Current Breast Cancer Reports

, Volume 7, Issue 1, pp 53–58 | Cite as

Circulating Tumour Cells as Liquid Biopsy in Breast Cancer—Advancing from Prognostic to Predictive Potential

  • Christopher D. Hart
  • Francesca Galardi
  • Francesca De Luca
  • Marta Pestrin
  • Angelo Di LeoEmail author
Systemic Research (J Cortes, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Systemic Research


Circulating tumour cells (CTCs) in breast cancer offer a unique opportunity to sample tissue that can derive from multiple sites in the body and may be more representative of the whole disease than a single standard biopsy. Their presence is now clearly associated with worse prognosis and can indicate treatment failure. Improved techniques to isolate single CTCs have also permitted in-depth molecular studies, revealing marked heterogeneity. Whilst giving a novel window into tumour evolution and resistance, it also raises new questions regarding treatment approaches. The ongoing challenge remains the translation of new information gleaned from CTCs into clinical benefit.


Circulating tumour cells CTC Breast cancer Predictive Prognostic Liquid biopsy 



We would like to thank the Sando Pitigliani Foundation, the Breast Cancer Research Fund, and the Italian Association for Cancer Research (AIRC) for their generous support.

Compliance with Ethics Guidelines

Conflict of Interest

Christopher D Hart, Francesca Galardi, Francesca De Luca, Marta Pestrin, and Angelo Di Leo declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Aceto N, Bardia A, Miyamoto DT, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158:1110–22.CrossRefPubMedGoogle Scholar
  2. 2.
    Ignatiadis M, Riethdorf S, Bidard FC, et al. International study on inter-reader variability for circulating tumor cells in breast cancer. Breast Cancer Res. 2014;16:R43.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–4.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Satelli A, Brownlee Z, Mitra A, et al. Circulating tumor cell enumeration with a combination of epithelial cell adhesion molecule- and cell-surface vimentin-based methods for monitoring breast cancer therapeutic response. Clin Chem. 2014. Article In Press.Google Scholar
  5. 5.
    Mostert B, Kraan J, Bolt-de Vries J, et al. Detection of circulating tumor cells in breast cancer may improve through enrichment with anti-CD146. Breast Cancer Res Treat. 2011;127:33–41.CrossRefPubMedGoogle Scholar
  6. 6.
    Ozkumur E, Shah AM, Ciciliano JC, et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med. 2013;5:179ra47.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.••
    Yu M, Bardia A, Aceto N, et al. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 2014;345:216–20. Describes ability to culture CTCs to allow NGS and then test drugs tailored to the acquired oncogenic mutations, showing the potential of CTCs to personalise treatments. CrossRefPubMedGoogle Scholar
  8. 8.
    Jaeger BA, Jueckstock J, Andergassen U, et al. Evaluation of two different analytical methods for circulating tumor cell detection in peripheral blood of patients with primary breast cancer. Biomed Res Int. 2014;2014:491459. Epub 2014 Apr 8.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Müller V, Riethdorf S, Rack B, et al. Prognostic impact of circulating tumor cells assessed with the Cell Search System™ and AdnaTest Breast™ in metastatic breast cancer patients: the DETECT study. Breast Cancer Res. 2012;14:R118.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–91.CrossRefPubMedGoogle Scholar
  11. 11.
    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;12:4218–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Pierga JY, Hajage D, Bachelot T, et al. High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Ann Oncol. 2012;23:618–24.CrossRefPubMedGoogle Scholar
  13. 13.
    Georgoulias V, Apostolaki S, Bozionelou V, et al. Effect of front-line chemotherapy on circulating CK-19 mRNA-positive cells in patients with metastatic breast cancer. Cancer Chemother Pharmacol. 2014;74:1217–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Wallwiener M, Hartkopf AD, Baccelli I, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat. 2013;137:503–10.CrossRefPubMedGoogle Scholar
  15. 15.
    Wallwiener M, Riethdorf S, Hartkopf AD, et al. Serial enumeration of circulating tumor cells predicts treatment response and prognosis in metastatic breast cancer: a prospective study in 393 patients. BMC Cancer. 2014;14:512.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.••
    Bidard FC, Peeters DJ, Fehm T, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406–14. High level and comprehensive evidence of prognostic potential of CTCs. CrossRefPubMedGoogle Scholar
  17. 17.
    Lucci A, Hall CS, Lodhi AK, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13:688–95.CrossRefPubMedGoogle Scholar
  18. 18.
    Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;15:106.Google Scholar
  19. 19.
    Liao Y, Wang SY, Meng XY, et al. Circulating tumor cells in breast cancer and its association with tumor clinicopathological characteristics: a meta-analysis. Med Oncol. 2014;31:343.CrossRefPubMedGoogle Scholar
  20. 20.
    Karhade M, Hall C, Mishra P, et al. Circulating tumor cells in non-metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2014;147:325–33.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Zhang L, Riethdorf S, Wu G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012;18:5701–10.CrossRefPubMedGoogle Scholar
  22. 22.•
    Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014;32:3483–9. First phase III trial to use CTC enumeration to guide therapy, although a negative study. Sets the scene for future trials in this area. CrossRefPubMedGoogle Scholar
  23. 23.
    Powell AA, Talasaz AH, Zhang H, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One. 2012;7:e33788.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Polzer B, Medoro G, Pasch S, et al. Molecular profiling of single circulating tumor cells with diagnostic intention. EMBO Mol Med. 2014;6:1371–86.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Fina E, Callari M, Reduzzi C, et al. Gene expression profiling of circulating tumor cells in breast cancer. Clin Chem. 2014. Article in Press.Google Scholar
  26. 26.
    Paoletti C, Muniz MC, Thomas DG, et al. development of circulating tumor cell-endocrine therapy index in patients with hormone receptor positive breast cancer. Clin Cancer Res. 2014. Article In PressGoogle Scholar
  27. 27.
    Turner NH, Di Leo A. HER2 discordance between primary and metastatic breast cancer: assessing the clinical impact. Cancer Treat Rev. 2013;39:947–57.CrossRefPubMedGoogle Scholar
  28. 28.
    Thompson AM, Jordan LB, Quinlan P, et al. Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res. 2010;12:R92.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Babayan A, Hannemann J, Spötter J, et al. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS One. 2013;8:e75038.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Fehm T, Müller V, Aktas B, et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010;124:403–12.CrossRefPubMedGoogle Scholar
  31. 31.
    Ignatiadis M, Rothé F, Chaboteaux C, et al. HER2-positive circulating tumor cells in breast cancer. PLoS One. 2011;6:e15624.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Turner N, Pestrin M, Galardi F, et al. Can biomarker assessment on circulating tumor cells help direct therapy in metastatic breast cancer? Cancers. 2014;6:684–707.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Pestrin M, Bessi S, Puglisi F, et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat. 2012;134:283–9.CrossRefPubMedGoogle Scholar
  34. 34.
    Kalykaki A, Agelaki S, Kallergi G, et al. Elimination of EGFR-expressing circulating tumor cells in patients with metastatic breast cancer treated with gefitinib. Cancer Chemother Pharmacol. 2014;73:685–93.CrossRefPubMedGoogle Scholar
  35. 35.
    Cizkova M, Susini A, Vacher S, et al. PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res. 2012;14:R28.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Pestrin M, Salvianti F, Galardi F, et al. Heterogeneity of PIK3CA mutational status at the single cell level in circulating tumor cells from metastatic breast cancer patients. Mol Oncol. 2014. Article In Press.Google Scholar
  37. 37.•
    Deng G, Krishnakumar S, Powell AA, et al. Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC Cancer. 2014;14:456. Important evaluation of single tumour cells, revealing marked heterogeneity between CTCs and tumour sites over time. CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.•
    Markou A, Farkona S, Schiza C, et al. PIK3CA mutational status in circulating tumor cells can change during disease recurrence or progression in patients with breast cancer. Clin Cancer Res. 2014;20:5823–34. Offers unique insight into heterogeneity of CTCs and PIK3CA mutation, and correlates mutation with poor prognosis. CrossRefPubMedGoogle Scholar
  39. 39.
    Baccelli I, Schneeweiss A, Riethdorf S, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–44.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Christopher D. Hart
    • 1
  • Francesca Galardi
    • 2
  • Francesca De Luca
    • 2
  • Marta Pestrin
    • 1
  • Angelo Di Leo
    • 1
    Email author
  1. 1.Sandro Pitigliani Medical Oncology DepartmentHospital of Prato, Instituto Toscano TumoriPratoItaly
  2. 2.Translational Research LaboratoryHospital of PratoPratoItaly

Personalised recommendations