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