Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting the human EGFR family in esophagogastric cancer

Nature Reviews Clinical Oncology volume 8, pages 492–503 (2011)Cite this article

Subjects

Abstract

Esophagogastric cancer represents a significant global health problem, with most patients presenting with advanced-stage disease and consequently with a poor prognosis. Chemotherapy improves survival compared with supportive care alone, and combination chemotherapy regimens are more effective than monotherapy. Overexpression of EGFR and possibly HER2 confer a poor prognosis, providing potentially important therapeutic targets for selected patients. Inhibition of HER2 with the monoclonal antibody trastuzumab in patients with HER2 overexpression, HER2 gene amplification, or both, is effective and has been the standard of care for HER2-positive breast cancer for almost a decade. In patients with advanced-stage gastric or esophagogastric-junction adenocarcinomas, the addition of trastuzumab to a cisplatin plus fluoropyrimidine doublet was reported to improve response rate, progression-free survival and overall survival, with the greatest benefit reported in the subgroup of patients with the highest expression of HER2. Cetuximab and panitumumab, two monoclonal antibodies against EGFR, and the dual EGFR and HER2 tyrosine kinase inhibitor lapatinib are currently undergoing phase III evaluation in esophagogastric cancer. We discuss the preclinical rationale for targeting human EGFRs and recent clinical reports of these targeted agents in esophagogastric cancer.

Key Points

  • EGFR overexpression is a common finding in advanced-stage esophagogastric cancer and correlates with poor prognosis

  • Early efficacy data from phase II studies indicate that inhibition of EGFR using monoclonal antibodies in combination with chemotherapy might be beneficial in advanced-stage esophagogastric cancer

  • KRAS and EGFR mutations are established biomarkers for use of anti-EGFR antibodies and tyrosine kinase inhibitors in colorectal and lung cancer, respectively, but their role in esophagogastric cancer remains undefined

  • Phase III data supporting combination of anti-EGFR antibodies or tyrosine kinase inhibitors with neoadjuvant chemoradiotherapy for localized esophageal cancer are still lacking—therefore, this combination is not a standard approach

  • HER2 overexpression is most commonly seen in intestinal-type esophagogastric cancer and might correlate with a poor prognosis

  • The combination of trastuzumab with chemotherapy improves response rate and survival of patients with advanced-stage gastric or esophagogastric-junction cancer and represents a new standard of care

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The EGFR pathway.
Figure 2: HER dimers and their ligands.
Figure 3: Molecular targets and relevant drugs in advanced-stage esophagogastric cancer.

Similar content being viewed by others

References

  1. Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Macdonald, J. S. et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N. Engl. J. Med. 345, 725–730 (2001).

    CAS  PubMed  Google Scholar 

  3. Cunningham, D. et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophagael cancer. N. Engl. J. Med. 355, 11–20 (2006).

    CAS  PubMed  Google Scholar 

  4. Wagner, A. D. et al. Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews, Issue 3. Art. No.: CD004064. doi:10.1002/14651858.CD004064.pub3 (2010).

    Google Scholar 

  5. Cunningham, D. et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N. Engl. J. Med. 358, 36–46 (2008).

    CAS  PubMed  Google Scholar 

  6. Kang, Y. K. et al. Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann. Oncol. 20, 666–673 (2009).

    PubMed  Google Scholar 

  7. Koizumi, W. et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 9, 215–221 (2008).

    CAS  PubMed  Google Scholar 

  8. Van Cutsem, E. et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J. Clin. Oncol. 24, 4991–4997 (2006).

    CAS  PubMed  Google Scholar 

  9. Bang, Y. J. 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 376, 687–697 (2010).

    CAS  PubMed  Google Scholar 

  10. Marshall, J. Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 107, 1207–1218 (2006).

    CAS  PubMed  Google Scholar 

  11. Harari, D. & Yarden, Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19, 6102–6114 (2000).

    CAS  PubMed  Google Scholar 

  12. Pinkas-Kramarski, R. et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 15, 2452–2467 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Karamouzis, M. V., Badra, F. A. & Papavassiliou, A. G. Breast cancer: the upgraded role of HER-3 and HER-4. Int. J. Biochem. Cell Biol. 39, 851–856 (2007).

    CAS  PubMed  Google Scholar 

  14. Kim, M. A. et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology 52, 738–746 (2008).

    CAS  PubMed  Google Scholar 

  15. Galizia, G. et al. Epidermal growth factor receptor (EGFR) expression is associated with a worse prognosis in gastric cancer patients undergoing curative surgery. World J. Surg. 31, 1458–1468 (2007).

    PubMed  Google Scholar 

  16. Lieto, E. et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann. Surg. Oncol. 15, 69–79 (2008).

    PubMed  Google Scholar 

  17. Moutinho, C. et al. Epidermal growth factor receptor structural alterations in gastric cancer. BMC Cancer 8, 10 (2008).

    PubMed  PubMed Central  Google Scholar 

  18. Wang, K. L. et al. Expression of epidermal growth factor receptor in esophageal and esophagogastric junction adenocarcinomas: association with poor outcome. Cancer 109, 658–667 (2007).

    CAS  PubMed  Google Scholar 

  19. Langer, R. et al. Prognostic significance of expression patterns of c-erbB-2, p53, p16INK14A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J. Clin. Pathol. 59, 631–634 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Itakura, Y. et al. Epidermal growth factor receptor overexpression in esophageal carcinoma. An immunohistochemical study correlated with clinicopathologic findings and DNA amplification. Cancer 74, 795–804 (1994).

    CAS  PubMed  Google Scholar 

  21. Hanawa, M. et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int. J. Cancer 118, 1173–1180 (2006).

    CAS  PubMed  Google Scholar 

  22. Kitagawa, Y. et al. Further evidence for prognostic significance of epidermal growth factor receptor gene amplification in patients with esophageal squamous cell carcinoma. Clin. Cancer Res. 2, 909–914 (1996).

    CAS  PubMed  Google Scholar 

  23. Kwak, E. L. et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin. Cancer Res. 12, 4283–4287 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Spector, N. L. & Blackwell, K. L. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J. Clin. Oncol. 27, 5838–5847 (2009).

    CAS  PubMed  Google Scholar 

  25. Enzinger, P. C. et al. CALGB 80403/ECOG 1206: a randomized phase II study of three standard chemotherapy regimens (ECF, IC, FOLFOX) plus cetuximab in metastatic esophageal and GE junction cancer [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a4006 (2010).

    Google Scholar 

  26. Chan, J. A. et al. A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma. Ann. Oncol. doi:10.1093/annonc/mdq604.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gold, P. J. et al. Cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma: a phase II Southwest Oncology Group Study (S0415). J. Thorac. Oncol. 5, 1472–1476 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    CAS  PubMed  Google Scholar 

  29. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).

    CAS  PubMed  Google Scholar 

  30. Bonner, J. A. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567–578 (2006).

    CAS  PubMed  Google Scholar 

  31. Vermorken, J. B. et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359, 1116–1127 (2008).

    CAS  PubMed  Google Scholar 

  32. Lorenzen, S. et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann. Oncol. 20, 1667–1673 (2009).

    CAS  PubMed  Google Scholar 

  33. Sgroi, M. M. et al. Preoperative cetuximab and radiation (XRT) for patients (pts) with surgically resectable esophageal and gastroesophageal (GE) junction carcinomas: A pilot study from the Hoosier Oncology Group and the University of Texas-Southwestern [abstract]. J. Clin. Oncol. 26 (15 Suppl.), a4564 (2008).

    Google Scholar 

  34. Enzinger, P. C. et al. Phase II cisplatin, irinotecan, cetuximab and concurrent radiation therapy followed by surgery for locally advanced esophageal cancer [abstract]. J. Clin. Oncol. 24 (18 Suppl.), a4064 (2006).

    Google Scholar 

  35. Lledo, G. et al. Chemoradiation with FOLFOX plus cetuximab in stage III cardia or esophageal cancer: Interim analysis from a GERCOR phase II trial (ERaFOX) [abstract]. ASCO Gastrointestinal Symp. a68 (2010).

  36. De Vita, F. et al. A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer. Br. J. Cancer 104, 427–432 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu, J. M. et al. An open label, multicenter clinical study of cetuximab combined with concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: Preliminary results of a phase II trial [abstract]. J. Clin. Oncol. 28 (15 Suppl.), e14520 (2010).

    Google Scholar 

  38. Safran, H. et al. Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity. Int. J. Radiat. Oncol. Biol. Phys. 70, 391–395 (2008).

    CAS  PubMed  Google Scholar 

  39. Wanebo, H. J., DiPetrillo, T. & Kennedy, T. Cetuximab-based neoadjuvant chemoradiation appears to facilitate surgical resection in patients with locally advanced esophageal and gastric cancer [abstract]. ASCO Gastrointestinal Cancers Symp. a33 (2008).

  40. Walsh, T. N. et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N. Engl. J. Med. 335, 462–467 (1996).

    CAS  PubMed  Google Scholar 

  41. Tepper, J. et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J. Clin. Oncol. 26, 1086–1092 (2008).

    CAS  PubMed  Google Scholar 

  42. Ruhstaller, T. et al. Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II trial (SAKK 75/06). J. Clin. Oncol. 29, 626–631 (2011).

    CAS  PubMed  Google Scholar 

  43. Rao, S. et al. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann. Oncol. 21, 2213–2219 (2010).

    CAS  PubMed  Google Scholar 

  44. Rao, S. et al. Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer. Br. J. Cancer 99, 868–874 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Okines, A. F. et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial. J. Clin. Oncol. 28, 3945–3950 (2010).

    CAS  PubMed  Google Scholar 

  46. Adams, R. A. et al. Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience. Br. J. Cancer 100, 251–258 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    CAS  PubMed  Google Scholar 

  48. Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).

    CAS  PubMed  Google Scholar 

  49. Allgayer, H. et al. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J. Clin. Oncol. 18, 2201–2209 (2000).

    CAS  PubMed  Google Scholar 

  50. Tanner, M. et al. Amplification of HER-2 in gastric carcinoma: association with topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann. Oncol. 16, 273–278 (2005).

    CAS  PubMed  Google Scholar 

  51. Grabsch, H., Sivakumar, S., Gray, S., Gabbert, H. E. & Muller, W. HER2 expression in gastric cancer: rare, heterogeneous and of no prognostic value—conclusions from 924 cases of two independent series. Cell. Oncol. 32, 57–65 (2010).

    PubMed  PubMed Central  Google Scholar 

  52. Ohguri, T., Sato, Y., Koizumi, W., Saigenji, K. & Kameya, T. 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, 75–79 (1993).

    CAS  PubMed  Google Scholar 

  53. Bang, Y. 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 [abstract]. J. Clin. Oncol. 27 (15 Suppl.), a4556 (2009).

    Google Scholar 

  54. Hofmann, M. et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 52, 797–805 (2008).

    CAS  PubMed  Google Scholar 

  55. Herceptin®(Genentech, Inc., San Francisco, CA) (trastuzumab) prescribing information [online]. (2010).

  56. Chau, I. et al. The impact of primary tumour origins in patients with advanced oesophageal, oesophago-gastric junction and gastric adenocarcinoma—individual patient data from 1775 patients in four randomised controlled trials. Ann. Oncol. 20, 885–891 (2009).

    CAS  PubMed  Google Scholar 

  57. Doi, T. et al. Efficacy, tolerability and pharmacokinetics of gefitinib (ZD1839) in pretreated patients with metastatic gastric cancer [abstract]. Proc. Am. Soc. Clin. Oncol. 22, a1036 (2003).

    Google Scholar 

  58. Dragovich, T. et al. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J. Clin. Oncol. 24, 4922–4927 (2006).

    CAS  PubMed  Google Scholar 

  59. US National Library of Medicine. Clinicaltrials.gov [online]. (2011).

  60. Taira, N. et al. Gefitinib, an epidermal growth factor receptor blockade agent, shows additional or synergistic effects on the radiosensitivity of esophageal cancer cells in vitro. Acta Med. Okayama 60, 25–34 (2006).

    CAS  PubMed  Google Scholar 

  61. Javle, M. et al. Pilot study of gefitinib, oxaliplatin, and radiotherapy for esophageal adenocarcinoma: tissue effect predicts clinical response. Am. J. Clin. Oncol. 31, 329–334 (2008).

    CAS  PubMed  Google Scholar 

  62. Rodriguez, C. P. et al. A phase II study of perioperative concurrent chemotherapy, gefitinib, and hyperfractionated radiation followed by maintenance gefitinib in locoregionally advanced esophagus and gastroesophageal junction cancer. J. Thorac. Oncol. 5, 229–235 (2010).

    PubMed  Google Scholar 

  63. Li, G. et al. Phase II study of concurrent chemoradiation in combination with erlotinib for locally advanced esophageal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 78, 1407–1412 (2010).

    CAS  PubMed  Google Scholar 

  64. Meluch, A. A. et al. A phase II trial of preoperative chemoradiation therapy plus bevacizumab and erlotinib in the treatment of localized esophageal cancer [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a4108 (2010).

    Google Scholar 

  65. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    CAS  PubMed  Google Scholar 

  66. Tsao, M. S. et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N. Engl. J. Med. 353, 133–144 (2005).

    CAS  PubMed  Google Scholar 

  67. Kim, J. W. et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 272, 296–306 (2008).

    CAS  PubMed  Google Scholar 

  68. LaBonte, M. J. et al. The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38. Int. J. Cancer 125, 2957–2969 (2009).

    CAS  PubMed  Google Scholar 

  69. Tanizaki, J. et al. Synergistic antitumor effect of S-1 and HER2-targeting agents in gastric cancer with HER2 amplification. Mol. Cancer Ther. 9, 1198–1207 (2010).

    CAS  PubMed  Google Scholar 

  70. Wainberg, Z. A. et al. Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin. Cancer Res. 16, 1509–1519 (2010).

    CAS  PubMed  Google Scholar 

  71. Iqbal, S. et al. S0413: a phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer [abstract]. J. Clin. Oncol. 25 (18 Suppl.), a4621 (2007).

    Google Scholar 

  72. Satoh, T. et al. Interim safety analysis from TYTAN: a phase III Asian study of lapatinib in combination with paclitaxel as second-line therapy in gastric cancer [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a4057 (2010).

    Google Scholar 

  73. Hecht, J. et al. A phase III study of CapeOx ± lapatinib in HER2 positive locally-advanced/metastatic upper gastrointestinal adenocarcinoma: interim safety results [abstract]. Eur. J. Cancer Suppl. 7, 385 (2009).

  74. Gonzales, A. J. et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol. Cancer Ther. 7, 1880–1889 (2008).

    CAS  PubMed  Google Scholar 

  75. Engelman, J. A. et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 67, 11924–11932 (2007).

    CAS  PubMed  Google Scholar 

  76. Mok, T. et al. Efficacy and safety of PF-00299804 (PF299), an oral, irreversible, pan-human epidermal growth factor receptor (pan-HER) tyrosine kinase inhibitor (TKI), as first-line treatment (tx) of selected patients (pts) with advanced (adv) non-small cell lung cancer (NSCLC) [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a7537 (2010).

    Google Scholar 

  77. Baselga, J. & Swain, S. M. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, 463–475 (2009).

    CAS  PubMed  Google Scholar 

  78. Hayashi, M. et al. High expression of HER3 is associated with a decreased survival in gastric cancer. Clin. Cancer Res. 14, 7843–7849 (2008).

    CAS  PubMed  Google Scholar 

  79. Sanidas, E. E. et al. Expression of the c-erbB-3 gene product in gastric cancer. Int. J. Cancer 54, 935–940 (1993).

    CAS  PubMed  Google Scholar 

  80. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 68, 9280–9290 (2008).

    CAS  PubMed  Google Scholar 

  81. Burris, H. A. 3rd et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J. Clin. Oncol. 29, 398–405 (2011).

    CAS  PubMed  Google Scholar 

  82. Gelmon, K. A. et al. Results of a phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy [abstract]. J. Clin. Oncol. 26 (15 Suppl.), a1026 (2008).

    Google Scholar 

  83. Miller, K. et al. A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T) [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a1012 (2010).

    Google Scholar 

  84. Jones, F. E., Welte, T., Fu, X-Y. & Stern, D. F. ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation. J. Cell Biol. 147, 77–87 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Junttila, T. T. et al., Cleavable ErbB4 isoform in estrogen receptor-regulated growth of breast cancer cells. Cancer Res. 65, 1384–1393 (2005).

    CAS  PubMed  Google Scholar 

  86. Ott, K. et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction. J. Clin. Oncol. 24, 4692–4698 (2006).

    PubMed  Google Scholar 

  87. Lordick, F. et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol. 8, 797–805 (2007).

    PubMed  Google Scholar 

  88. Pinto, C. et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann. Oncol. 18, 510–517 (2007).

    CAS  PubMed  Google Scholar 

  89. Di Fabio, F. et al. The predictive value of 18F-FDG-PET early evaluation in patients with metastatic gastric adenocarcinoma treated with chemotherapy plus cetuximab. Gastric Cancer 10, 221–227 (2007).

    CAS  PubMed  Google Scholar 

  90. Maughan, T. S. et al. Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial [abstract]. J. Clin. Oncol. 28 (15 Suppl.), a3502 (2010).

    Google Scholar 

  91. Alberts, S. R. et al. Adjuvant mFOLFOX6 with or without cetuxiumab (Cmab) in KRAS wild-type (WT) patients (pts) with resected stage III colon cancer (CC): results from NCCTG Intergroup Phase III Trial N0147 [abstract]. J. Clin. Oncol. 28 (18 Suppl.), CRA3507 (2010).

    Google Scholar 

  92. Lynch, T. J. et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J. Clin. Oncol. 28, 911–917 (2010).

    CAS  PubMed  Google Scholar 

  93. Khambata-Ford, S. et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 918–927 (2010).

    CAS  PubMed  Google Scholar 

  94. Stella, G. et al. KRAS and BRAF mutational status as response biomarkers to cetuximab combination therapy in advanced gastric cancer patients [abstract]. J. Clin. Oncol. 27 (15 Suppl.), e15503 (2009).

    Google Scholar 

  95. Lord, V. N., O'Grady, R., Sheehan, C., Field, A. F. & Ward, R. L. K-ras codon 12 mutations in Barrett's oesophagus and adenocarcinomas of the oesophagus and oesophagogastric junction. J. Gastroenterol. Hepatol. 15, 730–736 (2000).

    CAS  PubMed  Google Scholar 

  96. De Roock, W. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753–762 (2010).

    CAS  PubMed  Google Scholar 

  97. Sommerer, F. et al. Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma. Oncogene 23, 554–558 (2004).

    CAS  PubMed  Google Scholar 

  98. Velho, S. et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer 41, 1649–1654 (2005).

    CAS  PubMed  Google Scholar 

  99. Phillips, W. A. et al. Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus. Int. J. Cancer 118, 2644–2646 (2006).

    CAS  PubMed  Google Scholar 

  100. Im, S. A. et al. Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas. Tumori 91, 513–521 (2005).

    CAS  PubMed  Google Scholar 

  101. Laurent-Puig, P. et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol. 27, 5924–5930 (2009).

    CAS  PubMed  Google Scholar 

  102. Jacobs, B. et al. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab. J. Clin. Oncol. 27, 5068–5074 (2009).

    CAS  PubMed  Google Scholar 

  103. Wu, W. K. et al. Expression of ErbB receptors and their cognate ligands in gastric and colon cancer cell lines. Anticancer Res. 29, 229–234 (2009).

    CAS  PubMed  Google Scholar 

  104. Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351, 337–345 (2004).

    CAS  PubMed  Google Scholar 

  105. Hecht, J. R. et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 110, 980–988 (2007).

    CAS  PubMed  Google Scholar 

  106. Sartore-Bianchi, A. et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J. Clin. Oncol. 25, 3238–3245 (2007).

    CAS  PubMed  Google Scholar 

  107. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    CAS  PubMed  Google Scholar 

  108. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).

    CAS  PubMed  Google Scholar 

  109. Pinto, C. et al. Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). Br. J. Cancer 101, 1261–1268 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lordick, F. et al. Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Br. J. Cancer 102, 500–505 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Kim, C. et al. A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer. Invest. New Drugs 29, 366–373 (2009).

    PubMed  Google Scholar 

  112. Han, S. W. et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br. J. Cancer 100, 298–304 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ferry, D. R. et al. A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response. Clin. Cancer Res. 13, 5869–5875 (2007).

    CAS  PubMed  Google Scholar 

  114. Janmaat, M. L. et al. Predictive factors for outcome in a phase II study of gefitinib in second-line treatment of advanced esophageal cancer patients. J. Clin. Oncol. 24, 1612–1619 (2006).

    CAS  PubMed  Google Scholar 

  115. Adelstein, D. J., Rybicki, L. A., Carroll, M. A., Rice, T. W. & Mekhail, T. Phase II trial of gefitinib for recurrent or metastatic esophageal or gastroesophageal junction (GEJ) cancer [abstract]. J. Clin. Oncol. 23 (16 Suppl.), a4054 (2005).

    Google Scholar 

  116. Ilson, D. H. et al. A phase 2 trial of erlotinib in patients with previously treated squamous cell and adenocarcinoma of the esophagus. Cancer doi:10.1002/cncr.25602 (2010).

Download references

Acknowledgements

We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Center.

Author information

Authors and Affiliations

  1. Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, Surrey, UK

    Alicia Okines, David Cunningham & Ian Chau

Authors
  1. Alicia Okines
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Cunningham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian Chau
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A. Okines and I. Chau researched the data for the article, wrote the article and provided a substantial contribution to discussion of the content. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Ian Chau.

Ethics declarations

Competing interests

A. Okines declares that she received grant/research support from Roche, Amgen, and Bayer. D. Cunningham declares that he is a consultant and and received grant/research support from Roche, Amgen, and Merck. I. Chau declares that he is consultant for Roche, Merck Serono, Novartis, ImClone, and OSI. He is on the speaker's bureau (honoraria) for Roche and Sanofi-Aventis, and received grant/research support from Merck Serono and Novartis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okines, A., Cunningham, D. & Chau, I. Targeting the human EGFR family in esophagogastric cancer. Nat Rev Clin Oncol 8, 492–503 (2011). https://doi.org/10.1038/nrclinonc.2011.45

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2011.45

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer