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Circulating Her-2/Neu Extracellular Domain in Breast Cancer Patients-Correlation with Prognosis and Clinicopathological Parameters Including Steroid Receptor, Her-2/Neu Receptor Coexpression


HER-2/neu extracellular domain (ECD) can be detected in blood as a soluble circulating protein. The aim of this study was to analyze the relationship between HER-2/neu extracellular domain in the serum and the prognosis in breast cancer patients. We also correlated HER-2/neu ECD with various clinicopathological factors including steroid receptor, HER-2/neu receptor coexpression. The serum from seventy nine patients with invasive breast cancer and twenty individuals without malignancy was analyzed using the enzyme-linked immune adsorbent assay method. The cut-off value was estimated by the ROC curve analysis (15.86 μg/L). HER-2/neu ECD values in the serum of patients with breast cancer were significantly higher than in control subjects. Circulating HER-2/neu ECD was significantly associated with the histological grade of tumors and the status of axillary lymph nodes. Negative correlation was observed between HER-2/neu ECD in the serum and estrogen receptor positivity. When we analyzed HER-2/neu ECD in relation with coexpression of steroid receptor and HER-2/neu receptor in tissue, statistically higher values were found in the subgroup of patients with steroid receptor negative, HER-2/neu negative tumors than in the other subgroups. HER-2/neu ECD was not an independent factor in the univariate and multivariate analysis. However, elevated HER-2/neu ECD levels were found in patients with breast cancer possessing more aggressive phenotype.

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  1. 1.

    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, Mcguire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: 10 years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 4:320–368

    Article  Google Scholar 

  3. 3.

    Suzuki M, Shigematsu H, Hiroshima K, Iizasa T, Nakatani Y, Minna JD et al (2005) Epidermal growth factor receptor expression status in lung cancer correlates with its mutation. Hum Pathol 36:1127–1134

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Zeng S, Yang Y, Tan Y, Lu C, Pan Y, Chen L et al (2012) ERBB2-induced inflammation in lung carcinogenesis. Mol Biol Rep 39:7911–7917

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Minner S, Jessen B, Stiedenroth L, Burandt E, Köllermann J, Mirlacher M et al (2010) Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res 16:1553–1560

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR (2003) Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the gynecologic oncology group. J Clin Oncol 21:283–290

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Giuffrè G, Ieni A, Barresi V, Caruso RA, Tuccari G (2012) HER2 status in unusual histological variants of gastric adenocarcinomas. J Clin Pathol 65:237–241

    Article  PubMed  Google Scholar 

  8. 8.

    Tsé C, Gauchez AS, Jacot W, Lamy PJ (2012) HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. Cancer Treat Rev 38:133–142

    Article  PubMed  Google Scholar 

  9. 9.

    Sasso M, Bianchi F, Ciravolo V, Tagliabue E, Campiglio M (2011) HER2 splice variants and their relevance in breast cancer. J Nucleic Acids Investig 2:e9

    Article  Google Scholar 

  10. 10.

    Horwitz KB, Mcguire WL (1977) Progesterone and progesterone receptors in experimental breast cancer. Cancer Res 37:1733–1738

    CAS  PubMed  Google Scholar 

  11. 11.

    Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11(3):359–377

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 12.

    Carney WP, Neumann R, Lipton A, Leitzel K, Ali S, Price CP (2003) Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer. Clin Chem 49:1579–1598

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Dresse M MD, Heinemann V, Kahlert S, Bauerfeind I, Nagel D, et al.. (2009) HER-2/neu in tissue and serum at time of primary breast cancer. J Clin Oncol Abstract #11500.

  14. 14.

    Leary AF, Hanna WM, van de Vijver MJ, Penault-Llorca F, Rüschoff J, Osamura RY et al (2009) Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer patients. J Clin Oncol 27:1694–1705

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Carney WP, Bernhardt D, Jasani B (2013) Circulating HER2 extracellular domain: a specific and quantitative biomarker of prognostic value in all breast cancer patients? Biomark Cancer 5:31–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. 16.

    Thriveni K, Deshmane V, Bapsy PP, Krishnamoorthy L, Ramaswamy G (2007) Clinical utility of serum human epidermal receptor-2/neu detection in breast cancer patients. Indian J Med Res 125:137–142

    CAS  PubMed  Google Scholar 

  17. 17.

    Garoufali A, Kyriakou F, Kountourakis P, Yioti I, Malliou S, Nikaki A et al (2008) Extracellular domain of HER2: a useful marker for the initial workup and follow-up of HER2-positive breast cancer. J BUON 13:409–413

    CAS  PubMed  Google Scholar 

  18. 18.

    Pallud C, Guinebretiere JM, Guepratte S, Hacene K, Neumann R, Carney W et al (2005) Tissue expression and serum levels of the oncoprotein HER-2/neu in 157 primary breast tumours. Anticancer Res 25:1433–1440

    CAS  PubMed  Google Scholar 

  19. 19.

    Saghatchian M, Guepratte S, Hacene K, Neumann R, Floiras JL, Pichon MF (2004) Serum HER-2 extracellular domain: relationship with clinicobiological presentation and prognostic value before and after primary treatment in 701 breast cancer patients. Int J Biol Markers 19:14–22

    CAS  PubMed  Google Scholar 

  20. 20.

    Kong Y, Dai S, Xie X, Xiao X, Lv N, Guo J et al (2012) High serum HER2 extracellular domain levels: correlation with a worse disease-free survival and overall survival in primary operable breast cancer patients. J Cancer Res Clin Oncol 138:275–284

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (2001) Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 61:4744–4749

    CAS  PubMed  Google Scholar 

  22. 22.

    Codony-Servat J, Albanell J, Lopez-Talavera J, Arribas J, Baselga J (1999) Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. Cancer Res 59:1196–1201

    CAS  PubMed  Google Scholar 

  23. 23.

    Quaranta M, Daniele A, Coviello M, Savonarola A, Abbate I, Venneri MT et al (2006) c-erbB-2 protein level in tissue and sera of breast cancer patients: a possibly useful clinical correlation. Tumori 92:311–317

    CAS  PubMed  Google Scholar 

  24. 24.

    Ludovini V, Gori S, Colozza M, Pistola L, Rulli E, Floriani I et al (2008) Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival. Ann Oncol 19:883–890

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Ma L, Yang HY, Han XH, Li J, Wang F, Zhang CL et al (2012) Relationship between serum HER2 extracellular domain levels, tissue HER2 expression, and clinico-pathological parameters in early stage breast cancer. Chin Med J 125:4104–4110

    CAS  PubMed  Google Scholar 

  26. 26.

    Molina R, Augé JM, Escudero JM, Filella X, Zanon G, Pahisa J et al (2010) Evaluation of tumor markers (HER-2/neuoncoprotein, CEA, and CA 15.3) in patients with locoregional breast cancer: prognostic value. Tumour Biol 31:171–180

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Duru N, Candas D, Jiang G, Li JJ (2014) Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. J Cancer Res Clin Oncol 140(1):1–14

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. 28.

    Lee CY, Lin Y, Bratman SV, Feng W, Kuo AH, Scheeren FA et al (2014) Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation. Cancer Res 74(1):341–352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. 29.

    Samy N, Ragab HM, El Maksoud NA, Shaalan M (2010) Prognostic significance of serum Her2/neu, BCL2, CA15-3 and CEA in breast cancer patients: a short follow-up. Cancer Biomark 6:63–72

    PubMed  Google Scholar 

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This work was supported by the Ministry of Science, Education and Sports, Republic of Croatia (grant 108-1080058-0046).

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Correspondence to Marina Barić.

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Barić, M., Kulić, A., Sirotković-Skerlev, M. et al. Circulating Her-2/Neu Extracellular Domain in Breast Cancer Patients-Correlation with Prognosis and Clinicopathological Parameters Including Steroid Receptor, Her-2/Neu Receptor Coexpression. Pathol. Oncol. Res. 21, 589–595 (2015).

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  • HER-2/neu ECD
  • Breast cancer
  • Prognosis
  • Steroid receptor/HER-2/neu receptor coexpression