Skip to main content

Advertisement

SpringerLink
Log in

The influence of removal of primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Recent studies have shown that the detection of circulating tumor cells (CTC) pre and postoperatively in the peripheral blood of primary breast cancer patients may be an indicator for poor survival. This study aimed to investigate the influence of removal of the primary tumor on incidence and phenotype of circulating tumor cells in primary breast cancer. 209 primary breast cancer patients could be included into this analysis. Blood sampling was performed both pre and postoperatively. The blood specimens were immunomagnetically enriched using AdnaTest BreastCancerSelect within 4 h after blood withdrawal, followed by RNA isolation and subsequent gene expression analysis by reverse transcription and multiplex PCR using AdnaTest BreastCancerDetect. Three breast cancer-associated tumor markers and two hormone receptor genes were amplified: GA733-2, Muc-1, Her-2, ER, PR. In addition, bone marrow (BM) status was intraoperatively determined. Forty-three of 209 patients (21%) had pre and/or postoperatively circulating tumor cells. The positivity rates after surgery were higher but did not differ significantly (12% pre and 16% postoperatively, P = 0.264). Disseminated tumor cells in BM were seen in 32 of 209 cases (15%). Patients with positive BM status had significantly higher CTC positivity rates both pre and postoperatively compared to those with negative BM status. The most common CTC phenotype was triple negative (24 patients) followed by HER2+/ER−/PR− subtype (10) and ER and/or PR positive (9). Interestingly, 41 of 43 primary tumors (95%) were ER and PR positive. Removal of the primary tumor did not alter the phenotype of CTC. Surgery does not significantly influence the tumor cell load in the blood stream. CTC phenotype before and after the surgery generally remains identical but may differ from that of the primary tumor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

BM:

Bone marrow

CK:

Cytokeratin

CTC:

Circulating tumor cell

DTC:

Disseminated tumor cell

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

MRD:

Minimal residual disease

PR:

Progesterone receptor

References

  1. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802

    Article  PubMed  CAS  Google Scholar 

  2. Becker S, Solomayer E, Becker-Pergola G, Wallwiener D, Fehm T (2007) Primary systemic therapy does not eradicate disseminated tumor cells in breast cancer patients. Breast Cancer Res Treat 106:239–243

    Google Scholar 

  3. Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K (2005) The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer 103(5):884–891

    Article  PubMed  Google Scholar 

  4. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791

    Article  PubMed  CAS  Google Scholar 

  5. Rack BK, Schindlbeck C, Andergassen U, Schneeweiss A, Zwingers T, Lichtenegger W, Beckmann M, Sommer HL, Pantel K, Janni W (2010) 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 28(15 s):(suppl; abstr 1003)

  6. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162

    Article  PubMed  Google Scholar 

  7. Rankovic B, Mrdja V (2002) Use of disodium pamidronate in patients with bone metastases in patients with pulmonary carcinoma. Vojnosanit Pregl 59(1):33–36

    Article  PubMed  Google Scholar 

  8. Fehm T, Becker S, Pergola-Becker G, Kramer B, Gruber I, Sotlar K, Kurek R, Wallwiener D, Solomayer E (2004) Influence of tumor biological factors on tumor cell dissemination in primary breast cancer. Anticancer Res 24(6):4211–4216

    PubMed  CAS  Google Scholar 

  9. Tewes M, Aktas B, Welt A, Mueller S, Hauch S, Kimmig R, Kasimir-Bauer S (2008) Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat 115(3):581–590

    Google Scholar 

  10. Demel U, Tilz GP, Foeldes-Papp Z, Gutierrez B, Albert WH, Bocher O (2004) 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 23(3):465–468

    PubMed  CAS  Google Scholar 

  11. Lankiewicz S, Rivero BG, Bocher O (2006) Quantitative real-time RT-PCR of disseminated tumor cells in combination with immunomagnetic cell enrichment. Mol Biotechnol 34(1):15–27

    Article  PubMed  CAS  Google Scholar 

  12. Banys M, Solomayer EF, Becker S, Krawczyk N, Gardanis K, Staebler A, Neubauer H, Wallwiener D, Fehm T (2009) Disseminated tumor cells in bone marrow may affect prognosis of patients with gynecologic malignancies. Int J Gynecol Cancer 19(5):948–952

    Article  PubMed  Google Scholar 

  13. Fehm T, Braun S, Muller V, Janni W, Gebauer G, Marth C, Schindlbeck C, Wallwiener D, Borgen E, Naume B, Pantel K, Solomayer E (2006) A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer 107(5):885–892

    Article  PubMed  Google Scholar 

  14. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235

    Article  PubMed  Google Scholar 

  15. Weitz J, Kienle P, Lacroix J, Willeke F, Benner A, Lehnert T, Herfarth C, von Knebel Doeberitz M (1998) Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res 4(2):343–348

    PubMed  CAS  Google Scholar 

  16. Sandri MT, Zorzino L, Cassatella MC, Bassi F, Luini A, Casadio C, Botteri E, Rotmensz N, Adamoli L, Nole F (2010) Changes in circulating tumor cell detection in patients with localized breast cancer before and after surgery. Ann Surg Oncol 17(6):1539–1545

    Article  PubMed  Google Scholar 

  17. Biggers B, Knox S, Grant M, Kuhn J, Nemunatitis J, Fisher T, Lamont J (2009) Circulating tumor cells in patients undergoing surgery for primary breast cancer: preliminary results of a pilot study. Ann Surg Oncol 16(4):969–971

    Article  PubMed  Google Scholar 

  18. Krag DN, Ashikaga T, Moss TJ, Kusminsky RE, Feldman S, Carp NZ, Moffat FL, Beitsch PD, Frazier TG, Gaskin TA, Shook JW, Harlow SP, Weaver DL (1999) Breast cancer cells in the blood: a pilot study. Breast J 5(6):354–358

    Article  PubMed  Google Scholar 

  19. Sawabata N, Okumura M, Utsumi T, Inoue M, Shiono H, Minami M, Nishida T, Sawa Y (2007) Circulating tumor cells in peripheral blood caused by surgical manipulation of non-small-cell lung cancer: pilot study using an immunocytology method. Gen Thorac Cardiovasc Surg 55(5):189–192

    Article  PubMed  Google Scholar 

  20. Bessa X, Castells A, Lacy AM, Elizalde JI, Delgado S, Boix L, Pinol V, Pellise M, Garcia-Valdecasas JC, Pique JM (2001) Laparoscopic-assisted vs. open colectomy for colorectal cancer: influence on neoplastic cell mobilization. J Gastrointest Surg 5(1):66–73

    Article  PubMed  CAS  Google Scholar 

  21. Mehes G, Witt A, Kubista E, Ambros PF (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159(1):17–20

    Article  PubMed  CAS  Google Scholar 

  22. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46

    Article  PubMed  Google Scholar 

  23. Setoguchi T, Taga T, Kondo T (2004) Cancer stem cells persist in many cancer cell lines. Cell Cycle 3(4):414–415

    Article  PubMed  CAS  Google Scholar 

  24. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, Dinulescu DM, Connolly D, Foster R, Dombkowski D, Preffer F, Maclaughlin DT, Donahoe PK (2006) Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 103(30):11154–11159

    Article  PubMed  CAS  Google Scholar 

  25. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12(19):5615–5621

    Article  PubMed  CAS  Google Scholar 

  26. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  PubMed  CAS  Google Scholar 

  27. Pachmann K, Camara O, Kavallaris A, Krauspe S, Malarski N, Gajda M, Kroll T, Jorke C, Hammer U, Altendorf-Hofmann A, Rabenstein C, Pachmann U, Runnebaum I, Hoffken K (2008) Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 26(8):1208–1215

    Article  PubMed  Google Scholar 

  28. Pierga JY, Bonneton C, Vincent-Salomon A, de Cremoux P, Nos C, Blin N, Pouillart P, Thiery JP, Magdelenat H (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10(4):1392–1400

    Article  PubMed  CAS  Google Scholar 

  29. Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11(10):3678–3685

    Article  PubMed  Google Scholar 

  30. Solomayer EF, Becker S, Pergola-Becker G, Bachmann R, Kramer B, Vogel U, Neubauer H, Wallwiener D, Huober J, Fehm TN (2006) Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat 98(2):179–184

    Article  PubMed  CAS  Google Scholar 

  31. Krawczyk N, Banys M, Neubauer H, Solomayer EF, Gall C, Hahn M, Becker S, Bachmann R, Wallwiener D, Fehm T (2009) HER2 status on persistent disseminated tumor cells after adjuvant therapy may differ from initial HER2 status on primary tumor. Anticancer Res 29(10):4019–4024

    PubMed  Google Scholar 

  32. Fehm T, Hoffmann O, Aktas B, Becker S, Solomayer EF, Wallwiener D, Kimmig R, Kasimir-Bauer S (2009) 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 11(4):R59

    Article  PubMed  Google Scholar 

  33. Fehm T, Krawczyk N, Solomayer EF, Becker-Pergola G, Durr-Storzer S, Neubauer H, Seeger H, Staebler A, Wallwiener D, Becker S (2008) ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients. Breast Cancer Res 10(5):R76

    Article  PubMed  Google Scholar 

  34. Jückstock J, Rack B, Schindlbeck C, Hofmann S, Zill B, Rengel A, Feuerecker R, Mylonas I, Blankenstein T, Kost B, Janni W, Friese K (2008) Treatment with trastuzumab in recurrence free patients with early breast cancer and persistent disseminated tumor cells (DTC) in bone marrow. Paper presented at the San Antonio Breast Cancer Symposium, San Antonio, Texas

  35. 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 LW, Fleming T, Fehm T, Tucker T, Lane N, Wang J, Uhr J (2004) HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci USA 101(25):9393–9398

    Article  PubMed  CAS  Google Scholar 

  36. Hemsen A, Riethdorf L, Brunner N, Berger J, Ebel S, Thomssen C, Janicke F, Pantel K (2003) Comparative evaluation of urokinase-type plasminogen activator receptor expression in primary breast carcinomas and on metastatic tumor cells. Int J Cancer 107(6):903–909

    Article  PubMed  CAS  Google Scholar 

  37. Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312

    Article  PubMed  CAS  Google Scholar 

  38. Friberg S, Mattson S (1997) On the growth rates of human malignant tumors: implications for medical decision making. J Surg Oncol 65(4):284–297

    Article  PubMed  CAS  Google Scholar 

  39. Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Muller P, Bischoff J, Harich D, Schlimok G, Riethmuller G, Eils R, Klein CA (2003) From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA 100(13):7737–7742

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Professor Ludwig Spätling (Department of Gynecology and Obstetrics, Klinikum Fulda) and Dr. Mustafa Aydogdu (Department of Gynecology and Obstetrics, Klinikum Bremen-Mitte) for their support. We also thank Anna-Sophia McKenney (Cornell University, NY) for revising the manuscript and Lucian Plostinaru for designing Fig. 3.

Conflict of interest

The authors declare that they have no conflicts of interests.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany

    Malgorzata Banys, Natalia Krawczyk, Sven Becker, Jolanta Jakubowska, Diethelm Wallwiener, Tanja Fehm & Ralf Rothmund

  2. Department of Pathology, University of Tuebingen, Calwerstrasse 7, 72076, Tuebingen, Germany

    Annette Staebler

Authors
  1. Malgorzata Banys
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Krawczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sven Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jolanta Jakubowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annette Staebler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Diethelm Wallwiener
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tanja Fehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ralf Rothmund
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Malgorzata Banys or Ralf Rothmund.

Additional information

Malgorzata Banys and Natalia Krawczyk contributed equally to this publication.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 132, 121–129 (2012). https://doi.org/10.1007/s10549-011-1569-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1569-0

Keywords

Search

Navigation