon A, de Cremoux P, Nos C, Blin N, Pouillart P, Thiery J P, Magdelenat H. Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res. 2004; 10 1392-1400
27 Choesmel V, Anract P, Hoifodt H, Thiery J P, Blin N. A relevant immunomagnetic assay to detect and characterize epithelial cell adhesion molecule-positive cells in bone marrow from patients with breast carcinoma: immunomagnetic purification of micrometastases. Cancer. 2004; 101 693-703
28 Kraeft S K, Sutherland R, Gravelin L, Hu G H, Ferland L H, Richardson P, Elias A, Chen L B. Detection and analysis of cancer cells in blood and bone marrow using a rare event imaging system. Clin Cancer Res. 2000; 6 434-442
29 Borgen E, Naume B, Nesland J M, Nowels K W, Pavlak N, Ravkin I, Goldbard S. Use of automated microscopy for the detection of disseminated tumor cells in bone marrow samples. Cytometry. 2001; 46 215-221
30 Fehm T, Becker S, Pergola-Becker G, Kramer B, Gruber I, Sotlar K, Kurek R, Wallwiener D, Solomayer E. Influence of tumor biological factors on tumor cell dissemination in primary breast cancer. Anticancer Res. 2004; 24 4211-4216
31 Pantel K, Schlimok G, Angstwurm M, Weckermann D, Schmaus W, Gath H, Passlick B, Izbicki J R, Riethmuller G. Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother. 1994; 3 165-173
32 Schlimok G, Funke I, Holzmann B, Gottlinger G, Schmidt G, Hauser H, Swierkot S, Warnecke H H, Schneider B, Koprowski H. Micrometastatic cancer cells in bone marrow: in vitro detection with anti-cytokeratin and in vivo labeling with anti-17-1 A monoclonal antibodies. Proc Natl Acad Sci USA. 1987; 84 8672-8676
33 Thor A, Viglione M J, Ohuchi N, Simpson J, Steis R, Cousar J, Lippman M, Kufe D W, Schlom J. Comparison of monoclonal antibodies for the detection of occult breast carcinoma metastases in bone marrow. Breast Cancer Res Treat. 1988; 11 133-145
34 Becker S, Becker-Pergola G, Fehm T, Emig R, Wallwiener D, Solomayer E F. Image analysis systems for the detection of disseminated breast cancer cells on bone-marrow cytospins. J Clin Lab Anal. 2005; 19 115-119
35 Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein T J, Kaufmann M, Diebold J, Arnholdt H, Muller P, Bischoff J, Harich D, Schlimok G, Riethmuller G, Eils R, Klein C A. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci. 2003; 100 7737-7742
36 Gangnus R, Langer S, Breit E, Pantel K, Speicher M R. Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clin Cancer Res. 2004; 10 3457-3464
37 Klein C A, Blankenstein T J, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein N H, Riethmuller G. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet. 2002; 360 683-689
38 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; 8 2073-2084
39 Schardt J A, Meyer M, Hartmann C H, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein C A. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell. 2005; 8 227-239
40 Naume B, Wiedswang G, Borgen E, Kvalheim G, Karesen R, Qvist H, Janbu J, Harbitz T, Nesland J M. The prognostic value of isolated tumor cells in bone marrow in breast cancer patients: evaluation of morphological categories and the number of clinically significant cells. Clin Cancer Res. 2004; 10 3091-3097
41 Wong G YC, Yu Q Q, Osborne M P. Bone marrow micrometastasis is a significant predictor of long-term relapse-free survival for breast cancer by a non-proportional hazards model. Breast Cancer Res Treat. 2003; 82 99
42 Janni W, Naume B, Rack B, Gerber B, Braun S, Friese K. Persistierende Tumorzellen (PTZ) im Knochenmark von Brustkrebspatientinnen als Surrogatmarker für ein erhöhtes Rezidivrisiko in der onkologischen Nachsorge - Resultate einer europäischen Pooled-Analysis. Geburtsh Frauenheilk. 2005; 66 DOI: 10.1055/s-2005-920770
43 Becker S, Fehm T, Wallwiener D, Solomayer E F. Disseminierte Tumorzellen im Knochenmark nach adjuvanter systemischer Therapie. Senologie. 2005; 2 DOI: 10.1055/s-2005-917682
44 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; 85 1419-1424
45 Meng S, Tripathy D, Frenkel E P, Shete S, Naftalis E Z, Huth J F, Beitsch P D, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming T P, Herylyn D, Terstappen L WMM, Fehm T, Tucker T F, Lane N, Uhr J W. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004; 10 8152-8162
46 Braun S, Hepp F, Kentenich C R, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer H L. Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res. 1999; 5 3999-4004
47 Kirchner E M, Gerhards R, Voigtmann R. Sequential immunochemotherapy and edrecolomab in the adjuvant therapy of breast cancer: reduction of 17-1 A-positive disseminated tumour cells. Ann Oncol. 2002; 7 1044-1048
48 Janni W, Rack B, Sommer, 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. Geburtsh Frauenheilk. 2003; 63 DOI: 10.1055/s-2003-815162
49 Krämer B, Solomayer E F, Wallwiener D. Einfluss von Zoledronsäure auf die Tumorzelldissemination beim primären Mammakarzinom. Geburtsh Frauenheilk. 2003; 63 DOI: 10.1055/s-2003-815241
50 Solomayer E F, Wallwiener D, Fehm T. Aktuelle Bedeutung der Bisphosphonate in der systemischen Therapie des Mammakarzinoms. Senologie. 2005; 2
51 Fehm T, Gebauer G, Becker S, Vogel U, Bültmann B, Wallwiener D, Solomayer E. Genotypisierung von disseminierten epithelialen Zellen bei Mammakarzinompatientinnen. Geburtsh Frauenheilk. 2004; 64 255-260
52 Fehm T, Becker S, Neubauer, Huober J, Wallwiener D, Solomayer E. HER 2 Status disseminierter Tumorzellen im Vergleich zum Primärtumor bei Mammakarzinompatientinnen. Geburtsh Frauenheilk. 2005; 66 DOI: 10.1055/s-2005-920828
53 Braun S, Naume J. Circulating and disseminated tumor cells. Clin Oncol. 2005; 23 1623-1626
54 Fehm T, Becker S, Wallwiener D, Solomayer E. Einfluss der neoadjuvanten Therapie auf den Nachweis disseminierter Zellen im Knochenmark bei Mammakarzinompatientinnen. Senologie. 2006; 3 162
55 Wiedswang G, Borgen E, Schirmer C, Karesen R, Kvalheim G, Nesland J M, Naume B. Comparison of the clinical significance of occult tumor cells in blood and bone marrow in breast cancer. Int J Cancer. 2006; 118 2013-2019
56 Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res. 2005; 11 3678-3685
57 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; 351 781-791

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Universitätsfrauenklinik Tübingen

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Email: tanja.fehm@t-online.de