Clinical and Translational Oncology

, Volume 18, Issue 3, pp 322–330 | Cite as

Prognostic value of circulating tumor cells in metastatic breast cancer: a systemic review and meta-analysis

  • Q. Lv
  • L. Gong
  • T. Zhang
  • J. Ye
  • L. Chai
  • C. Ni
  • Y. Mao
Research Article

Abstract

Objective

Metastatic breast cancer (MBC) remains the main cause of cancer-related death, and the clinical significance and prognostic role of circulating tumor cells (CTCs) in metastatic breast cancer are still controversial. Here, we conducted a meta-analysis to clarify the correlation between CTCs and the clinicopathological features and prognosis of MBC.

Methods

We performed a comprehensive search of Pubmed and the ISI Web of Science through December 2014. Only articles that focused on MBC patients and detected CTCs using the CellSearch system were included. The associations between CTCs and survival rate and clinicopathological parameters, including molecular pattern, metastatic region and treatment response, were evaluated.

Results

This meta-analysis included 24 studies (3701 MBC patients), 13 prospective studies and 11 retrospective studies. We found that CTCs were more frequently detected with HER2 + primary tumors (pooled RR = 0.73, 95 % CI = 0.63–0.84). Additionally, higher CTC numbers indicated a worse treatment response (RR = 0.56, 95 % CI = 0.40–0.79), poorer PFS (RR = 0.64, 95 % CI = 0.56–0.73) and poorer OS (RR = 0.69, 95 % CI = 0.64–0.75) in MBC patients.

Conclusion

Based on these results, we propose that HER2 positivity could be a significant risk factor for the presence of CTCs. Additionally, CTCs have a significant prognostic value for MBC patients. Therefore, CTCs should be continually monitored to guide the treatment of MBC patients, especially those with HER2 + primary tumors.

Keywords

Breast cancer Circulating tumor cells Her2 Prognosis Meta-analysis 

References

  1. 1.
    Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(20):5701–10. doi:10.1158/1078-0432.CCR-12-1587.CrossRefGoogle Scholar
  2. 2.
    Pukazhendhi G, Gluck S. Circulating tumor cells in breast cancer. J Carcinogen. 2014;13:8. doi:10.4103/1477-3163.135578.CrossRefGoogle Scholar
  3. 3.
    Esmaeilsabzali H, Beischlag TV, Cox ME, Parameswaran AM, Park EJ. Detection and isolation of circulating tumor cells: principles and methods. Biotechnol Adv. 2013;31(7):1063–84. doi:10.1016/j.biotechadv.2013.08.016.CrossRefPubMedGoogle Scholar
  4. 4.
    Jiang ZF, Cristofanilli M, Shao ZM, Tong ZS, Song EW, Wang XJ, et al. Circulating tumor cells predict progression-free and overall survival in Chinese patients with metastatic breast cancer, HER2-positive or triple-negative (CBCSG004): a multicenter, double-blind, prospective trial. Annals Oncol Off J Eur Soc Med Oncol ESMO. 2013;24(11):2766–72. doi:10.1093/annonc/mdt246.CrossRefGoogle Scholar
  5. 5.
    Giordano A, Giuliano M, De Laurentiis M, Arpino G, Jackson S, Handy BC, et al. Circulating tumor cells in immunohistochemical subtypes of metastatic breast cancer: lack of prediction in HER2-positive disease treated with targeted therapy. Annals Oncol Off J European Soc Med Oncol ESMO. 2012;23(5):1144–50. doi:10.1093/annonc/mdr434.CrossRefGoogle Scholar
  6. 6.
    Zhao S, Liu Y, Zhang Q, Li H, Zhang M, Ma W, et al. The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature. Breast Cancer Res Treat. 2011;130(3):809–16. doi:10.1007/s10549-011-1379-4.CrossRefPubMedGoogle Scholar
  7. 7.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA J Am Med Assoc. 2000;283(15):2008–12.CrossRefGoogle Scholar
  8. 8.
    Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329–40. doi:10.1038/nrc2375.CrossRefPubMedGoogle Scholar
  9. 9.
    Alix-Panabieres C, Vendrell JP, Pelle O, Rebillard X, Riethdorf S, Muller V, et al. Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem. 2007;53(3):537–9. doi:10.1373/clinchem.2006.079509.CrossRefPubMedGoogle Scholar
  10. 10.
    Miller MC, Doyle GV, Terstappen LW. Significance of Circulating Tumor Cells Detected by the Cell Search System in Patients with Metastatic Breast Colorectal and Prostate Cancer. J Oncol. 2010;2010:617421. doi:10.1155/2010/617421.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, 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 Off J Am Assoc Cancer Res. 2006;12(14 Pt 1):4218–24. doi:10.1158/1078-0432.CCR-05-2821.CrossRefGoogle Scholar
  12. 12.
    Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, et al. Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2006;12(21):6403–9. doi:10.1158/1078-0432.CCR-05-1769.CrossRefGoogle Scholar
  13. 13.
    Cristofanilli M, Broglio KR, Guarneri V, Jackson S, Fritsche HA, Islam R, et al. Circulating tumor cells in metastatic breast cancer: biologic staging beyond tumor burden. Clin Breast Cancer. 2007;7(6):471–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Bidard FC, Vincent-Salomon A, Sigal-Zafrani B, Dieras V, Mathiot C, Mignot L, et al. Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Annals Oncol Off J Eur Soc Med Oncol ESMO. 2008;19(3):496–500. doi:10.1093/annonc/mdm507.CrossRefGoogle Scholar
  15. 15.
    Yagata H, Nakamura S, Toi M, Bando H, Ohno S, Kataoka A. Evaluation of circulating tumor cells in patients with breast cancer: multi-institutional clinical trial in Japan. Int J Clin Oncol. 2008;13(3):252–6. doi:10.1007/s10147-007-0748-9.CrossRefPubMedGoogle Scholar
  16. 16.
    De Giorgi U, Valero V, Rohren E, Dawood S, Ueno NT, Miller MC, et al. Circulating tumor cells and [18F]fluorodeoxyglucose positron emission tomography/computed tomography for outcome prediction in metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(20):3303–11. doi:10.1200/JCO.2008.19.4423.CrossRefGoogle Scholar
  17. 17.
    Liu MC, Shields PG, Warren RD, Cohen P, Wilkinson M, Ottaviano YL, et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(31):5153–9. doi:10.1200/JCO.2008.20.6664.CrossRefGoogle Scholar
  18. 18.
    Mego M, De Giorgi U, Hsu L, Ueno NT, Valero V, Jackson S, et al. Circulating tumor cells in metastatic inflammatory breast cancer. Annals Oncol Off J Eur Soc Med Oncol ESMO. 2009;20(11):1824–8. doi:10.1093/annonc/mdp207.CrossRefGoogle Scholar
  19. 19.
    De Giorgi U, Valero V, Rohren E, Mego M, Doyle GV, Miller MC, et al. Circulating tumor cells and bone metastases as detected by FDG-PET/CT in patients with metastatic breast cancer. Annals Oncol Off J Eur Soc Med Oncol ESMO. 2010;21(1):33–9. doi:10.1093/annonc/mdp262.CrossRefGoogle Scholar
  20. 20.
    Consoli F, Grisanti S, Amoroso V, Almici C, Verardi R, Marini M, et al. Circulating tumor cells as predictors of prognosis in metastatic breast cancer: clinical application outside a clinical trial. Tumori. 2011;97(6):737–42. doi:10.1700/1018.11090.PubMedGoogle Scholar
  21. 21.
    Giuliano M, Giordano A, Jackson S, Hess KR, De Giorgi U, Mego M, et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res BCR. 2011;13(3):R67. doi:10.1186/bcr2907.CrossRefPubMedGoogle Scholar
  22. 22.
    Hartkopf AD, Wagner P, Wallwiener D, Fehm T, Rothmund R. Changing levels of circulating tumor cells in monitoring chemotherapy response in patients with metastatic breast cancer. Anticancer Res. 2011;31(3):979–84.PubMedGoogle Scholar
  23. 23.
    Tokudome N, Ito Y, Takahashi S, Kobayashi K, Taira S, Tsutsumi C, et al. Detection of circulating tumor cells in peripheral blood of heavily treated metastatic breast cancer patients. Breast Cancer. 2011;18(3):195–202. doi:10.1007/s12282-011-0259-4.CrossRefPubMedGoogle Scholar
  24. 24.
    De Giorgi U, Mego M, Scarpi E, Giuliano M, Giordano A, Reuben JM, et al. Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer. Clin Breast Cancer. 2012;12(4):264–9. doi:10.1016/j.clbc.2012.04.004.CrossRefPubMedGoogle Scholar
  25. 25.
    Hayashi N, Nakamura S, Tokuda Y, Shimoda Y, Yagata H, Yoshida A, et al. Prognostic value of HER2-positive circulating tumor cells in patients with metastatic breast cancer. Int J Clin Oncol. 2012;17(2):96–104. doi:10.1007/s10147-011-0260-0.CrossRefPubMedGoogle Scholar
  26. 26.
    Muller V, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer E, 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 BCR. 2012;14(4):R118. doi:10.1186/bcr3243.CrossRefPubMedGoogle Scholar
  27. 27.
    Pierga JY, Hajage D, Bachelot T, Delaloge S, Brain E, Campone M, 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. Annals Oncol Off J Eur Soc Med Oncol ESMO. 2012;23(3):618–24. doi:10.1093/annonc/mdr263.CrossRefGoogle Scholar
  28. 28.
    Weissenstein U, Schumann A, Reif M, Link S, Toffol-Schmidt UD, Heusser P. Detection of circulating tumor cells in blood of metastatic breast cancer patients using a combination of cytokeratin and EpCAM antibodies. BMC Cancer. 2012;12:206. doi:10.1186/1471-2407-12-206.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Liu Y, Liu Q, Wang T, Bian L, Zhang S, Hu H, et al. Circulating tumor cells in HER2-positive metastatic breast cancer patients: a valuable prognostic and predictive biomarker. BMC Cancer. 2013;13:202. doi:10.1186/1471-2407-13-202.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Tarhan MO, Gonel A, Kucukzeybek Y, Erten C, Cuhadar S, Yigit SC, et al. Prognostic significance of circulating tumor cells and serum CA15-3 levels in metastatic breast cancer, single center experience, preliminary results. Asian Pacific journal of cancer prevention : APJCP. 2013;14(3):1725–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Turker I, Uyeturk U, Sonmez OU, Oksuzoglu B, Helvaci K, Arslan UY, et al. Detection of circulating tumor cells in breast cancer patients: prognostic predictive role. Asian Pacific J Cancer Prevent APJCP. 2013;14(3):1601–7.CrossRefGoogle Scholar
  32. 32.
    Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat. 2013;137(2):503–10. doi:10.1007/s10549-012-2382-0.CrossRefPubMedGoogle Scholar
  33. 33.
    Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(31):3483–9. doi:10.1200/JCO.2014.56.2561.CrossRefGoogle Scholar
  34. 34.
    Martin M, Custodio S, de Las Casas ML, Garcia-Saenz JA, de la Torre JC, Bellon-Cano JM, et al. Circulating tumor cells following first chemotherapy cycle: an early and strong predictor of outcome in patients with metastatic breast cancer. Oncologist. 2013;18(8):917–23. doi:10.1634/theoncologist.2012-0479.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Ignatiadis M, Rothe F, Chaboteaux C, Durbecq V, Rouas G, Criscitiello C, et al. HER2-positive circulating tumor cells in breast cancer. PLoS One. 2011;6(1):e15624. doi:10.1371/journal.pone.0015624.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Munzone E, Botteri E, Sandri MT, Esposito A, Adamoli L, Zorzino L, et al. Prognostic value of circulating tumor cells according to immunohistochemically defined molecular subtypes in advanced breast cancer. Clin Breast Cancer. 2012;12(5):340–6. doi:10.1016/j.clbc.2012.07.001.CrossRefPubMedGoogle Scholar
  37. 37.
    Banys M, Krawczyk N, Becker S, Jakubowska J, Staebler A, Wallwiener D, 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. 2012;132(1):121–9. doi:10.1007/s10549-011-1569-0.CrossRefPubMedGoogle Scholar
  38. 38.
    Lavrov AV, Zubtsova ZhI, Zubtsov DA, Frolova MA, Ignatova EO, Skrypnikova MA, et al. Analysis of circulating tumor cells in patients with triple negative breast cancer during preoperative chemotherapy. Bull Exp Biol Med. 2014;157(1):159–61. doi:10.1007/s10517-014-2514-0.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  • Q. Lv
    • 1
  • L. Gong
    • 2
  • T. Zhang
    • 1
  • J. Ye
    • 1
  • L. Chai
    • 3
  • C. Ni
    • 4
  • Y. Mao
    • 3
  1. 1.Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, National Ministry of Education, Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
  2. 2.Department of OtorhinolaryngologyAffiliated Cixi Hospital of Wenzhou Medical CollegeCixiChina
  3. 3.Department of Otorhinolaryngology, First Affiliated Hospital, Medical SchoolZhejiang UniversityHangzhouChina
  4. 4.Department of Breast SurgeryZhejiang Provincial People’s HospitalHangzhouChina

Personalised recommendations