HER-2/neu Gene Overexpression in Resectable Gastric Cancer and its Relationship with Histopathologic Subtype, Grade, and Stage

Document Type : Original Article

Authors

1 Radiation Oncology Department, Cancer Research Center, Omid Hospital, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

2 Pathology Department, Cancer Research Center, Omid Hospital, MUMS, Mashhad, Iran

3 Biostatistics Department, MUMS, Mashhad, Iran

Abstract

Objective
HER-2/neu gene is overexpressed in diverse human cancers and studies suggest a role of its product – p185 protein – in tumor progression by specifically promoting the invasive capacity of tumor cells. Our aim was to evaluate HER-2/neu content in resectable gastric cancer in this geographical region and assess the relationship between p185 expression and clinicopathologic tumor parameters.
Materials and Methods
This was a retrospective analysis of 100 specimens from 100 patients with resectable gastric carcinoma. Indirect immunostaining was used to evaluate the expression of this receptor in formalin-fixed paraffin-embedded tissue samples.
Results
HER-2/neu overexpression was present in 26 (26%) of 100 gastric carcinomas. This was significantly more common in the intestinal type of gastric cancer (33%) compared to diffuse (5%) or the mixed type (0%). HER-2/neu overexpression was also more common in well-differentiated gastric cancer versus other grades as. However, it was not associated with gender, age at diagnosis or clinical stage.
Conclusion
HER-2/neu amplification is common in the intestinal and well-differentiated gastric carcinomas. There is no correlation between HER-2/neu expression and tumor stage. The relatively high percentage of HER-2/neu positive tumors may provide a useful target for immunotherapy of these cancers.

Keywords


1. Press MF, Cordon-Cardo C and Slamon DJ: Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissue. Oncogene 5: 953-962, 1990.
2.Yamamoto T, Ikawa S, Akiyama T, et al: Similarity of protein encoded by the human c-erbB-2 gene to epidermal growth factor receptor. Nature 319:230-236, 1986
3.Bongiorno PF, Whyte RI, Lesser EJ, et al: Alterations of K-ras, p53, and erbB-2/neu in human lung adenocarcinomas. J Thorac Cardiovasc Surg 107:590-595, 1994
4. Mitra AB, Murty VVS, Pratap M, et al: ERBB2 (HER-2/neu) oncogene is frequently amplified in squamous cell carcinoma of the uterine cervix. Cancer Res 54:637-639, 1994
5. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/ neu oncogene. Science 235:177-182, 1987
6. Beckhardt RN, Kiyokawa N, Liu TJ, et al: Neu oncogene in head and neck squamous cell carcinoma. Proc Am Assoc Cancer Res 35:153, 1994
7.  Hynes N, Stern D: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198:165-184, 1994
8.  Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/ neu oncogene. Science 235:177-182, 1987
9. Guerin M, Gabillot M, Mathieu MC, et al: Structure and expression of c-erbB-2 and EGF receptor genes in inflammatory and non-inflammatory breast cancer: Prognostic significance. Int J Cancer 43:201-208, 1989
10. Van de Vijiver MJ, Peterse JL, Mooi WJ, et al: Neu protein overexpression in breast cancer: Association with comedo type-ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 319:1239-1245, 1988
11. Berger MS, Locher GW, Sauer S, et al: Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res 48:1238-1243, 1988
12. Paik S, Bryant J, Tan-Chiu E, Yothers G, Park C, Wickerham DL and Wolmark N: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 92:1991-1998, 2000.
13. Fornier M, Risio M, van Poznak C and Seidman A: HER2 testing and correlation with the efficacy of trastuzumab therapy. Oncology 16: 1340-1352, 2002.
14.Allgayer H, Babic R, Gruetzner UG, Tarabichi A, Schildberg FW and Heiss MA: C-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease system. J Clin Oncol 18: 2201-2209,2000.
15.Ross JS, McKenna B. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest 2001; 19: 554–568.
16. M. Tanner, M. Hollmen. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIa gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab Annals of Oncology 16: 273–278, 2005
17. Lin JT, Wu MS, Shun CT et al. Occurrence of microsatellite instability in gastric carcinoma is associated with enhanced expression of erbB-2 oncoprotein. Cancer Res 1995; 55: 1428–1430.
18. Wu MS, Shun CT, Wang HP et al. Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology 1997; 112: 1457–1465.
19. Polkowski W, van Sandick JW, Offerhaus GL et al. Prognostic value of Lauren’s classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 1999; 6: 290–297.
20.  Berx G, Becker KF, Hofler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 1998; 12: 226–237.
21. Motojima K, Furui J, Kohara N, et al: erbB-2 expression in welldifferentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery 115:349-354, 1994.
22. Shimada E, Kato M, Saito Y: Immunohistochemical study of the c-erbB-2 protein in human gastric carcinoma. Nippon Geka Gakkai Zasshi 94: 33-40, 1993.
23. Motojima K, Furui J, Kohara N, Izawa K, Kanematsu T and Shiku H: erbB-2 expression in well-differentiated adenocarcinoma of the stomach predicts shorter survival after curative resection. Surgery 115: 349-354, 1994.
24. Soto T, Abe K, Kurose A, Uesugi N, Todoroki T and Sasaki K: Amplification of the c-erbB-2 gene detected by FISH in gastric cancers. Pathol Int 47: 179-182, 1997.
25. Martin IG, Dixon MF, Sue-Ling H, Axon AT and Johnston D: Goseki histological grading of gastric cancer is an important predictor of outcome. Gut 35: 758-763, 1994.
26. Pegram MD, Finn RS, Arzoo K et al. The effect of Her-2/neu overexpression
on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene 1997; 15: 537–547.
27. 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 1999; 18: 2241–2251.
28. Normanno N, Campiglio M, De LA et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002; 13: 89.
29. Funato T, Kozawa K, Fujimaki S, Miura T, Kaku M. Increased sensitivity to cisplatin in gastric cancer by antisense inhibition of the HER-2/neu (c-erbB-2) gene. Chemotherapy 2001;47:297–303.