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Breast Cancer Research and Treatment

, Volume 84, Issue 3, pp 215–223 | Cite as

Her-2/neu Gene Amplification and Protein Expression in Primary Male Breast Cancer

  • Christian Rudlowski
  • Nicolaus Friedrichs
  • Andree Faridi
  • Lazlo Füzesi
  • Roland Moll
  • Gunther Bastert
  • Werner Rath
  • Reinhard Büttner
Article

Abstract

The role of HER-2/neu in male breast cancer is not well defined. The purpose of the current study was to measure the frequency of HER-2/neu expression in primary male breast cancer, to demonstrate HER-2/neu gene amplification in cases found to be positive for protein overexpression, and to correlate HER-2/neu positivity with clinicopathological variables. Formalin-fixed, paraffin-embedded archival material from 99 primary male breast carcinomas was evaluated by immunohistochemistry (IHC) using the HercepTest™ (DAKO Corp., Hamburg, Germany). Scoring was performed according to established guidelines. All cases demonstrating HER-2/neu staining by IHC (1+/2+ and 3+) were analyzed for HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) utilizing the PathVysion™ assay (Vysis Corp., Downers Grove, Illinois) to assess HER-2/neu amplification status. The immunohistochemical staining of the HER-2/neu protein revealed HER-2/neu positivity in 15/99 (15.1%) cases, eight tumors showed 2+ and 7 tumors 3+ staining. HER-2/neu gene amplification was observed in 11/99 cases (11,1%), and all of the 3+ and 4/8 from the 2+ cases were amplified. HER-2/neu gene amplification/protein overexpression did not correlate with tumor state, histological grade or estrogen/progesterone receptor status nor the axillary lymph node status. This is the first comprehensive study of HER-2/neu gene amplification by FISH analysis in primary male breast cancer. Compared to female primary breast cancer the percentage of HER-2/neu positivity in our study was lower. Our data provide first evidence for HER-2/neu gene amplification in male breast cancer. Further studies should be addressed on the potential application of the monoclonal rhuMAB HER-2/neu antibody for treatment of HER-2/neu positive male breast cancer.

FISH HER-2/neu immunohistochemistry male breast cancer 

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References

  1. 1.
    Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987Google Scholar
  2. 2.
    Slamon DJ, Godolphin W, Jones LA et al.: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712, 1989Google Scholar
  3. 3.
    Khan AJ, King BL, Smith BD et al.: Characterization of the HER-2/neu oncogene by immunohistochemical and fluorescence in situ hybridization analysis in oral and oropharyngeal squamous cell carcinoma. Clin Cancer Res 8: 540–548, 2002Google Scholar
  4. 4.
    Press MF, Pike MC, Hung G et al.: Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis. Cancer Res 54: 5675–5682, 1994Google Scholar
  5. 5.
    Reese DM, Small EJ, Magrane G, Waldman FM, Chew K, Sudilovsky D: HER2 protein expression and gene amplifi-cation in androgen-independent prostate cancer. Am J Clin Pathol 116: 234–239, 2001Google Scholar
  6. 6.
    Cox G, Vyberg M, Melgaard B, Askaa J, Oster A, O'Byrne KJ: Herceptest: HER2 expression and gene amplification in non-small cell lung cancer. Int J Cancer 92: 480–483, 2001Google Scholar
  7. 7.
    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 19: 2334–2356, 2001Google Scholar
  8. 8.
    Andrulis IL, Bull SB, Blackstein ME et al.: neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 16: 1340–1349, 1998Google Scholar
  9. 9.
    Farabegoli F, Ceccarelli C, Santini D et al.: c-erbB-2 overexpression in amplified and non-amplified breast carcinoma samples. Int J Cancer 84: 273–277, 1999Google Scholar
  10. 10.
    Wright C, Angus B, Nicholson S et al.: Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res 49: 2087–2090, 1989Google Scholar
  11. 11.
    Pauletti G, Godolphin W, Press MF, Slamon DJ: Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13: 63–72, 1996Google Scholar
  12. 12.
    Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A: p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9: 1165–1172, 1989Google Scholar
  13. 13.
    Pietras RJ, Pegram MD, Finn RS, Maneval DA, Slamon DJ: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNAreactive drugs. Oncogene 17: 2235–2249, 1998Google Scholar
  14. 14.
    Pegram M, Hsu S, Lewis G et al.: Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18: 2241–2251, 1999Google Scholar
  15. 15.
    Slamon DJ, Leyland-Jones B, Shak S et al.: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792, 2001Google Scholar
  16. 16.
    Pauletti G, Dandekar S, Rong H et al.: Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18: 3651–3664, 2000Google Scholar
  17. 17.
    Schnitt SJ: Breast cancer in the 21st century: neu opportunities and neu challenges. Mod Pathol 14: 213–218, 2001Google Scholar
  18. 18.
    Giordano SH, Buzdar AU, Hortobagyi GN: Breast cancer in men. Ann Intern Med 137: 678–687, 2002Google Scholar
  19. 19.
    Yildirim E, Berberoglu U: Male breast cancer: a 22-year experience. Eur J Surg Oncol 24: 548–552, 1998Google Scholar
  20. 20.
    Ravandi-Kashani F, Hayes TG: Male breast cancer: a review of the literature. Eur J Cancer 34: 1341–1347, 1998Google Scholar
  21. 21.
    Wang-Rodriguez J, Cross K, Gallagher S et al.: Male breast carcinoma: correlation of ER, PR, Ki-67, Her2-neu, and p53 with treatment and survival, a study of 65 cases. Mod Pathol 15: 853–861, 2002Google Scholar
  22. 22.
    Bloom KJ, Govil H, Gattuso P, Reddy V, Francescatti D: Status of HER-2 in male and female breast carcinoma. Am J Surg 182: 389–392, 2001Google Scholar
  23. 23.
    Joshi MG, Lee AK, Loda M et al.: Male breast carcinoma: an evaluation of prognostic factors contributing to a poorer outcome. Cancer 77: 490–498, 1996Google Scholar
  24. 24.
    Rudlowski C, Rath W, Becker AJ, Wiestler OD, Buttner R: Trastuzumab and breast cancer. N Engl J Med 345: 997–998, 2001Google Scholar
  25. 25.
    Sobin LH, Wittekind C (eds): TNM Classification of Malignant Tumours. John Wiley and Sons, Inc., New York, 1997Google Scholar
  26. 26.
    Elston CW, Ellis IO: Pathological prognostic factors in breast cancer. I. The value of histologcial grade in breast cancer: experience from a large study with lob-term follow-up. Histopathology 19(5): 403–410, 1993Google Scholar
  27. 27.
    Remmele W, Stegner HE: Vorschlag zur einheitlichen Definition eines Immunreaktiven Score (IRS) für den immunhistochemischen Östrogenrezeptor-Nachweis (ERICA) im Mammakarzinomgeweben. Pathologe 8: 138–140, 1987Google Scholar
  28. 28.
    Seshadri R, Firgaira FA, Horsfall DJ, McCaul K, Setlur V, Kitchen P: Clinical significance of HER-2/neu oncogene amplification in primary breast cancer The South Australian Breast Cancer Study Group. J Clin Oncol 11: 1936–1942, 1993Google Scholar
  29. 29.
    Rayson D, Erlichman C, Suman VJ et al.: Molecular markers in male breast carcinoma. Cancer 83: 1947–1955, 1998Google Scholar
  30. 30.
    Clark JL, Nguyen PL, Jaszcz WB, Jatoi A, Niehans GA: Prognostic variables in male breast cancer. Am Surg 66: 502–511, 2000Google Scholar
  31. 31.
    Bruce DM, Heys SD, Payne S, Miller ID, Eremin O: Male breast cancer: clinico-pathological features, immunocytochemical characteristics and prognosis. Eur J Surg Oncol 22: 42–46, 1996Google Scholar
  32. 32.
    Fox SB, Day CA, Rogers S: Lack of c-erbB-2 oncoprotein expression in male breast carcinoma. J Clin Pathol 44: 960–961, 1991Google Scholar
  33. 33.
    Jacobs TW, Gown AM, Yaziji H, Barnes MJ, Schnitt SJ: Comparison of fluorescence in situ hybridization and immunohistochemistry for the evaluation of HER-2/neu in breast cancer. J Clin Oncol 17: 1974–1982, 1999Google Scholar
  34. 34.
    Slamon DJ, Clark GM: Amplification of c-erbB-2 and aggressive human breast tumors? Science 240: 1795–1798, 1988Google Scholar
  35. 35.
    Wick MR, Sayadi H, Ritter JH, Hill DA, Reddy VB, Gattuso P: Low-stage carcinoma of the male breast. A histologic, immunohistochemical, and flow cytometric comparison with localized female breast carcinoma. Am J Clin Pathol 111: 59–69, 1999Google Scholar
  36. 36.
    Newman SP, Bates NP, Vernimmen D, Parker MG, Hurst HC: Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of erbB2 expression in breast cancer. Oncogene 19: 490–497, 2000Google Scholar
  37. 37.
    Bloom KJ, Govil H, Gattuso P, Reddy V, Francescatti D: Status of HER-2 in male and female breast carcinoma. Am J Surg 182: 389–392, 2001Google Scholar
  38. 38.
    Muir D, Kanthan R, Kanthan S: Male versus female breast cancers. A population-based comparative immunohistochemical analysis. Arch Pathol Lab Med 127: 36–41, 2003Google Scholar
  39. 39.
    Willsher PC, Leach IH, Ellis IO, Bourke JB, Blamey RW, Robertson JF: A comparison outcome of male breast cancer with female breast cancer. Am J Surg 173: 185–188, 1997Google Scholar
  40. 40.
    Joshi MG, Lee AK, Loda M et al.: Male breast carcinoma: an evaluation of prognostic factors contributing to a poorer outcome. Cancer 77: 490–498, 1996Google Scholar
  41. 41.
    Rayson D, Erlichman C, Suman VJ et al.: Molecular markers in male breast carcinoma. Cancer 83: 1947–1955, 1998Google Scholar
  42. 42.
    Wang-Rodriguez J, Cross K, Gallagher S et al.: Male breast carcinoma: correlation of ER, PR, Ki-67, HER2-neu, and p53 with treatment and survival, a study of 65 cases. Mod Pathol 15: 853–861, 2002Google Scholar
  43. 43.
    Pich A, Margaria E, Chiusa L: Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival. J Clin Oncol 18: 2948–2956, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Christian Rudlowski
    • 1
  • Nicolaus Friedrichs
    • 2
  • Andree Faridi
    • 3
  • Lazlo Füzesi
    • 4
  • Roland Moll
    • 5
  • Gunther Bastert
    • 1
  • Werner Rath
    • 3
  • Reinhard Büttner
    • 2
  1. 1.Department of Gynecology and ObstetricsUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Institute of PathologyUniversity Hospital BonnBonnGermany
  3. 3.Department of Gynecology and ObstetricsUniversity Hospital AachenAachenGermany
  4. 4.Institute of PathologyUniversity Hospital GöttingenGöttingenGermany
  5. 5.Institute of PathologyUniversity HospitalMarburgGermany

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