Current Treatment Options in Oncology

, Volume 15, Issue 3, pp 395–404

HER2 Directed Therapy for Gastric/Esophageal Cancers

  • Elizabeth Won
  • Yelena J. Janjigian
  • David H. Ilson
Upper Gastrointestinal Cancers (L Rajdev, Section Editor)

Opinion Statement

The majority of patients with esophagogastric cancer present with advanced disease, which is incurable. Systemic chemotherapy can lead to a decrease in cancer-related symptoms and prolongs survival. However, even with treatment, the prognosis remains poor; most patients with advanced disease have a median overall survival less than one year. Molecularly targeted therapies, such as those targeting human epidermal growth factor receptor 2 (HER2), are anticipated to improve the current status of systemic treatment beyond conventional cytotoxic therapy. Trastuzumab in combination with chemotherapy in patients is the first molecular agent in metastatic HER2 positive gastric and gastroesophageal adenocarcinomas to result in improvements in response rates, time to progression and survival. Trastuzumab is now being investigated in the neoadjuvant and adjuvant setting. Unfortunately, as with breast cancer, many esophagogastric patients will develop resistance to trastuzumab. Several promising therapies are currently under investigation as monotherapy and in combination with chemotherapy in the first and second line setting.


HER2 positive Gastric cancer Esophageal cancer Gastroesophageal junction Treatment 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRefGoogle Scholar
  2. 2.
    Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 1996;335:462–7.CrossRefGoogle Scholar
  3. 3.••
    Bang YJ, Van Custem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for the treatment of HER2-positive advanced gastric or gastro-oesophageal cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010;376:687–97. This phase III study showed a survival and PFS benefit of trastuzumab in combination with chemotherapy for HER2 positive EG cancers and provides the rationale for FDA approval of the drug.PubMedCrossRefGoogle Scholar
  4. 4.
    Yarden Y. The EGFR family and its ligands in human cancer, signaling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37 Suppl 4:S3–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Bang Y, Chung H, Xu J, et al. Pathological features of advanced gastric cancer (GC): relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial. J Clin Oncol. 2009;27(Suppl):15. abst 4556.Google Scholar
  6. 6.
    Tanner M, Hollmén M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma: association with topoisomerase IIα gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273–8.PubMedCrossRefGoogle Scholar
  7. 7.••
    Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805. This study discusses the development and validation of the HER2 scoring system for gastric cancer, which was subsequently used in the ToGA trial.PubMedCrossRefGoogle Scholar
  8. 8.••
    Rüschoff J, Dietel M, Baretton G, et al. HER2 diagnostics in gastric cancer—guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457:299–307. This paper validates the HER2 immunohistochemical (IHC) scoring system for gastric cancer, which was subsequently used in the ToGA trial, and discusses specific modifications for gastric cancer HER2 testing that differ from breast cancer testing.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    National Comprehensive Cancer Network (NCCN). Esophageal and Esophagogastric Junction Cancers. Version 2.2013. Available at: Accessed 11 March 2014.
  10. 10.••
    Ruschoff J, Hanna W, Bilous M, et al. HER2 testing in gastric cancer: a practical approach. Mod Pathol. 2012;25:637–50. These guidelines represent the European consensus standard of care for the diagnosis and testing of HER2 status in gastric and gastroesophageal cancers.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakajim M, Sawad H, Yamada Y, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85:1894–902.CrossRefGoogle Scholar
  12. 12.
    Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006;51:1371–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Terashima M, Ochiai A, Kitada K, et al. Impact of human epidermal growth factor (EGFR) and ERBB2 (HER2) expressions on survival in patients with stage II/III gastric cancer, enrolled in the ACTS-GC study. J Clin Oncol. 2011;(Suppl)29:abstr 4013.Google Scholar
  14. 14.
    Yoon HH, Shi Q, Sukov WR, et al. HER2expression/amplification: frequency, clinicopathologic features, and prognosis in 713 patients with esophageal adenocarcinoma (EAC). J Clin Oncol. 2011;29(Suppl):abstr 4012.Google Scholar
  15. 15.
    Grabsch H, Sivakumar S, Gray S, et al. 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
  16. 16.
    Janjigian YY, Werner D, Pauligk C, et al. Prognostic significance of human epidermal growth factor-2 (HER2) in advanced gastric cancer: a US and European international collaborative analysis. Ann Oncol. 2012;23:2656–62.PubMedCrossRefGoogle Scholar
  17. 17.
    Ajani JA, Rodriguez W, Bodoky G, et al. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusion fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010;28:1547–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Vanhoefer U, Rougier P, Wilke H, et al. Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol. 2000;18:2648–57.PubMedGoogle Scholar
  19. 19.
    Lordick F, Kang YK, Chung HC, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomized, open-label phase 3 trial. Lancet Oncol. 2013;14:490–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Bruno R, Washington CB, Lu JF, et al. Population pharmacokinetics of trastuzumab in patients with HER2 + metastatic breast cancer. Cancer Chemother Pharmacol. 2005;56:361–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Roche, Inc. Herceptin package insert. Available at: Accessed 3 April 2014.
  22. 22.
    Hoffmann-La Roche. HELOISE study: a study of Herceptin (trastuzumab) in combination with chemotherapy in patients with HER2-positive metastatic gastric or gastro-esophageal cancer. In: Bethesda, MD: National Library of Medicine (US). Available at: NLM Identifier: NCT01450696. Accessed 3 April 2014.
  23. 23.
    Hoffmann-La Roche. A study of capecitabine (Xeloda) in combination with trastuzumab (Herceptin) and oxaliplatin in patients with resectable gastric cancer. In: Bethesda, MD: National Library of Medicine (US). Available at: NLM Identifier: NCT01130337. Accessed 18 March 2014.
  24. 24.
    National Cancer Institute (NCI.) Radiation therapy, paclitaxel, and carboplatin with or without trastuzumab in treating patients with esophageal cancer (RTOG 1010 Trial) In: Bethesda, MD: National Library of Medicine (US). Available at: NCT01196390. NLM Identifier: NCT01196390. Accessed 18 March 2014.
  25. 25.
    Hoffmann-La Roche. A study of the combination of oxaliplatin, capecitabine and Herceptin (trastuzumab) and chemoradiotherapy in the adjuvant setting in operated patients with HER2+ gastric or gastroesophageal junction cancer (TOXAG Study). In: Bethesda, MD: National Library of Medicine (US). Available at: NCT01748773. NLM Identifier: NCT01748773. Accessed 18 March 2014.
  26. 26.•
    Gajria D, Chandarlapaty S. Her2-amplified breast cancer: mechanisms of resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11:263–75. This paper provides an excellent overview on the putative mechanisms of resistance in HER2 breast cancers.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the P13K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.PubMedCrossRefGoogle Scholar
  28. 28.
    Nahta R, Yuan LXH, Zhang B, et al. Insulin-like growth factor-1 receptor/human epidermal growth factor receptor2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.PubMedCrossRefGoogle Scholar
  29. 29.
    Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13:4909–19.PubMedCrossRefGoogle Scholar
  30. 30.
    Scaltriti M, Rojo F, Ocana A, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.PubMedCrossRefGoogle Scholar
  31. 31.
    Fountzilas G, Razis E, Tsavdaridis D, et al. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the Hellenic Cooperative Oncology Group. Clin Breast Cancer. 2003;4:120–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Tripathy D, Slamon DJ, Cobleigh M, et al. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004;22:1063–70.PubMedCrossRefGoogle Scholar
  33. 33.•
    Iqbal S, Goldman B, Fenoglio-Preiser CM, et al. Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol. 2011;22:2610–5. This phase II study showed single agent activity of lapatinib in non-selected metastatic gastric patients.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.•
    Hecht JR, Bang Y-J, Qin S, et al. Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): the TRIO-013/LOGiC Trial. J Clin Oncol. 2013;31(Suppl)abstr LBA4001. Presented June 3, 2013 at 2013 ASCO Annual Meeting, Chicago, IL. A phase III study of chemotherapy with or without lapatinib in the first line metastatic setting failed to meet overall survival endpoint, but showed improvements in survival only in subgroup analysis.Google Scholar
  35. 35.•
    Bang YJ. A randomized, open-label, phase III study of lapatinib in combination with paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer (AGC) in Asian population: Tytan study. J Clin Oncol. 2012;30 (suppl 34;abstr 11.) The phase III TYTAN study showed a nonsignificant trend towards overall survival with lapatinib plus paclitaxel in the second line setting compared to chemotherapy alone. In the subset of patients with HER2 IHC3+ overexpression, there was a significant OS benefit compared with the lapatinib combination compared to chemotherapy alone.Google Scholar
  36. 36.
    Yamashita-Kashima Y, Iijima S, Yoruzu K, et al. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res. 2011;15:5060–70.CrossRefGoogle Scholar
  37. 37.
    Baselga J, Cortes J, Kim S-B, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. New Engl J Med. 2012;366:109–19.PubMedCrossRefGoogle Scholar
  38. 38.
    Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory early HER2-positive breast cancer (NeoSphere): a randomized multicentre, open-label, phase 2 trial.Google Scholar
  39. 39.
    Tabernero J, Marcelo Hoff P, Shen L, et al. Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: an international phase III study (JACOB). J Clin Oncol. 2013;(Suppl) TPS4150.Google Scholar
  40. 40.
    Barok M, Tanner M, Koninki K, et al. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 2011;306:171–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Yamashita-Kashima Y, Shu S, Harada N, et al. Potentiation of trastuzumab emtansine (T-DM1)-driven antitumor activity by pertuzumab in a HER2-positive gastric cancer model. J Clin Oncol 2012;(Suppl)abstr e13502.Google Scholar
  42. 42.
    Hoffmann-La Roche. A study of trastuzumab emtansine versus taxane in patients with advanced gastric cancer. In: Bethesda, MD: National Library of Medicine (US). Available at: NLM Identifier: NCT01641939. Accessed 18 March 2014.
  43. 43.
    Janjigian YY, Capanu M, Imtiaz T, et al. A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer. J Clin Oncol. 2014;(Suppl 3)abstr 52.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Elizabeth Won
    • 1
  • Yelena J. Janjigian
    • 1
  • David H. Ilson
    • 1
  1. 1.Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA

Personalised recommendations