Tumor Biology

, Volume 35, Issue 6, pp 5315–5321 | Cite as

Prognostic significance of HER2 expression based on trastuzumab for gastric cancer (ToGA) criteria in gastric cancer: an updated meta-analysis

  • Jianchun Gu
  • Leizhen Zheng
  • Yajie Wang
  • Meiling Zhu
  • Qin Wang
  • Xiaoping Li
Research Article


The prognostic significance of HER2 expression in patients with gastric cancer remains controversial, partially due to the significant heterogeneity of the approaches and criteria used for HER2 assessment among different studies. We therefore conducted a meta-analysis enrolling only studies defining HER2 status by trastuzumab for gastric cancer (ToGA) criteria. Published studies investigating the association between HER2 expression and survival were identified. Only publications that defined HER2 expression using ToGA criteria were enrolled. Meta-analyses were performed by Revman 5.2. Pooled hazard ratio (HR) and its 95 % confidence interval (CI) were calculated to evaluate the risk of disease. A total of 11 studies were enrolled in meta-analyses. Pooled data of nine studies using univariate analysis showed that HER2 expression is not associated with overall survival (OS; pooled HR, 0.97; 95 % CI, 0.84–1.12; P = 0.63), which are maintained in six studies of multivariate analysis (pooled HR, 1.01; 95 % CI, 0.75–1.35; P = 0.95). The Q statistic test for nine studies of univariate analysis and for six studies of multivariate analysis showed no and low heterogeneity (I 2 = 22 % and P = 0.25; I 2 = 41 % and P = 0.13, respectively). Furthermore, pooled data of four studies without heterogeneity (I 2 = 0 %, P = 0.74) showed that HER2 expression were not associated with relapse-free survival as well, with a pooled HR of 1.08 (95 % CI, 0.84–1.37; P = 0.55) in patients with HER2 expression. In conclusion, this meta-analysis indicated that HER2 expression based on ToGA criteria is not related to the survival in patients with gastric cancer.


HER2 Human epidermal growth factor receptor Gastric cancer Prognosis Meta-analysis 


Conflict of interest



  1. 1.
    Hechtman JF, Polydorides AD. Her2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: a review of histopathology, diagnostic testing, and clinical implications. Arch Pathol Lab Med. 2012;136:691–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Chua TC, Merrett ND. Clinicopathologic factors associated with her2-positive gastric cancer and its impact on survival outcomes—a systematic review. Int J Cancer. 2012;130:2845–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Gomez-Martin C, Garralda E, Echarri MJ, Ballesteros A, Arcediano A, Rodriguez-Peralto JL, et al. Her2/neu testing for anti-her2-based therapies in patients with unresectable and/or metastatic gastric cancer. J Clin Pathol. 2012;65:751–7.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Gravalos C, Jimeno A. Her2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19:1523–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Jorgensen JT, Hersom M. Her2 as a prognostic marker in gastric cancer—a systematic analysis of data from the literature. J Cancer. 2012;3:137–44.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Chen C, Yang JM, Hu TT, Xu TJ, Yan G, Hu SL, et al. Prognostic role of human epidermal growth factor receptor in gastric cancer: a systematic review and meta-analysis. Arch Med Res. 2013;44:380–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang S, Zheng G, Chen L, Xiong B. Effect of her-2/neu over-expression on prognosis in gastric cancer: a meta-analysis. Asian Pac J Cancer Prev. 2011;12:1417–23.PubMedGoogle Scholar
  8. 8.
    Grabsch H, Sivakumar S, Gray S, Gabbert HE, Muller W. Her2 expression in gastric cancer: rare, heterogeneous and of no prognostic value—conclusions from 924 cases of two independent series. Cell Oncol. 2010;32:57–65.PubMedGoogle Scholar
  9. 9.
    Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, et al. Assessment of a her2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.CrossRefPubMedGoogle Scholar
  10. 10.
    Albarello L, Pecciarini L, Doglioni C. Her2 testing in gastric cancer. Adv Anat Pathol. 2011;18:53–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Ruschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, et al. Her2 diagnostics in gastric cancer—guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of her2-positive advanced gastric or gastro-oesophageal junction cancer (toga): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P: The newcastle-ottawa scale (nos) for assessing the quality of nonrandomised studies in meta-analyses, 2013, Accessed 15 Nov 2013.
  15. 15.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Cidon EU, Centeno RG, Lagarto EG, Peral JI. Her-2 evaluation in a specific gastric cancer population with the highest rate of mortality in spain. J Oncol. 2011;2011:391564.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Hsu JT, Chen TC, Tseng JH, Chiu CT, Liu KH, Yeh CN, et al. Impact of her-2 overexpression/amplification on the prognosis of gastric cancer patients undergoing resection: a single-center study of 1,036 patients. Oncologist. 2011;16:1706–13.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Zhou F, Li N, Jiang W, Hua Z, Xia L, Wei Q, et al. Prognosis significance of her-2/neu overexpression/amplification in chinese patients with curatively resected gastric cancer after the toga clinical trial. World J Surg Oncol. 2012;10:274.PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Aizawa M, Nagatsuma AK, Kitada K, Kuwata T, Fujii S, Kinoshita T, et al. Evaluation of her2-based biology in 1,006 cases of gastric cancer in a Japanese population. Gastric Cancer. 2014;17:34–42.CrossRefPubMedGoogle Scholar
  20. 20.
    Aoyama T, Yoshikawa T, Miyagi Y, Kameda Y, Shirai J, Hayashi T, et al. Human epidermal growth factor receptor 2 (her-2) and s-1 adjuvant chemotherapy in stage 2/3 gastric cancer patients who underwent d2 gastrectomy. Surg Today. 2013;43:1390–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Bar-Sela G, Hershkovitz D, Haim N, Kaidar-Person O, Shulman K, Ben-Izhak O. The incidence and prognostic value of her2 overexpression and cyclin d1 expression in patients with gastric or gastroesophageal junction adenocarcinoma in Israel. Oncol Lett. 2013;5:559–63.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Berezowska S, Novotny A, Bauer K, Feuchtinger A, Slotta-Huspenina J, Becker K, et al. Association between hsp90 and her2 in gastric and gastroesophageal carcinomas. PLoS One. 2013;8:e69098.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jager E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by her2 status: a European and USA international collaborative analysis. Ann Oncol. 2012;23:2656–62.CrossRefPubMedGoogle Scholar
  24. 24.
    Kataoka Y, Okabe H, Yoshizawa A, Minamiguchi S, Yoshimura K, Haga H, et al. Her2 expression and its clinicopathological features in resectable gastric cancer. Gastric Cancer. 2013;16:84–93.CrossRefPubMedGoogle Scholar
  25. 25.
    Okines AF, Thompson LC, Cunningham D, Wotherspoon A, Reis-Filho JS, Langley RE, et al. Effect of her2 on prognosis and benefit from peri-operative chemotherapy in early oesophago-gastric adenocarcinoma in the magic trial. Ann Oncol. 2013;24:1253–61.CrossRefPubMedGoogle Scholar
  26. 26.
    Sheng WQ, Huang D, Ying JM, Lu N, Wu HM, Liu YH, et al. Her2 status in gastric cancers: a retrospective analysis from four Chinese representative clinical centers and assessment of its prognostic significance. Ann Oncol. 2013;24:2360–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Shitara K, Yatabe Y, Matsuo K, Sugano M, Kondo C, Takahari D, et al. Prognosis of patients with advanced gastric cancer by her2 status and trastuzumab treatment. Gastric Cancer. 2013;16:261–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Terashima M, Kitada K, Ochiai A, Ichikawa W, Kurahashi I, Sakuramoto S, et al. Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer. Clin Cancer Res. 2012;18:5992–6000.CrossRefPubMedGoogle Scholar
  29. 29.
    Xu CC, Yue L, Wei HJ, Zhao WW, Sui AH, Wang XM, et al. Significance of tff3 protein and her-2/neu status in patients with gastric adenocarcinoma. Pathol Res Pract. 2013;209:479–85.CrossRefPubMedGoogle Scholar
  30. 30.
    Guo P, Li Y, Zhu Z, Sun Z, Lu C, Wang Z, et al. Prognostic value of tumor size in gastric cancer: an analysis of 2,379 patients. Tumour Biol. 2013;34:1027–35.CrossRefPubMedGoogle Scholar
  31. 31.
    Bu Z, Zheng Z, Li Z, Zhang L, Wu A, Wu X, et al. Lymphatic vascular invasion is an independent correlated factor for lymph node metastasis and the prognosis of resectable t2 gastric cancer patients. Tumour Biol. 2013;34:1005–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Qiu MZ, Wang ZQ, Luo HY, Zhang DS, Zhou ZW, Li YH, et al. Prognostic analysis in node-negative gastric cancer patients in China. Tumour Biol. 2011;32:489–92.CrossRefPubMedGoogle Scholar
  33. 33.
    Chae S, Lee A, Lee JH. The effectiveness of the new (7th) UICC N classification in the prognosis evaluation of gastric cancer patients: a comparative study between the 5th/6th and 7th UICC N classification. Gastric Cancer. 2011;14:166–71.CrossRefPubMedGoogle Scholar
  34. 34.
    Qiu MZ, Wang ZQ, Zhang DS, Luo HY, Zhou ZW, Wang FH, et al. Clinicopathological characteristics and prognostic analysis of gastric cancer in the young adult in china. Tumour Biol. 2011;32:509–14.CrossRefPubMedGoogle Scholar
  35. 35.
    Qiu MZ, Cai MY, Zhang DS, Wang ZQ, Wang DS, Li YH, et al. Clinicopathological characteristics and prognostic analysis of Lauren classification in gastric adenocarcinoma in china. J Transl Med. 2013;11:58.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Sasako M, Inoue M, Lin JT, Khor C, Yang HK, Ohtsu A. Gastric cancer working group report. Jpn J Clin Oncol. 2010;40:i28–37.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of OncologyXinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
  2. 2.Department of OncologyChanghai Hospital of the Second Military Medical UniversityShanghaiChina

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