Zusammenfassung
Bei Patientinnen mit Mammakarzinom kommt es bereits früh im Krankheitsverlauf zu einer hämatogenen Streuung von Tumorzellen. Eine solche, in der Metastasierungskaskade frühe Tumorzelldissemination kann mithilfe sensitiver Nachweisverfahren im Blut und Knochenmark erfasst werden. Der immunzytochemische Nachweis disseminierter Tumorzellen im Knochenmark ist bei Patientinnen mit primärem Mammakarzinom mittlerweile als ein unabhängiger Prognosefaktor anerkannt. Dies ist ein Beweis für die biologische Relevanz dieser Zellen. Trotzdem hat sich die Erhebung des Knochenmarkstatus in der Routinediagnostik bis dato nicht etabliert. Disseminierte Tumorzellen lassen sich auch im Blut nachweisen und werden als zirkulierende Tumorzellen bezeichnet. Der Tumorzellnachweis im Blut ist einfach durchzuführen und erlaubt auch serielle Bestimmungen. In dieser Übersicht sollen klinisch relevante Fragestellungen sowie bislang vorliegende Studienergebnisse für den Nachweis von zirkulierenden Tumorzellen vorgestellt werden. Eine Reihe von Studienprojekten in Deutschland untersucht in diesem Zusammenhang wichtige Aspekte. Trotz der jüngsten ermutigenden Studienresultate sollten unseres Erachtens im Regelfall außerhalb von Studien in der klinischen Routine noch keine therapeutischen Konsequenzen aus dem Nachweis zirkulierender Tumorzellen im Blut gezogen werden.
Abstract
Hematogenous tumor cell dissemination is known to be an early event in breast cancer progression. This early step in the metastatic cascade can be detected using modern methods. Clinical studies have demonstrated that the detection of disseminated tumor cells in the bone marrow of patients with primary breast cancer is a strong prognostic factor. This is evidence for the biological relevance of these cells. Despite these findings, bone marrow aspiration is not widely established in clinical routine. Circulating tumor cells can be detected in the blood. Blood sampling is easy to perform and repeated sampling is possible. Clinically relevant applications and study results on the detection of circulating tumor cells are presented in this article. Several studies in Germany examine unsolved questions in this context. Despite encouraging study results, in our opinion therapeutic consequences should not be drawn routinely outside clinical trials.
Schlüsselwörter
Mammakarzinom - zirkulierende Tumorzellen - Blut - Therapie - Knochenmark
Key words
breast cancer - circulating tumor cells - blood - therapy - bone marrow
Literatur
1
Paget S.
Distribution of secondary growths in cancer of the breast.
Lancet.
1889;
1
571
2
Rohr K, Hegglin R.
Tumorzellen im Sternalpunktat.
Deutsch Arch Klin Med.
1936;
179
61-79
3
Sloane J P, Ormerod M G, Neville A M.
Potential pathological application of immunocytochemical methods to the detection of micrometastases.
Cancer Res.
1980;
40
3079-3082
4
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
5
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
6
Braun S, Vogl F D, Naume B, Janni W, Osborne M, Coombes R C, Schlimok G, Diel I, Gerber B, Gebauer G, Pierga J Y, Marth C, Oruzio D, Wiedswang G, Solomayer E, Kundt G, Strobl B, Fehm T, Wong G Y, Bliss J, Vincent-Salomon A, Pantel K.
International pooled analysis of prognostic significance of bone marrow micrometastasis in patients with stage I, II, or III breast cancer.
N Engl J Med.
2005;
353
793-802
7
Fehm T, Braun S, Müller V, Janni W, Marth C, Pantel K, Schindlbeck C, Solomayer E.
A concept for the standardized detection of disseminated tumor cells in bone marrow of patients with primary breast cancer and its clinical implementation.
Cancer.
2006;
107
885-892
8
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
9
Slade M J, Singh A, Smith B M, Tripuraneni G, Hall E, Peckitt C, Fox S, Graham H, Luchtenborg M, Sinnett H D, Cross N C, Coombes R C.
Persistence of bone marrow micrometastases in patients receiving adjuvant therapy for breast cancer: results at 4 years.
Int J Cancer.
2005;
114
94-100
10
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
11
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
12
Janni W, Wiedswang G, Borgen E, Braun S, Rack B, Schindlbeck C, Sommer H, Pantel K, Heinrigs M, Nesland J, Scholz C, Friese K, Jeschke U, Naume B.
Persistence of isolated tumor cells (ITC) in bone marrow (BM) of breast cancer patients predicts increased risk for relapse - results of pooled European data.
Breast Cancer Res Treat.
2005;
94 (Supplement 1)
Abstract 1016
13
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
14
Cristofanilli M, Hayes D F, Budd G T, Ellis M J, Stopeck A, Reuben J M, Doyle G V, Matera J, Allard W J, Miller M C, Fritsche H A, Hortobagyi G N, Terstappen L W.
Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer.
J Clin Oncol.
2005;
23
1420-1430
15
Hayes D F, Walker T M, Singh B, Vitetta E S, Uhr J W, Gross S, Rao C, Doyle G V, Terstappen L W.
Monitoring expression of HER‐2 on circulating epithelial cells in patients with advanced breast cancer.
Int J Oncol.
2002;
21
1111-1117
16
Wülfing P, Borchard J, Buerger H, Heidl S, Zanker K S, Kiesel L, Brandt B.
HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients.
Clin Cancer Res.
2006;
12
1715-1720
17
Mavroudis D, Apostolaki S, Perraki M, Politaki E, Xenidis N, Stathopoulou A, Lianidou E, Georgoulias V.
Detection of HER2 and CK‐19 mRNA-positive circulating tumor cells (CTCs) in the peripheral blood of patients with early stage breast cancer.
Proc Amer Assoc Cancer Res.
2006;
47
Abstract 5148
18
Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, Clifford E, Vitetta E, Morrison L, Herlyn D, Terstappen L W, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J.
HER‐2 gene amplification can be acquired as breast cancer progresses.
Proc Natl Acad Sci USA.
2004;
101
9393-9398
19
Stathopoulou A, Vlachonikolis I, Mavroudis D, Perraki M, Kouroussis C, Apostolaki S, Malamos N, Kakolyris S, Kotsakis A, Xenidis N, Reppa D, Georgoulias V.
Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance.
J Clin Oncol.
2002;
20
3404-3412
20
Xenidis N, Perraki M, Kafousi M, Apostolaki S, Bolonaki I, Stathopoulou A, Kalbakis K, Androulakis N, Kouroussis C, Pallis T, Christophylakis C, Argyraki K, Lianidou E S, Stathopoulos S, Georgoulias V, Mavroudis D.
Predictive and prognostic value of peripheral blood cytokeratin-19 mRNA-positive cells detected by real-time polymerase chain reaction in node-negative breast cancer patients.
J Clin Oncol.
2006;
24
3756-3762
21
Rack B K, Schindlbeck C, Janni W, Jeschke U, Hofmann S, Beckmann M, Pantel K, Lichtenegger W, Sommer H, Friese K.
Incidence of circulating tumor cells (CTCs) in peripheral blood of breast cancer patients at primary diagnosis - A potential tool for risk stratification.
J Clin Oncol.
2006;
24
Abstract 20053
22
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
23
Müller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Jänicke 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
24
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
Dr. med. Volkmar Müller
Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Gynäkologie
Martinistraße 52
20246 Hamburg
Email: vmueller@uke.uni-hamburg.de