Advertisement

Digestive Diseases and Sciences

, Volume 51, Issue 8, pp 1371–1379 | Cite as

HER-2/neu Amplification Is an Independent Prognostic Factor in Gastric Cancer

  • Dong Il Park
  • Jung Won Yun
  • Jung Ho Park
  • Suk Joong Oh
  • Hong Joo Kim
  • Yong Kyun Cho
  • Chong Il Sohn
  • Woo Kyu Jeon
  • Byung Ik Kim
  • Chang Hak Yoo
  • Byung Ho Son
  • Eun Yoon Cho
  • Seoung Wan Chae
  • Eo-Jin Kim
  • Jin Hee Sohn
  • Seung Ho Ryu
  • Antonia R. Sepulveda
Original Paper

Abstract

The HER-2/neu protein is intimately involved with normal cell proliferation and tissue growth and is extensively homologous and related to the epidermal growth factor receptor. HER-2/neu protein expression has been most intensively studied in the context of breast carcinoma, in which its amplification and overexpression correlate with the overall course of disease, and with a poor prognosis, and constitute a predictive factor of poor response to chemotherapy and endocrine therapy. In this study, we investigated the relationship between the expression of HER-2/neu and the clinicopathological characteristics of tumors, including survival. This study was performed with a view toward the future introduction of Herceptin therapy for gastric cancer patients. HER-2/neu overexpression and gene amplification was examined with semiquantitative standardized immunohistochemical staining, chromogenic in situ hybridization (CISH), and fluorescence in situ hybridization (FISH) in 182 gastric cancer patients who underwent curative surgery at the Kangbuk Samsung Hospital. Twenty-nine (15.9%) of 182 patients expressed the HER-2/neu protein by immunohistochemistry. HER-2/neu gene amplification was detected in seven patients by CISH and FISH. Intestinal-type cancers exhibited higher rates of HER-2/neu amplification than did diffuse-type cancers (P < 0.05). Tumors with HER-2/neu amplification were associated with poor mean survival rates (922 vs 3243 days) and 5-year survival rates (21.4% vs 63.0%; P < 0.05). Age, TNM stage, and amplification of HER-2/neu were found to be independently related to survival by multivariate analysis. HER-2/neu amplification may constitute an independent prognostic factor in gastric cancer patients, and patients exhibiting HER-2/neu amplification might constitute potential candidates for new adjuvant therapies which involve the use of humanized monoclonal antibodies.

Keywords

Gastric neoplasms HER-2/neu 

Notes

Acknowledgement

This study was supported by Samsung Biomedical Research Institute Grant SBRI C-A4-212-1.

References

  1. 1.
    Watanabe S, Tsugane S, Ohno Y (1988) Prediction of the gastric cancer mortality in 2000 in Japan. Jpn J Cancer Res 79:439–444PubMedGoogle Scholar
  2. 2.
    Ministry of Health and Welfare and National Cancer Center (2002) Annual Report of the Korea Central Cancer RegistryGoogle Scholar
  3. 3.
    Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T (1986) The product of the human c-erbB–2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644–1646PubMedCrossRefGoogle Scholar
  4. 4.
    Coussens L, Yang-Feng TL, Liao YC, et al. (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230:1132–1139PubMedCrossRefGoogle Scholar
  5. 5.
    Kaptain S, Tan LK, Chen B (2001) Her–2/neu and breast cancer. Diagn Mol Pathol 10:139–152PubMedCrossRefGoogle Scholar
  6. 6.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  7. 7.
    Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726PubMedCrossRefGoogle Scholar
  8. 8.
    McKenzie SJ, DeSombre KA, Bast BS, Hollis DR, Whitaker RS, Berchuck A, Boyer CM, Bast RCJr (1993) Serum levels of HER-2 neu (C-erbB-2) correlate with overexpression of p185neu in human ovarian cancer. Cancer 71:3942–3946PubMedCrossRefGoogle Scholar
  9. 9.
    Hirashima N, Takahashi W, Yoshii S, Yamane T, Ooi A (2001) Protein overexpression and gene amplification of c-erb B-2 in pulmonary carcinomas: a comparative immunohistochemical and fluorescence in situ hybridization study. Mod Pathol 14:556–662PubMedCrossRefGoogle Scholar
  10. 10.
    Cohen JA, Weiner DB, More KF, Kokai Y, Williams WV, Maguire HCJr, LiVolsi VA, Greene MI (1989) Expression pattern of the neu (NGL) gene–encoded growth factor receptor protein (p185neu) in normal and transformed epithelial tissues of the digestive tract. Oncogene 4:81–88PubMedGoogle Scholar
  11. 11.
    Ishikawa T, Kobayashi M, Mai M, Suzuki T, Ooi A (1997) Amplification of the c-erbB-2 (HER-2/neu) gene in gastric cancer cells. Detection by fluorescence in situ hybridization. Am J Pathol 151:761–768PubMedGoogle Scholar
  12. 12.
    Webb A, Scott-Mackie P, Cunningham D, Norman A, Andreyev J, O’Brien M, Bensted J (1996) The prognostic value of serum and immunohistochemical tumour markers in advanced gastric cancer. Eur J Cancer 32A:63–68PubMedCrossRefGoogle Scholar
  13. 13.
    Orita H, Maehara Y, Emi Y, Kakeji Y, Baba H, Korenaga D, Sugimachi K (1997) c-erbB-2 expression is predictive for lymphatic spread of clinical gastric carcinoma. Hepatogastroenterology 44:294–298PubMedGoogle Scholar
  14. 14.
    Tokunaga A, Onda M, Okuda T, Teramoto T, Fujita I, Mizutani T, Kiyama T, Yoshiyuki T, Nishi K, Matsukura N (1995) Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer. Cancer 75(Suppl 6):1418–1425PubMedCrossRefGoogle Scholar
  15. 15.
    Ooi A, Kobayashi M, Mai M, Nakanishi I (1998) Amplification of c-erbB-2 in gastric cancer: detection in formalin-fixed, paraffin-embedded tissue by fluorescence in situ hybridization. Lab Invest 78:345–351PubMedGoogle Scholar
  16. 16.
    Sato T, Abe K, Kurose A, Uesugi N, Todoroki T, Sasaki K (1997) Amplification of the c-erbB-2 gene detected by FISH in gastric cancers. Pathol Int 47:179–182PubMedCrossRefGoogle Scholar
  17. 17.
    Uchino S, Tsuda H, Maruyama K, Kinoshita T, Sasako M, Saito T, Kobayashi M, Hirohashi S (1993) Overexpression of c-erbB-2 protein in gastric cancer. Its correlation with long-term survival of patients. Cancer 72:3179–184PubMedCrossRefGoogle Scholar
  18. 18.
    Chariyalertsak S, Sugano K, Ohkura H, Mori Y (1994) Comparison of c-erbB-2 oncoprotein expression in tissue and serum of patients with stomach cancer. Tumour Biol 15:294–303PubMedCrossRefGoogle Scholar
  19. 19.
    Mizutani T, Onda M, Tokunaga A, Yamanaka N, Sugisaki Y (1993) Relationship of C-erbB-2 protein expression and gene amplification to invasion and metastasis in human gastric cancer. Cancer 72:2083–2038PubMedCrossRefGoogle Scholar
  20. 20.
    Hilton DA, West KP (1992) c-erbB-2 oncogene product expression and prognosis in gastric carcinoma. J Clin Pathol 45:454–456PubMedCrossRefGoogle Scholar
  21. 21.
    Kolodziejczyk P, Yao T, Oya M, Nakamura S, Utsunomiya T, Ishikawa T, Tsuneyoshi M (1994) Long-term follow-up study of patients with gastric adenomas with malignant transformation. An immunohistochemical and histochemical analysis. Cancer 74:2896–2907PubMedCrossRefGoogle Scholar
  22. 22.
    Tateishi M, Toda T, Minamisono Y, Nagasaki S (1992) Clinicopathological significance of c-erbB-2 protein expression in human gastric carcinoma. J Surg Oncol 49:209–212PubMedCrossRefGoogle Scholar
  23. 23.
    Sasano H, Date F, Imatani A, Asaki S, Nagura H (1993) Double immunostaining for c-erbB-2 and p53 in human stomach cancer cells. Hum Pathol 24:584–589PubMedCrossRefGoogle Scholar
  24. 24.
    Sobin LH, Wittekind C (eds) (1997) TNM classification of malignant tumors, 5th ed. Wiley-Liss, New YorkGoogle Scholar
  25. 25.
    Fenoglio-Preiser C, Carneiro F, Correa O, et al. (2000) Tumors of the stomach. In: Hamilton SR, Aaltonen LA (eds) World Health Organization classification of tumors, pathology and genetics of tumors of the digestive system. IARC, Lyon, pp 37–52Google Scholar
  26. 26.
    Pauletti G, Dandekar S, Rong H, et al. (2000) 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 18:3651–3664PubMedGoogle Scholar
  27. 27.
    Yonemura Y, Ninomiya I, Ohoyama S, et al. (1991) Expression of c-erbB-2 oncoprotein in gastric carcinoma. Immunoreactivity for c-erbB-2 protein is an independent indicator of poor short-term prognosis in patients with gastric carcinoma. Cancer 67:2914–2918PubMedCrossRefGoogle Scholar
  28. 28.
    Yonemura Y, Ninomiya I, Yamaguchi A, Fushida S, Kimura H, Ohoyama S, Miyazaki I, Endou Y, Tanaka M, Sasaki T (1991) Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res 51:1034–1038PubMedGoogle Scholar
  29. 29.
    Ohguri T, Sato Y, Koizumi W, Saigenji K, Kameya T (1993) An immunohistochemical study of c-erbB-2 protein in gastric carcinomas and lymph-node metastases: Is the c-erbB-2 protein really a prognostic indicator? Int J Cancer 53:75–79PubMedCrossRefGoogle Scholar
  30. 30.
    Falck VG, Gullick WJ (1989) c-erbB-2 oncogene product staining in gastric adenocarcinoma. An immunohistochemical study. J Pathol 159:107–111PubMedCrossRefGoogle Scholar
  31. 31.
    Lemoine NR, Jain S, Silvestre F, Lopes C, Hughes CM, McLelland E, Gullick WJ, Filipe MI (1991) Amplification and overexpression of the EGF receptor and c-erbB-2 proto-oncogenes in human stomach cancer. Br J Cancer 64:79–83PubMedGoogle Scholar
  32. 32.
    Seidal T, Balaton AJ, Battifora H (2001) Interpretation and quantification of immunostains. Am J Surg Pathol 25:1204–1207PubMedCrossRefGoogle Scholar
  33. 33.
    Jain S, Filipe MI, Gullick WJ, Linehan J, Morris RW (1991) c-erbB-2 proto-oncogene expression and its relationship to survival in gastric carcinoma: an immunohistochemical study on archival material. Int J Cancer 48:668–671PubMedCrossRefGoogle Scholar
  34. 34.
    Pauletti G, Godolphin W, Press MF, Slamon DJ (1996) Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13:63–72PubMedGoogle Scholar
  35. 35.
    Kameda T, Yasui W, Yoshida K, Tsujino T, Nakayama H, Ito M, Ito H, Tahara E (1990) Expression of ERBB2 in human gastric carcinomas: relationship between p185ERBB2 expression and the gene amplification. Cancer Res 50:8002–8029PubMedGoogle Scholar
  36. 36.
    Kraus MH, Popescu NC, Amsbaugh SC, King CR (1987) Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J 6:605–610PubMedGoogle Scholar
  37. 37.
    Hollywood DP, Hurst HC (1993) A novel transcription factor, OB2-1, is required for overexpression of the proto-oncogene c-erbB-2 in mammary tumour lines. EMBO J 12:2369–2375PubMedGoogle Scholar
  38. 38.
    Slamon DJ, Godolphin W, Jones LA, et al.(1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712PubMedCrossRefGoogle Scholar
  39. 39.
    Joh JW, Noh DY, Bae CD, Choi KJ, Park JB (1996) Amplification and over-expression of erbB–2 oncogene in primary human breast tumors. Exp Mol Med 28:47–53Google Scholar
  40. 40.
    Schnitt SJ (2001) Breast cancer in the 21st century: new opportunities and new challenges. Mod Pathol 14:213–218PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Dong Il Park
    • 1
  • Jung Won Yun
    • 1
  • Jung Ho Park
    • 1
  • Suk Joong Oh
    • 1
  • Hong Joo Kim
    • 1
  • Yong Kyun Cho
    • 1
  • Chong Il Sohn
    • 6
  • Woo Kyu Jeon
    • 1
  • Byung Ik Kim
    • 1
  • Chang Hak Yoo
    • 2
  • Byung Ho Son
    • 2
  • Eun Yoon Cho
    • 3
  • Seoung Wan Chae
    • 3
  • Eo-Jin Kim
    • 3
  • Jin Hee Sohn
    • 3
    • 6
  • Seung Ho Ryu
    • 4
  • Antonia R. Sepulveda
    • 5
  1. 1.Department of MedicineKangbuk Samsung Hospital, Sungkyunkwan University School of MedicineSeoulKorea
  2. 2.Department of SurgeryKangbuk Samsung Hospital, Sungkyunkwan University School of MedicineSeoulKorea
  3. 3.Department of PathologyKangbuk Samsung Hospital, Sungkyunkwan University School of MedicineSeoulKorea
  4. 4.Department of Occupational MedicineKangbuk Samsung Hospital, Sungkyunkwan University School of MedicineSeoulKorea
  5. 5.Department of PathologyUniversity of Pittsburgh Medical Center, PittsburghPennsylvaniaUSA
  6. 6.SeoulKorea

Personalised recommendations