Tumor Biology

, Volume 31, Issue 3, pp 171–180 | Cite as

Evaluation of tumor markers (HER-2/neu oncoprotein, CEA, and CA 15.3) in patients with locoregional breast cancer: prognostic value

  • Rafael Molina
  • Jose M. Augé
  • Jose M. Escudero
  • Xavier Filella
  • Gabriel Zanon
  • Jaume Pahisa
  • Blanca Farrus
  • Montserrat Muñoz
  • Martin Velasco
Research Article


Tumor markers were studied in the sera of 883 untreated patients with primary breast cancer diagnosed between 1989 and 2007. Abnormal human epidermal growth factor receptor 2 (HER-2)/neu levels (>15 ng/mL) were found in 9.5%, carcinoembryonic antigen (CEA) in 15.9%, and cancer antigen (CA) 15.3 in 19.7% of the patients. One or more tumor markers were abnormal in 305 (34.5%) of the 883 studied patients. Significantly higher serum HER-2/neu levels were found in patients with tissue overexpression of this oncoprotein (p < 0.0001). CEA, CA 15.3, and HER-2/neu (only in those patients with tissue overexpression) serum levels were related with tumor stage (tumor size and nodal involvement) and steroid receptors (higher values in estrogen receptor-negative (ER−) tumors). Univariate analysis showed that HER-2/neu serum levels were prognostic factors in disease-free survival (DFS) and overall survival (OS) only in patients with tissue overexpression. Multivariate analysis in 834 patients show that nodal involvement, tumor size, ER, CEA, and adjuvant treatment were independent prognostic factors in DFS and OS. When only patients with HER-2/neu overexpression in tissue were studied, tumor size, nodal involvement, and tumor markers (one or another positive) were independent prognostic factors for both DFS and OS. HER-2/neu serum levels were also an independent prognostic factor, with CEA, ER, and nodes in 106 patients treated with neoadjuvant treatment. In summary, serum HER-2/neu, CEA, and CA 15.3 are useful tools in the prognostic evaluation of patients with primary breast cancer.


Tumor markers Breast cancer Disease-free survival 


Conflict of interest

The authors confirm that there is not any conflict of interest including any financial, personal, or other relationships with other people or organizations that could influence their work.


  1. 1.
    Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1999. Int J Cancer. 1999;80:827–41.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E. Cancer statistics, 2004. CA Cancer J Clin. 2003;53:4–25.CrossRefGoogle Scholar
  3. 3.
    Early Breast Cancer Trialist's Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised clinical trials. Lancet. 1998;352:930–42.CrossRefGoogle Scholar
  4. 4.
    Bieglmayer C, Szepesi T, Kopp B, Hoffmann G, Petrik W, Guettuoche K, et al. CA15.3, MCA, CAM26, CAM29 are members of a polymorphic family of mucin-like glycoproteins. Tumor Biol. 1991;12:138–48.CrossRefGoogle Scholar
  5. 5.
    Price MR, Rye PD, Petrakou R, Murray A, et al. Summary report on the ISOBM TD-4 workshop: analysis of 56 monoclonal antibodies against the MUC1 mucin. Tumor Biol. 1998;19(1):1–20.CrossRefGoogle Scholar
  6. 6.
    Dnistrian AM, Schwartz MK, Greenberg EJ, Smith CA, Schwartz DC. Evaluation of CAM26, CAM29, CA15.3 and CEA as circulating tumor markers in breast cancer patients. Tumor Biol. 1991;12:1282–90.CrossRefGoogle Scholar
  7. 7.
    Heinze T, Schurenkamper P, Minguillon C, Lichtenegger W. Mammary serum antigen (MSA), Ca 549, CA 15-3 and CEA in breast cancer preoperative sensitivity and correlation to prognostic factors. Anticancer Res. 1997;17:2953–4.PubMedGoogle Scholar
  8. 8.
    Molina R, Jo J, Filella X, Zanon G, Pahisa J, Muñoz M, et al. C-erbB-2 oncoprotein in the sera and tissue of patients with breast cancer: utility in prognosis. Anticancer Res. 1996;16:2295–300.PubMedGoogle Scholar
  9. 9.
    Volas GH, Leitzel K, Teramoto Y, Grossberg H, Demers L, Lipton A. Serial serum c-erbB-2 levels in patients with breast carcinoma. Cancer. 1996;15(78):267–72.CrossRefGoogle Scholar
  10. 10.
    Molina R, Barak V, van Dalen A, Duffy MJ, Einarsson R, Gion M, et al. Tumor markers in breast cancer. European Group on Tumor Markers Recommendations. Tumor Biol. 2005;26:281–93.CrossRefGoogle Scholar
  11. 11.
    Lumachi F, Basso SM, Brandes AA, Pagano D, Ermani M. Relationship between tumor markers CEA and CA 15-3, TNM staging, estrogen receptor rate and MIB-1 index in patients with pT1-2 breast cancer. Anticancer Res. 2004;24:3221–4.PubMedGoogle Scholar
  12. 12.
    Canizares F, Sola J, Perez M, Tovar I, De Las HM, Salinas J, et al. Preoperative values of CA 15-3 and CEA as prognostic factors in breast cancer: a multivariate analysis. Tumour Biol. 2001;22:273–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Molina R, Filella X, Alicarte J, Zanon G, Pahisa J, Munoz M, et al. Prospective evaluation of CEA and CA 15.3 in patients with locoregional breast cancer. Anticancer Res. 2003;23:1035–41.PubMedGoogle Scholar
  14. 14.
    Gion M, Boracchi P, Dittadi R, Biganzoli E, Peloso L, Mione R, et al. Prognostic role of serum CA15.3 in 362 node-negative breast cancers. An old player for a new game. Eur J Cancer. 2002;38:1181–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Duffy MJ, Duggan C, Keane R, Hill AD, McDermott E, Crown J, et al. High preoperative CA 15-3 concentrations predict adverse outcome in node-negative and node-positive breast cancer: study of 600 patients with histologically confirmed breast cancer. Clin Chem. 2004;50:559–63.CrossRefPubMedGoogle Scholar
  16. 16.
    Olayioye MA, Neve RM, Lane HA, Hynes NE. The erbB signalling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67.CrossRefPubMedGoogle Scholar
  17. 17.
    Ross JS, Fletcher JA. HER-2/neu (C-erbB-2) gene and protein in breast cancer. Am J Clin Pathol. 1999;112:53–67.Google Scholar
  18. 18.
    Potter CR, van Doele S, van de Vijver MJ, Pauwells C, Maertens G, de Boever J, et al. The expression of the neu oncogene product in breast lesions and in normal fetal and adult human tissues. Histopathology. 1989;15:351–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Slamon D, Pegram M. Rationale for Trastuzumab (Herceptin) in adjuvant breast cancer trials. Sem Oncol. 2001;28:13–9.CrossRefGoogle Scholar
  20. 20.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25:5287–312.CrossRefPubMedGoogle Scholar
  21. 21.
    Harries M, Smith I. The development and clinical use of Trastuzumab. Endocr Relat Canc. 2002;9:75–85.CrossRefGoogle Scholar
  22. 22.
    Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, et al. The HER-2/neu gene and protein in breast cancer 2003; biomarker and target of therapy. Oncologist. 2003;8:307–25.CrossRefPubMedGoogle Scholar
  23. 23.
    Molina R, Jo J, Filella X, Bruix J, Castells A, Hague M, et al. Serum levels of C-erbB-2 (HER-2/neu) in patients with malignant and non-malignant diseases. Tumor Biol. 1997;18:188–96.CrossRefGoogle Scholar
  24. 24.
    Schwarz MK, Smith C, Schwartz DC, Dnistrian A, Neiman I. Monitoring therapy by serum HER-2/neu. Int J Biol Markers. 2000;15:324–9.Google Scholar
  25. 25.
    Wu JT, Astgill ME, Zhang P. Detection of the extracellular domain of c-erbB-2 oncoprotein in sera from patients with various carcinomas: correlation with tumor markers. J Clin Lab Anal. 1993;7:31–40.CrossRefPubMedGoogle Scholar
  26. 26.
    Cook GB, Neamann IB, Goldblatt JL, Cambetas DR, Hussain M, Luftner D, et al. Clinical utility of serum HER-2/neu testing on the Bayer Immuno 1 automated system in breast cancer. Anticancer Res. 2001;21:1465–70.PubMedGoogle Scholar
  27. 27.
    Carney WP, Neumann R, Lipton A, Leitzel K, Ali S, Price CP. Monitoring the circulating levels of the HER-2/neu oncoprotein in Breast cancer. Clin Breast Cancer. 2004;5:105–16.CrossRefPubMedGoogle Scholar
  28. 28.
    Carney WP. The emerging role of monitoring serum HER-2/neu oncoprotein levels in women with metastatic breast cancer. Lab Med. 2003;34:58–64.CrossRefGoogle Scholar
  29. 29.
    Fehm T, Gebauer G, Jager W. Clinical utility of serial serum c-erB-2 determinations in the follow-up of breast cancer patients. Breast Cancer Res Treat. 2002;75:97–106.CrossRefPubMedGoogle Scholar
  30. 30.
    Molina R, Filella X, Zanon G, Pahisa J, Alicarte J, Muñoz M, et al. Prospective evaluation of tumor markers (c-erbB-2 oncoprotein, CEA and CA 15.3) in patients with loco-regional breast cancer. Anticancer Res. 2003;23:1043–50.PubMedGoogle Scholar
  31. 31.
    Dittadi R, Zancan M, Perasole A, Gion M. Evaluation of HER-2/neu in serum and tissue of primary and metastatic breast cancer patients using an automated enzyme immunoassay. Int J Biol Markers. 2001;16:255–61.PubMedGoogle Scholar
  32. 32.
    Luftner D, Schnabel S, Possinger K. c-erbB-2 in serum of patients receiving fractionated paclitaxel chemotherapy. Int J Biol Markers. 1999;14:55–9.PubMedGoogle Scholar
  33. 33.
    Schippinger W, Regitnit P, Bauernhofer T, et al. The course of serum HER-2/neu levels as an independent prognostic factor for survival in metastatic breast cancer. Oncol Rep. 2004;11:1331–6.PubMedGoogle Scholar
  34. 34.
    Molina R, Jo J, Zanon G, Filella X, Farrus B, Muñoz M, et al. Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA15.3. Br J Cancer. 1996;74:1126–31.PubMedGoogle Scholar
  35. 35.
    Kostler WJ, Schwab B, Singer C, et al. Monitoring of serum HER-2/neu predicts response and progression-free survival to trastuzumab-based treatment in patients with metastatic breast cancer. Clin Cancer Res. 2004;10:1618–24.CrossRefPubMedGoogle Scholar
  36. 36.
    Early Breast Cancer Trialist's Collaborative Group. Tamoxifen for early breast cancer: an overview of randomized trials. Lancet. 1998;351:1451–67.CrossRefGoogle Scholar
  37. 37.
    Mirza AN, Mirza NQ, Vlastos G, Singletary E. Prognostic factors in node-negative breast cancer. A review of studies with sample size more than 200 and follow-up more than 5 years. Ann Surg. 2002;235:10–26.CrossRefPubMedGoogle Scholar
  38. 38.
    Yamauchi H, Stearns V, Hayes DF. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer. J Clin Oncol. 2001;19:2334–56.PubMedGoogle Scholar
  39. 39.
    Piccart MJ, Di Leo A, Hamilton A. HER2: a predictive factor ready to use in the daily management of breast cancer patients? Eur J Cancer. 2000;36:1755–61.CrossRefPubMedGoogle Scholar
  40. 40.
    Fehm T, Maimonis P, Weitz S, Teramoto Y, Katalinic A, Jager W. Influence of circulating c-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients. Br Cancer Res Treat. 1997;43:87–95.CrossRefGoogle Scholar
  41. 41.
    Fontana X, Ferrari P, Namer M, Peysson R, Salamon C, Bussiere C. C-erbB2 gene amplification and serum level of c-erb-B2 oncoprotein at primary breast cancer diagnosis. Anticancer Res. 1994;14:2099–104.PubMedGoogle Scholar
  42. 42.
    Park BW, Oh JW, Kim JH, Park SH, Kim KS, Kim JH, et al. Preoperative CA 15.3 and CEA serum levels for breast cancer outcome. Ann Oncol. 2008;19:675–81.CrossRefPubMedGoogle Scholar
  43. 43.
    Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54:11–79.CrossRefGoogle Scholar
  44. 44.
    O' Hanlon DM, Kerin MJ, Koent P, Maher D, Grimes H, Given HF. An evaluation of preoperative CA15.3 measurement in primary breast carcinoma. Br J Cancer. 1995;71:1288–91.Google Scholar
  45. 45.
    Molina R, Jo J, Filella X, et al. C-erbB-2 oncoprotein, CEA and CA 15.3 in patients with breast cancer: prognostic value. Br Cancer Res Treat. 1998;51:109–19.CrossRefGoogle Scholar
  46. 46.
    Sugano K, Ushiama M, Fukutomi T, Tsuda H, Kitoh T, Ohkura H. Combined measurement of the cérbB-2 protein in breast carcinoma tissues and sera is useful as a sensitive tumor marker for monitoring tumor relapse. Int J Cancer. 2000;89:329–36.CrossRefPubMedGoogle Scholar
  47. 47.
    Esteva FJ, Cheli CD, Fritsche H, Fornier M, Slamon D, Thiel RP, et al. Clinical utility of serum HER/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies. Breast Cancer Res. 2005;7:436–43.CrossRefGoogle Scholar
  48. 48.
    Ebeling FC, Schmitt UM, Untch M, et al. Tumor markers CEA and CA 15.3 as prognostic factors in breast cancer. Univariate and multivariate analysis. Anticancer Res. 1999;19:2545–50.PubMedGoogle Scholar
  49. 49.
    McLauglin R, McGrath J, Grimes H, Given HF. The prognostic value of the tumor marker CA 15.3 at initial diagnosis of patients with breast cancer. Int J Biol Markers. 2000;15:340–2.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • Rafael Molina
    • 1
  • Jose M. Augé
    • 1
  • Jose M. Escudero
    • 1
  • Xavier Filella
    • 1
  • Gabriel Zanon
    • 1
  • Jaume Pahisa
    • 1
  • Blanca Farrus
    • 1
  • Montserrat Muñoz
    • 1
  • Martin Velasco
    • 1
  1. 1.Hospital ClinicBarcelonaSpain

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