Nachweis zirkulierender Tumorzellen für die Prognose, Diagnostik und Therapie unter besonderer Berücksichtigung des Mammakarzinoms

Zusammenfassung

Seit vielen Jahren ist bekannt, dass sich für zahlreiche Tumorentitäten insbesondere mit Fortschreiten der Erkrankung zirkulierende Tumorzellen im Blut nachweisen lassen. Die Bedeutung zirkulierender Tumorzellen hinsichtlich ihres metastasierenden Potenzials ist nicht im Ganzen geklärt. Es ist jedoch eindeutig, dass frühe Prozesse der Metastasierung über das Blut- bzw. Lymphsystem erfolgen und der positive Nachweis zirkulierender Tumorzellen mit einer ungünstigen Prognose einhergeht, insbesondere bei Patientinnen mit einem Brusttumor. Mittlerweile stehen Verfahren zur Verfügung, die neben einer immunomagnetischen Anreicherung von Tumorzellen auch deren sensitive und spezifische Charakterisierung mit Hilfe molekulargenetischer Verfahren ermöglichen. Der positive Nachweis zirkulierender Tumorzellen kann einen Hinweis auf einen tumorproliferativen Prozess geben und wird nach dem aktuellen Stand der Literatur bei Patientinnen mit einem Brusttumor als unabhängiger prognostischer Faktor gewertet werden. Zukünftig kann der Nachweis zirkulierender Tumorzellen einen zeitnahen Hinweis auf das Therapieansprechen ermöglichen und zur Optimierung der Therapie eingesetzt werden.

Summary

Since many years it is well known that disseminated tumor cells may be present for a number of malignant diseases. Although the impact of circulating tumor cells in regard to their metatastic potential is not completely understood it seems to be unambiguously that metastasization results from the lymph and bloodstream. In addition, detection of circulating tumor cells is associated with an adverse prognosis especially in patients with breast cancer. Now there are methods available by means of immuno magnetic enrichment in combination with sensitive and specific molecular analyses that permits the detection of circulating tumor cells. The detection of circulating tumor cells gives evidence to the process of tumor proliferation. According to the state of the art the detection of circulating tumor cells is an independent prognostic factor at least at patients with breast cancer. The detection of circulating tumor cells is a realtime hint of therapy response and may be used to improve therapy response in the future.

Schlüsselwörter

Zirkulierende Tumorzellen - Genexpression - molekulare Marker - Metastasierung - Mammakarzinom - Therapieoptimierung

Keywords

Circulating tumor cells - gene expression - molecular marker - metastasis - breast cancer - therapy improvement

Literatur

• 01 Ashworth T R. A Case of cancer in which cells similar to those in the tumours were seen in the blood after death.  Aus Med. J.. 1869;  14 146-9
• 02 Bostick P J, Chatterjee S, Chi D D, Huynh K T, Giuliano A E, Cote R, Hoon D S. 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.. 1998;  16 (8) 2632-40
• 03 Bast R C, Ravdin P, Hayes D F, Bates S, Fritsche H, Jessup J M, Kemeny N, Locker G Y, Mennel R G, Somerfield M R. American Society of Clinical Oncology Tumor Markers Epert Panel: 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology.  J. Clin. Oncol.. 2001;  19 (6) 1865-78
• 04 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 (8) 793-802
• 05 Chambers A F, Naumov G N, Vantyghem S A, Tuck A B. Molecular biology of breast cancer metastasis. Clinical implications of experimental studies on metastatic inefficiency.  Breast Cancer Res.. 2000;  2 (6) 400-7
• 06 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 (8) 781-91
• 07 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 (7) 420-30
• 08 Christopherson W M. Cancer cells in the peripheral blood: A second look.  Acta Cytol.. 1965;  86 1965-74
• 09 Dong J T, Lamb P W, Rinker-Schaeffer C W, Vukanovic J, Ichikawa T, Isaacs J T, Barrett J C. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2.  1995;  268 (5212) 884-6
• 10 Fidler I J. Tumor heterogeneity and the biology of cancer invasion and metastasis.  Cancer Res.. 1978;  38 (9) 2651-60
• 11 Gilbey A M, Burnett D, Coleman R E, Holen I. The detection of circulating breast cancer cells in blood.  J. Clin. Pathol.. 2004;  57 (9) 903-11
• 12 Haber D, Harlow E. Tumour-suppressor genes: evolving definitions in the genomic age.  Nat. Genet.. 1997;  16 (4) 320-2
• 13 Habets G G, Scholtes E H, Zuydgeest D, Kammen R A van der, Stam J C, Berns A, Collard J G. Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins.  Cell. 1994;  77 (4) 537-49
• 14 Land H, Parada L F, Weinberg R A. Cellular oncogenes and multistep carcinogenesis.  Science. 1983;  222 (4625) 771-8
• 15 Lee J H, Welch D R. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1.  Cancer Res. 1997;  57 (12) 2384-7
• 16 Loktionov A. Common gene polymorphisms, cancer progression and prognosis.  Cancer Lett. 2004;  208 (1) 1-33
• 17 Malaguarnera L. Implications of apoptosis regulators in tumorigenesis.  Cancer Metastasis Rev. 2004;  23 (3-4) 367-387
• 18 Nagasaki K, Miki Y. Gene expression profiling of breast cancer.  Breast Cancer. 2006;  13 (1) 2-7
• 19 Pachmann K, Camara O, Kavallaris A, Schneider U, Schünemann S, Höffken K. Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring.  Breast Cancer Res. 2005;  7 (6) R975-R979
• 20 Paik S. Methods for gene expression profiling in clinical trials of adjuvant breast cancer therapy.  Clin. Cancer Res. 2006;  12 (3 Pt 2) 1019s-1023s
• 21 Paik S S, Tang G, Kim C, Baker J, Cronin M, Baehner F L, Walker M G, Watson D, Park T, Hiller W, Fisher E R, Wickerham D L, Bryant J, Wolmark N. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.  N. Engl. J. Med.. 2004;  351 (27) 2817-26
• 22 Pierga J Y, Bonneton C, Vincent-Salomon A, Cremoux P de, 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 (4) 1392-400
• 23 Ring A, Smith I E, Dowsett M. Circulating tumour cells in breast cancer.  Lancet Oncol. 2004;  5 (2) 79-88
• 24 Ring A E, Zabaglo L, Ormerod M G, Smith I E, Dowsett M. Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques.  Br. J. Cancer.. 2005;  92 (5) 906-12
• 25 Rody A, Karn T, Gatje R, Kourtis K, Minckwitz G, Loibl S, Munnes M, Ruckhaberle E, Holtrich U, Kaufmann M, Ahr A. Gene expression profiles of breast cancer obtained from core cut biopsies before neoadjuvant docetaxel, adriamycin, and cyclophoshamide chemotherapy correlate with routine prognostic markers and could be used to identify predictive signatures.  Zentralbl. Gynakol.. 2006;  128 (2) 76-81
• 26 Rolle A, Günzel R, Pachmann U, Willen B, Höffken K, Pachmann K. Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC(R) is a predictor for relapse: A preliminary report.  World J. Surg. Oncol.. 2005;  3 (1) 18
• 27 Sarantou T, Chi D D, Garrison D A, Conrad A J, Schmid P, Morton D L, Hoon D S. Melanoma-associated antigens as messenger RNA detection markers for melanoma.  Cancer Res. 1997;  57 (7) 1371-6
• 28 Schuster R, Max N, Mann B, Heufelder K, Thilo F, Grone J, Rokos F, Buhr H J, Thiel E, Keilholz U. Quantitative real-time RT-PCR for detection of disseminated tumor cells in peripheral blood of patients with colorectal cancer using different mRNA markers.  Int. J. Cancer.. 2004;  108 (2) 219-27
• 29 Smerage J B, Hayes D F. The measurement and therapeutic implications of circulating tumour cells in breast cancer.  Br. J. Cancer.. 2006;  94 (1) 8-12
• 30 Smirnov D A, Zweitzig D R, Foulk B W, Miller M C, Doyle G V, Pienta K J, Meropol N J, Weiner L M, Cohen S J, Moreno J G, Connelly M C, Terstappen L W, O'Hara S M. Global gene expression profiling of circulating tumor cells.  Cancer Res. 2005;  65 (12) 4993-7
• 31 Sorlie T, Wang Y, Xiao C, Johnsen H, Naums B, Samaha R R, Borresen-Dale A L. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: Gene expression analyses across three different platforms.  BMC Genomics. 2006;  7 (1) 127
• 32 Sotiriou C, Wirapati P, Loi S, Harris A, Fos S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains P, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Vijver M J van de, Bergh J, Piccart M, Delorenzi M. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.  J. Natl. Cancer Inst.. 2006;  98 (4) 262-72
• 33 Taback B, Chan A D, Kuo C T, Bostick P J, Wang H J, Giuliano H J, Hoon D S. Detection of occult metastatic breast cancer cells in blood by a multimolecular marker assay: correlation with clinical stage of disease.  Cancer Res. 2001;  61 (24) 8845-50
• 34 Thuerigen O, Schneeweiss A, Toedt G, Warnat P, Hahn M, Kramer H, Brors B, Rudlowski C, Benner A, Schuetz F, Tews B, Eils R, Sinn H P, Sohn C, Lichter P. Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer.  J. Clin. Oncol.. 2006;  24 (12) 1839-45
• 35 Witzig T E, Bossy, Kimlinger T, Roche P C, Ingle J N, Grant C, Donohue J, Suman V J, Harrington D, Torre-Bueno J, Bauer K D. Detection of circulating cytokeratin-positive cells in the blood of breast cancer patients using immunomagnetic enrichment and digital microscopy.  Clin. Cancer Res. 2002;  8 (5) 1085-91
• 36 Zieglschmid V, Hollmann C, Böcher O. Detection of disseminated tumor cells in peripheral blood.  Crit. Rev. Clin. Lab. Sci.. 2005;  42 (2) 155-96

Korrespondenzadresse