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EGFR inhibitors: what have we learned from the treatment of lung cancer?

Nature Clinical Practice Oncology volume 2, pages 554–561 (2005)Cite this article

Abstract

Tyrosine kinase inhibitors directed against the epidermal growth factor receptor (EGFR) are the first molecular-targeted agents to be approved in the US and other countries for the treatment of advanced non-small-cell lung cancer after failure of chemotherapy. Some patient characteristics, such as never-smoking, female gender, East Asian origin, adenocarcinoma histology, and bronchioloalveolar subtype, are associated with a greater benefit from treatment with EGFR inhibitors. Recently, studies have identified gene mutations targeting the kinase domain of the EGFR that are related to the response to inhibitors. Most EGFR mutations predict a higher benefit from treatment compared with wild-type receptors and are correlated with clinical features related to better outcome; some EGFR mutations, however, confer drug resistance. The analysis of material usually available from lung cancer patients, using techniques such as direct sequencing to determine EGFR mutational status, can be technically challenging. In this regard, high EGFR copy number and EGFR protein detected by immunohistochemistry can also be used to select those patients who would benefit from treatment. Prospective validation of biological and clinical markers of sensitivity needs to be performed.

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References

  1. Parkin DM et al. (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74–108

    Article  Google Scholar 

  2. Dubey S et al. (2005) Three emerging new drugs for NSCLC: pemetrexed, bortezomib, and cetuximab. Oncologist 10: 282–291

    Article  CAS  Google Scholar 

  3. Herbst RS et al. (2005) Angiogenesis and lung cancer: prognostic and therapeutic implications. J Clin Oncol 23: 3243–3256

    Article  CAS  Google Scholar 

  4. Giaccone G (2005) Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23: 3235–3242

    Article  CAS  Google Scholar 

  5. Paez JG et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500

    Article  CAS  Google Scholar 

  6. Lynch TJ et al. (2004) 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

    Article  CAS  Google Scholar 

  7. Pao W et al. (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101: 13306–13311

    Article  CAS  Google Scholar 

  8. Sordella R et al. (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305: 1163–1167

    Article  CAS  Google Scholar 

  9. Tracy S et al. (2004) Gefitinib induces apoptosis in the EGFRL858R non-small-cell lung cancer cell line H3255. Cancer Res 64: 7241–7244

    Article  CAS  Google Scholar 

  10. Fabian MA et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23: 329–336

    Article  CAS  Google Scholar 

  11. Settleman J (2004) Inhibition of mutant EGF receptors by gefitinib: targeting an achilles' heel of lung cancer. Cell Cycle 3: 1496–1497

    Article  CAS  Google Scholar 

  12. Janne PA et al. (2005) Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23: 3227–3234

    Article  CAS  Google Scholar 

  13. Shepherd FA et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353: 123–132

    Article  CAS  Google Scholar 

  14. Janmaat ML et al. (2003) Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9: 2316–2326

    CAS  PubMed  Google Scholar 

  15. Janmaat M et al. Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or PI3K pathways in non-small cell lung cancer cells. Int J Cancer [10.1002/ijc.21290]

  16. Fukuoka M et al. (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21: 2237–2246

    Article  CAS  Google Scholar 

  17. Kris MG et al. (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290: 2149–2158

    Article  CAS  Google Scholar 

  18. Chou TY et al. (2005) Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 11: 3750–3757

    Article  CAS  Google Scholar 

  19. Mitsudomi T et al. (2005) Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23: 2513–2520

    Article  CAS  Google Scholar 

  20. Pao W and Miller VA (2005) Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 23: 2556–2568

    Article  CAS  Google Scholar 

  21. Marchetti A et al. (2005) EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 23: 857–865

    Article  CAS  Google Scholar 

  22. Donohoe E (2005) Denaturing high-performance liquid chromatography using the WAVE DNA fragment analysis system. Methods Mol Med 108: 173–187

    CAS  PubMed  Google Scholar 

  23. Takano T et al. (2005) Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol [10.1200/JCO.2005.01.0793]

  24. Dressler LG et al. (2005) Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients. J Clin Oncol 23: 4287–4297

    Article  CAS  Google Scholar 

  25. Cappuzzo F et al. (2003) Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 21: 2658–2663

    Article  CAS  Google Scholar 

  26. Parra HS et al. (2004) Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer 91: 208–212

    Article  CAS  Google Scholar 

  27. Perez-Soler R et al. (2004) Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22: 3238–3247

    Article  CAS  Google Scholar 

  28. Cappuzzo F et al. (2005) Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97: 643–655

    Article  CAS  Google Scholar 

  29. Tsao MS et al. (2005) Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 353: 133–144

    Article  CAS  Google Scholar 

  30. Hirsch FR et al. (2005) Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol [10.1200/JCO.2005.01.2823]

  31. Amann J et al. (2005) Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65: 226–235

    CAS  PubMed  Google Scholar 

  32. Stephens P et al. (2004) Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431: 525–526

    Article  CAS  Google Scholar 

  33. Shigematsu H et al. (2005) Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 65: 1642–1646

    Article  CAS  Google Scholar 

  34. Kosaka T et al. (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 64: 8919–8923

    Article  CAS  Google Scholar 

  35. Pao W et al. (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2: e17

    Article  Google Scholar 

  36. Soung YH et al. (2005) Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch 446: 483–488

    Article  CAS  Google Scholar 

  37. Shigematsu H et al. (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97: 339–346

    Article  CAS  Google Scholar 

  38. Rodenhuis S et al. (1988) Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48: 5738–5741

    CAS  Google Scholar 

  39. Herbst RS et al. (2004) TRIBUTE—A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 22 (Suppl 14): S619

    Google Scholar 

  40. Eberhard DA et al. (2005) Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol [10.1200/JCO.2005.02.857]

  41. Cappuzzo F et al. (2004) Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 96: 1133–1141

    Article  CAS  Google Scholar 

  42. Pao W et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2: e73

    Article  Google Scholar 

  43. Kobayashi S et al. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352: 786–792

    Article  CAS  Google Scholar 

  44. Toyooka S et al. (2005) EGFR mutation and response of lung cancer to gefitinib. N Engl J Med 352: 2136

    Article  CAS  Google Scholar 

  45. Shih J -Y et al. (2005) EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med 353: 207–208

    Article  CAS  Google Scholar 

  46. Chen LL et al. (2004) A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64: 5913–5919

    Article  CAS  Google Scholar 

  47. Azam M et al. (2003) Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112: 831–843

    Article  CAS  Google Scholar 

  48. Carter TA et al. (2005) Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 102: 11011–11016

    Article  CAS  Google Scholar 

  49. Han SW et al. (2005) Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23: 2493–2501

    Article  CAS  Google Scholar 

  50. Lilenbaum R et al. (2005) A phase II trial of cetuximab as therapy for recurrent non-small cell lung cancer [abstract]. J Clin Oncol 23: S629

    Article  Google Scholar 

  51. Tsuchihashi Z et al.: (2005) Responsiveness to cetuximab without mutations in EGFR. N Engl J Med 353: 208–209

    Article  CAS  Google Scholar 

  52. Raez LE et al. (2005) Clinical responses to gefinitib after failure of treatment with cetuximab in advanced non-small-cell lung cancer. J Clin Oncol 23: 4244–4245

    Article  Google Scholar 

  53. Huang SF et al. (2004) High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res 10: 8195–8203

    Article  CAS  Google Scholar 

  54. Kim KS et al. (2005) Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res 11: 2244–2251

    Article  CAS  Google Scholar 

  55. Tokumo M et al. (2005) The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 11: 1167–1173

    CAS  PubMed  Google Scholar 

  56. Mu XL et al. (2005) Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in chinese patients with non-small cell lung cancer. Clin Cancer Res 11: 4289–4294

    Article  CAS  Google Scholar 

  57. Cortes-Funes H et al. (2005) Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol 16: 1081–1086

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology,

    Giuseppe Giaccone & Jose Antonio Rodriguez

  2. Department of Medical Oncology at the Free University Medical Center, Amsterdam, The Netherlands

    Giuseppe Giaccone & Jose Antonio Rodriguez

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  1. Giuseppe Giaccone
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  2. Jose Antonio Rodriguez
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Correspondence to Giuseppe Giaccone.

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Giaccone, G., Rodriguez, J. EGFR inhibitors: what have we learned from the treatment of lung cancer?. Nat Rev Clin Oncol 2, 554–561 (2005). https://doi.org/10.1038/ncponc0341

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