Detection of Circulating Tumor Cells in Breast Cancer Patients: Prognostic Predictive Role

  • Turker, Ibrahim ;
  • Uyeturk, Ummugul ;
  • Sonmez, Ozlem Uysal ;
  • Oksuzoglu, Berna ;
  • Helvaci, Kaan ;
  • Arslan, Ulku Yalcintas ;
  • Budakoglu, Burcin ;
  • Alkis, Necati ;
  • Aksoy, Sercan ;
  • Zengin, Nurullah
  • Published : 2013.03.30


A determination of circulating tumor cell (CTC) effectiveness for prediction of progression-free survival (PFS) and overall survival (OS) was conducted as an adjunct to standard treatment of care in breast cancer management. Between November 2008 and March 2009, 22 metastatic and 12 early stage breast carcinoma patients, admitted to Ankara Oncology Training and Research Hospital, were included in this prospective trial. Patients' characteristics, treatment schedules and survival data were evaluated. CTC was detected twice by CellSearch method before and 9-12 weeks after the initiation of chemotherapy. A cut-off value equal or greater than 5 cells per 7.5 ml blood sample was considered positive. All patients were female. Median ages were 48.0 (range: 29-65) and 52.5 (range: 35-66) in early stage and metastatic subgroups, respectively. CTC was positive in 3 (13.6%) patients before chemotherapy and 6 (27.3%) patients during chemotherapy in the metastatic subgroup whereas positive in only one patient in the early stage subgroup before and during chemotherapy. The median follow-up was 22.0 (range: 21-23) and 19.0 (range: 5-23) months in the early stage and metastatic groups, respectively. In the metastatic group, both median PFS and OS were significantly shorter in any time CTC positive patients compared to CTC negative patients (PFS: 4.0 vs 14.0 months, Log-Rank p=0.013; and OS: 8.0 months vs. 20.5 months, Log-Rank p<0.001). OS was affected from multiple visceral metastatic sites (p=0.055) and higher grade (p=0.044) besides CTC positivity (log rank p<0.001). Radiological response of chemotherapy was also correlated with better survival (p<0.001). As a result, CTC positivity was confirmed as a prospective marker even in a small patient population, in this single center study. Measurement of CTC by CellSearch method in metastatic breast carcinoma cases may allow indications of early risk of relapse or death with even as few as two measurements during a chemotherapy program, but this finding should be confirmed with prospective trials in larger study populations.


Breast cancer;circulating tumor cells;survival


  1. Alemar J, Schuur ER (2013). Progress in using circulating tumor cell information to improve metastatic breast cancer therapy. J Oncol, 10, 702732.
  2. Bidard FC, Mathiot C, Delaloge S, et al (2010). Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol, 21, 729-33.
  3. Bidard FC, Fehm T, Ignatiadis M, et al (2012). Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev, 10, 9398.
  4. Botteri E, Sandri MT, Bagnardi V, et al(2010). Modeling the relationship between circulating tomour cells number and prognosis of metastatic breast cancer. Breast Cancer Res Treat, 122, 211-7.
  5. Budd GT, Cristofanilli M, Ellis MJ, et al (2006). Circulating tumor cells versus imaging-predicting overall survival in metastatic breast cancer. Clin Cancer Res, 12, 6403-09.
  6. Camara O, Jorke C, Hammer U, et al (2009). Monitoring circulating epithelial tumour cells (CETC) to gauge therapy:in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment. J Cancer Res Clin Oncol, 135, 643-7.
  7. Cohen SJ, Punt JA, Iannotti N, et al (2008). Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol, 26, 3213-21.
  8. Coumans FA, Ligthart ST, Uhr JW, Terstappen LW (2012). Challenges in the enumeration and phenotyping of CTC. Clin Cancer Res, 18, 5711-8.
  9. Cristofanilli M, Budd GT, Ellis MJ, et al (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med, 351, 781-91.
  10. Cristofanilli M, Hayes DF, Budd GT, et al (2005). Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol, 23, 1420-30.
  11. Dawood S, Broglio K, Valero V, et al (2008). Circulating tumor cells in metastatic breast cancer. from prognostic stratification to modification of the staging system? Cancer, 113, 2422-30.
  12. Dawson SJ, Tsui DW, Murtaza M, et al.(2013). Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med, 368, 1199-209.
  13. De Bono JS, Scher HI, Montgomery RB, et al (2008). Circulating tumor cells predict survival benefit from treatment in metastatic casration-resistant prostat cancer. Clin Cancer Res, 14, 6302-09.
  14. Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer, 45, 228-47.
  15. Edge SB, Byrd DR, Compton CC, et al (2010). AJCC (American Joint Committee on Cancer) Cancer Staging Manual, 7th ed, Springer-Verlag, New York, 347-77.
  16. Franken B, de Groot MR, Mastboom WJ, et al (2012). Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Breast Cancer Res, 14, 133.
  17. Giordano A, Egleston BL, Hajage D, et al (2013). Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients. Clin Cancer Res, 19, 1596-602.
  18. Harris L, Fritsche H, Mennel R, et al (2007). Amarican Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 25, 5287.
  19. Hayes DF, Cristofanilli M, Budd GH, et al (2006). 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, 12, 4218-24.
  20. Kagan M, Howard D, Bendele T, et al (2002). A sample preparation and analysis system for identification of circulating tumor cells. J Clin Lig Assay, 25, 104-10.
  21. Liu MC, Shields PG, Warren RD, et al (2009). Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol, 27, 5153-9.
  22. Mathiesen RR, Borgen E, Renolen A, et al (2012). Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival. Breast Cancer Res, 14, 117.
  23. Miller MC, Doyle GV, Terstappen LWMM (2010). Significance of circulating tumor cells detected by the cellsearch system in patients with metastatic breast colorectal and prostate cancer. J Oncol, 9, 1-8.
  24. Munzone E, Botteri E, Sandri MT, et al (2012). Prognostic value of circulating tumor cells according to immunohistochemically defined molecular subtypes in advanced breast cancer. Clin Breast Cancer, 12, 340-6.
  25. Nakagawa T, Martinez SR, Goto Y, et al(2007). Detection of Circulating Tumor Cells in Early-Stage Breast Cancer Metastasis to Axillary Lymph Nodes. Clin Cancer Res, 13, 4105-10.
  26. Nakamura S, Yagata H, Ohno S, et al (2010). Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer, 17, 199-204.
  27. Riethdorf S, Fritsche H, Müller V, et al (2007). Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the cellsearch system. Clin Cancer Res, 13, 920-8.
  28. Riethdorf S, Wikman H, Pantel K (2008). Review: biological relevance of disseminated tumor cells in cancer patients. Int J Cancer, 123, 1991-2006.
  29. Tibbe AGJ, Miller MC, Terstappen LWMM (2007). Statistical Considerations for Enumeration of Circulating Tumor Cells. Cytometry Part A, 71, 154-62.
  30. Slade MJ, Payne R, Riethdorf S, et al (2009). Comparison of bone marrow, disseminated tumour cells and bloodcirculating tumour cells in breast cancer patients after primary treatment. Br J Cancer, 100, 160-6.
  31. Siegel R, Naishadham D, Jemal A (2013). Cancer statistics: 2013. CA Cancer J Clin, 63, 11-30.
  32. Wallwiener M, Hartkopf AD, Baccelli I, et al (2013). The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat, 137, 503-10.
  33. Yu M, Bardia A, Wittner BS, et al (2013). Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science, 339, 580-4
  34. Zhang L, Riethdorf S, Wu G, et al (2012). Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res, 18, 5701-10.

Cited by

  1. Circulating Tumor Cells are Associated with Bone Metastasis of Lung Cancer vol.15, pp.15, 2014,
  2. Single Cell Analysis and Circulating Tumor Cells in Prostate Cancer: Experience of an Observership at Cold Spring Harbor Laboratory, CSH and New York Presbyterian Hospital (Cornell Campus), New York vol.16, pp.14, 2015,
  3. Diagnostic Yield of Primary Circulating Tumor Cells in Women Suspected of Breast Cancer: the BEST (Breast Early Screening Test) Study vol.16, pp.5, 2015,
  4. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis vol.7, pp.2045-2322, 2017,