Circulating Tumor Cells in Early-Stage Breast Cancer

 

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Abstract

Disseminated tumor cells (DTC) are routinely detected in bone marrow (BM) in 30–40 % of primary breast cancer patients. Positive BM status at the time of diagnosis as well as DTC persistence after therapy are strong independent prognostic factors. Since repeated BM aspirations are not well tolerated, detection of single tumor cells in peripheral blood (circulating tumor cells; CTC) have become of interest in recent years. CTC are found in 10–80 % breast cancer patients. Variability can be explained by stage of the disease and detection method. Emerging data have shown CTC to be of prognostic relevance for both, patients with primary and metastatic disease. The assessment of CTC in blood may become an important biomarker for prognostication and therapy monitoring. Determination of their molecular characteristics will enable specific targeting of minimal residual as well as metastatic disease. This review summarizes recent research and future perspectives.

Zusammenfassung

Disseminierte Tumorzellen im Knochenmark können in 30–40 % aller Patientinnen mit primärem Mammakarzinom entdeckt werden. Der Nachweis von disseminierten Tumorzellen zum Zeitpunkt der Erstdiagnose, aber auch die Persistenz derselben unter einer Therapie sind ungünstige prognostische Faktoren. Die Praktikabilität von wiederholten Knochenmarkspunktionen unter einer Therapie ist jedoch zeit- und kostenintensiv und für die Patientin unangenehm. Deswegen bietet die Untersuchung von peripherem Blut deutliche Vorteile. Zirkulierende Tumorzellen können in 10–80 % aller Patientinnen entdeckt werden. Die Rate hängt von der Analysemethode und dem Stadium der Erkrankung ab. Es konnte bereits nachgewiesen werden, dass das Vorhandensein von Tumorzellen im peripheren Blut sowohl für Patientinnen mit Metastasen als auch für Patientinnen ohne Metastasen von prognostischer Bedeutung ist. Eine molekulare Charakterisierung der zirkulierenden Tumorzellen könnte weiterhelfen, spezifische Therapien zu entwicklen, die sich direkt gegen diese Tumorzellen richten und so helfen, diese zu eliminieren. Dieser Übersichtsartikel fasst die aktuelle Literatur zusammen und gibt eine Zukunftsperspektive zu dem Thema.

Footnote

^* equally contributed

• References

• 1 Ashworth TR. A case of cancer in which cells similar to those in tumors were seen in the blood after death. Aust Med J 1869; 14: 146
  PubMedGoogle Scholar
• 2 Paget S. Distribution of secondary growths in cancer of the breast. Lancet 1889; 1: 571
  PubMedGoogle Scholar
• 3 Gebauer G, Fehm T, Merkle E et al. 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
  PubMedGoogle Scholar
• 4 Allard WJ, Matera J, Miller MC et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004; 10: 6897-6904
  CrossrefPubMedGoogle Scholar
• 5 Banys M, Solomayer EF, Becker S et al. Disseminated tumor cells in bone marrow may affect prognosis of patients with gynecologic malignancies. Int J Gynecol Cancer 2009; 19: 948-952
  CrossrefPubMedGoogle Scholar
• 6 Braun S, Vogl FD, Naume B et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 2005; 353: 793-802
  CrossrefPubMedGoogle Scholar
• 7 Janni W, Vogl FD, Wiedswang G et al. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse – a European pooled analysis. Clin Cancer Res 2011; 17: 2967-2976
  CrossrefPubMedGoogle Scholar
• 8 Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-791
  CrossrefPubMedGoogle Scholar
• 9 Rack BK, Schindlbeck C, Andergassen U et al. Use of circulating tumor cells (CTC) in peripheral blood of breast cancer patients before and after adjuvant chemotherapy to predict risk for relapse: The SUCCESS trial. ASCO Annual Meeting 2010. J Clin Oncol 2010; 28: 15s (Suppl.; Abstr. 1003)
  PubMedGoogle Scholar
• 10 Janni W, Salmen J. Onkologie. Mammakarzinom: Was bringt die SUCCESS-Studie Neues?. Geburtsh Frauenheilk 2010; 70: 330-331
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Liedtke C, Wolf MK, Kiesel L. New concepts for targeted systemic therapy in breast cancer. Geburtsh Frauenheilk 2010; 70: 625-633
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Fehm T, Hoffmann O, Aktas B et al. Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res 2009; 11: R59
  CrossrefPubMedGoogle Scholar
• 13 Fehm T, Solomayer EF, Meng S et al. Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells. Cytotherapy 2005; 7: 171-185
  CrossrefPubMedGoogle Scholar
• 14 Cristofanilli M, Hayes DF, Budd GT et al. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2005; 23: 1420-1430
  CrossrefPubMedGoogle Scholar
• 15 Demel U, Tilz GP, Foeldes-Papp Z et al. Detection of tumour cells in the peripheral blood of patients with breast cancer. Development of a new sensitive and specific immunomolecular assay. J Exp Clin Cancer Res 2004; 23: 465-468
  PubMedGoogle Scholar
• 16 Lankiewicz S, Rivero BG, Bocher O. Quantitative real-time RT-PCR of disseminated tumor cells in combination with immunomagnetic cell enrichment. Mol Biotechnol 2006; 34: 15-27
  CrossrefPubMedGoogle Scholar
• 17 Pierga JY, Bonneton C, Vincent-Salomon A et al. 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
  CrossrefPubMedGoogle Scholar
• 18 Schoenfeld A, Kruger KH, Gomm J et al. The detection of micrometastases in the peripheral blood and bone marrow of patients with breast cancer using immunohistochemistry and reverse transcriptase polymerase chain reaction for keratin 19. Eur J Cancer 1997; 33: 854-861
  CrossrefPubMedGoogle Scholar
• 19 Ismail MS, Wynendaele W, Aerts JL et al. Detection of micrometastatic disease and monitoring of perioperative tumor cell dissemination in primary operable breast cancer patients using real-time quantitative reverse transcription-PCR. Clin Cancer Res 2004; 10: 196-201
  CrossrefPubMedGoogle Scholar
• 20 Muller V, Stahmann N, Riethdorf S et al. 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
  CrossrefPubMedGoogle Scholar
• 21 Stathopoulou A, Mavroudis D, Perraki M et al. Molecular detection of cancer cells in the peripheral blood of patients with breast cancer: comparison of CK-19, CEA and maspin as detection markers. Anticancer Res 2003; 23: 1883-1890
  PubMedGoogle Scholar
• 22 Banys M, Krawczyk N, Becker S et al. The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. Breast Cancer Res Treat 2011; in press
  PubMedGoogle Scholar
• 23 Meng S, Tripathy D, Frenkel EP et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004; 10: 8152-8162
  CrossrefPubMedGoogle Scholar
• 24 Giuliano M, Giordano A, Jackson S et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res 2011; 13: R67
  CrossrefPubMedGoogle Scholar
• 25 Dawood S, Broglio K, Valero V et al. Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system?. Cancer 2008; 113: 2422-2430
  CrossrefPubMedGoogle Scholar
• 26 Hayes DF, Cristofanilli M, Budd GT et al. Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006; 12: 4218-4224
  CrossrefPubMedGoogle Scholar
• 27 Budd GT, Cristofanilli M, Ellis MJ et al. Circulating tumor cells versus imaging – predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12: 6403-6409
  CrossrefPubMedGoogle Scholar
• 28 Nieto Y, Franklin WA, Jones RB et al. Prognostic significance of occult tumor cells in the apheresis products of patients with advanced breast cancer receiving high-dose chemotherapy and autologous hematopoietic progenitor cell support. Biol Blood Marrow Transplant 2004; 10: 415-425
  CrossrefPubMedGoogle Scholar
• 29 Bidard FC, Vincent-Salomon A, Sigal-Zafrani B et al. Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Ann Oncol 2008; 19: 496-500
  PubMedGoogle Scholar
• 30 Nole F, Munzone E, Zorzino L et al. Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications. Ann Oncol 2008; 19: 891-897
  CrossrefPubMedGoogle Scholar
• 31 Rack B, Schindlbeck C, Andergassen U et al. Prognostic relevance of circulating tumor cells in the peripheral blood of primary breast cancer patients. 33rd Annual San Antonio Breast Cancer Symposium 2010: S6-5
  PubMedGoogle Scholar
• 32 Bidard FC, Mathiot C, Delaloge S et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol 2010; 21: 729-733
  CrossrefPubMedGoogle Scholar
• 33 Daskalaki A, Agelaki S, Perraki M et al. Detection of cytokeratin-19 mRNA-positive cells in the peripheral blood and bone marrow of patients with operable breast cancer. Br J Cancer 2009; 101: 589-597
  CrossrefPubMedGoogle Scholar
• 34 Pierga JY, Bidard FC, Mathiot C et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 2008; 14: 7004-7010
  CrossrefPubMedGoogle Scholar
• 35 Xenidis N, Perraki M, Kafousi M et al. 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
  CrossrefPubMedGoogle Scholar
• 36 Ntoulia M, Stathopoulou A, Ignatiadis M et al. Detection of Mammaglobin A-mRNA-positive circulating tumor cells in peripheral blood of patients with operable breast cancer with nested RT-PCR. Clin Biochem 2006; 39: 879-887
  CrossrefPubMedGoogle Scholar
• 37 Stathopoulou A, Vlachonikolis I, Mavroudis D et al. 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
  CrossrefPubMedGoogle Scholar
• 38 Fehm T, Becker S, Becker-Pergola G et al. Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer. Breast Cancer Res 2006; 8: R60
  CrossrefPubMedGoogle Scholar
• 39 Fehm T, Mueller V, Marches R et al. Tumor cell dormancy: implications for the biology and treatment of breast cancer. APMIS 2008; 116: 742-753
  CrossrefPubMedGoogle Scholar
• 40 Janni W, Rack B, Schindlbeck C et al. 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
  CrossrefPubMedGoogle Scholar
• 41 Riethdorf S, Muller V, Zhang L et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 2010; 16: 2634-2645
  CrossrefPubMedGoogle Scholar
• 42 Camara O, Rengsberger M, Egbe A et al. The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Ann Oncol 2007; 18: 1484-1492
  CrossrefPubMedGoogle Scholar
• 43 Becker S, Solomayer E, Becker-Pergola G et al. Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 2007; 106: 239-243
  CrossrefPubMedGoogle Scholar
• 44 Schmidt-Kittler O, Ragg T, Daskalakis A et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA 2003; 100: 7737-7742
  CrossrefPubMedGoogle Scholar
• 45 Solomayer EF, Becker S, Pergola-Becker G et al. Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat 2006; 98: 179-184
  CrossrefPubMedGoogle Scholar
• 46 Krawczyk N, Banys M, Neubauer H et al. HER2 status on persistent disseminated tumor cells after adjuvant therapy may differ from initial HER2 status on primary tumor. Anticancer Res 2009; 29: 4019-4024
  PubMedGoogle Scholar
• 47 Fehm T, Krawczyk N, Solomayer EF et al. ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res 2008; 10: R76
  CrossrefPubMedGoogle Scholar
• 48 Pantel K, Schlimok G, Braun S et al. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst 1993; 85: 1419-1424
  CrossrefPubMedGoogle Scholar
• 49 Braun S, Kentenich C, Janni W et al. 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
  PubMedGoogle Scholar
• 50 Rüschoff J, Nagelmeier I, Middel P et al. The role of Her-2/neu in the carcinogenesis of breast cancer – when and where?. Geburtsh Frauenheilk 2009; 69: 711-716
  Article in Thieme ConnectPubMedGoogle Scholar
• 51 Meng S, Tripathy D, Shete S et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 2004; 101: 9393-9398
  CrossrefPubMedGoogle Scholar
• 52 Jückstock J, Rack B, Schindlbeck C et al. Treatment with trastuzumab in recurrence free patients with early breast cancer and persistent disseminated tumor cells (DTC) in bone marrow. in San Antonio Breast Cancer Symposium 2008 San Antonio, Texas:
  PubMedGoogle Scholar
• 53 Rack B, Juckstock J, Gunthner-Biller M et al. Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients. Arch Gynecol Obstet 2011; in press
  PubMedGoogle Scholar
• 54 Bozionellou V, Mavroudis D, Perraki M et al. Trastuzumab administration can effectively target chemotherapy-resistant cytokeratin-19 messenger RNA-positive tumor cells in the peripheral blood and bone marrow of patients with breast cancer. Clin Cancer Res 2004; 10: 8185-8194
  CrossrefPubMedGoogle Scholar
• 55 Aktas B, Muller V, Tewes M et al. Comparison of estrogen and progesterone receptor status of circulating tumor cells and the primary tumor in metastatic breast cancer patients. Gynecol Oncol 2011; 122: 356-360
  CrossrefPubMedGoogle Scholar
• 56 Broom RJ, Tang PA, Simmons C et al. Changes in estrogen receptor, progesterone receptor and Her-2/neu status with time: discordance rates between primary and metastatic breast cancer. Anticancer Res 2009; 29: 1557-1562
  PubMedGoogle Scholar
• 57 Noss D, Buchholz S, Ortmann O. Adjuvant endocrine therapy for breast cancer during perimenopause. Geburtsh Frauenheilk 2010; 70: 112-116
  Article in Thieme ConnectPubMedGoogle Scholar
• 58 Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 1999; 91: 80-85
  CrossrefPubMedGoogle Scholar
• 59 Gluz O, Liedtke C, Nitz U et al. Molecular mechanisms of chemoresistance and potential means of overcoming it. Geburtsh Frauenheilk 2009; 69: 138-144
  Article in Thieme ConnectPubMedGoogle Scholar
• 60 Diel I, Dresemann G, Fehm T et al. Interdisciplinary consensus on the use of adjuvant bisphosphonate therapy in breast cancer patients. Geburtsh Frauenheilk 2009; 69: 511-516
  Article in Thieme ConnectPubMedGoogle Scholar
• 61 Weiss L. Metastatic inefficiency. Adv Cancer Res 1990; 54: 159-211
  PubMedGoogle Scholar
• 62 Rajab TK, Neubauer H, Krämer B et al. Die Metastasierungskaskade – Neue Wege der Metastasierung. Geburtsh Frauenheilk 2009; 69: 69-70
  Article in Thieme ConnectPubMedGoogle Scholar
• 63 Aktas B, Tewes M, Fehm T et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 2009; 11: R46
  CrossrefPubMedGoogle Scholar
• 64 Setoguchi T, Taga T, Kondo T. Cancer stem cells persist in many cancer cell lines. Cell Cycle 2004; 3: 414-415
  CrossrefPubMedGoogle Scholar
• 65 Szotek PP, Pieretti-Vanmarcke R, Masiakos PT et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 2006; 103: 11154-11159
  CrossrefPubMedGoogle Scholar
• 66 Balic M, Lin H, Young L et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 2006; 12: 5615-5621
  CrossrefPubMedGoogle Scholar
• 67 Achuthan S, Santhoshkumar TR, Prabhakar J et al. Drug induced senescence generates chemoresistant stem like cells with low reactive oxygen species. J Biol Chem 2011; 286: 37813-37829
  CrossrefPubMedGoogle Scholar