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

Abstract

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed  Google 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.

    PubMed  Google 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.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Albarello L, Pecciarini L, Doglioni C. Her2 testing in gastric cancer. Adv Anat Pathol. 2011;18:53–9.

    CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 15 Nov 2013.

  15. 15.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed Central  Article  PubMed  Google 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.

    PubMed Central  CAS  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    PubMed Central  PubMed  Google 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.

    PubMed Central  CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    PubMed Central  Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Leizhen Zheng or Yajie Wang.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gu, J., Zheng, L., Wang, Y. et al. Prognostic significance of HER2 expression based on trastuzumab for gastric cancer (ToGA) criteria in gastric cancer: an updated meta-analysis. Tumor Biol. 35, 5315–5321 (2014). https://doi.org/10.1007/s13277-014-1693-7

Download citation

Keywords

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