Annals of Diagnostic Pathology
Volume 10, Issue 5 , Pages 306-315 , October 2006

Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications

  • Ludmila Prudkin, MD

      Affiliations

    • Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
  • ,
  • Ignacio I. Wistuba, MD

      Affiliations

    • Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
    • Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA
    • Corresponding Author InformationCorresponding author. Department of Pathology, M. D. Anderson Cancer Center, Houston, TX 77030-4009, USA. Tel.: +1 713 563 9184; fax: +1 713 563 1848.

References 

  1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56(2):106–130
  2. Minna JD, Gazdar A. Focus on lung cancer. Cancer Cell. 2002;1:49–52
  3. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18(6):1059–1068
  4. Wistuba I, Gazdar A. Lung cancer prenoplasia. Annu Rev Pathol Mech Dis. 2005;1:331–348
  5. Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol. 2001;54:257–271
  6. Ebbert JO, Yang P, Vachon CM, et al. Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women. J Clin Oncol. 2003;21(5):921–926
  7. Tong L, Spitz MR, Fueger JJ, Amos CA. Lung carcinoma in former smokers. Cancer. 1996;78:1004–1010
  8. Herbst RS. Targeted therapy in non–small-cell lung cancer. Oncology (Williston Park). 2002;16(9 Suppl 9):19–24
  9. Herbst RS. Role of novel targeted therapies in the clinic. Br J Cancer. 2005;92(Suppl 1):S21–S27
  10. Massarelli E, Herbst RS. Use of novel second-line targeted therapies in non–small cell lung cancer. Semin Oncol. 2006;33(1 Suppl 1):S9–S16
  11. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–1500
  12. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–2139
  13. Huse M, Kuriyan J. The conformational plasticity of protein kinases. Cell. 2002;109(3):275–282
  14. Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–5557
  15. Pisick E, Jagadeesh S, Salgia R. Receptor tyrosine kinases and inhibitors in lung cancer. Sci World J. 2004;4:589–604
  16. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–137
  17. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59(2 Suppl):21–26
  18. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor–related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19(3):183–232
  19. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;284(1):31–53
  20. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37(Suppl 4):S9–S15
  21. Scagliotti GV, Selvaggi G, Novello S, Hirsch FR. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res. 2004;10(12 Pt 2):4227s–4232s
  22. Franklin WA, Veve R, Hirsch FR, Helfrich BA, Bunn PA. Epidermal growth factor receptor family in lung cancer and premalignancy. Semin Oncol. 2002;29(1 Suppl 4):3–14
  23. Hirsch FR, Varella-Garcia M, Bunn PA, et al. Epidermal growth factor receptor in non–small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21(20):3798–3807
  24. Meert AP, Martin B, Delmotte P, et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J. 2002;20(4):975–981
  25. Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non–small cell lung cancers and adjacent benign lung. Cancer Res. 1993;53(10 Suppl):2379–2385
  26. Suzuki S, Dobashi Y, Sakurai H, Nishikawa K, Hanawa M, Ooi A. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas. An immunohistochemical and fluorescence in situ hybridization study. Cancer. 2005;103(6):1265–1273
  27. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A. 1983;80(5):1337–1341
  28. Gill GN, Kawamoto T, Cochet C, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor–stimulated tyrosine protein kinase activity. J Biol Chem. 1984;259(12):7755–7760
  29. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19(56):6550–6565
  30. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol. 2003;21(14):2787–2799
  31. FDA. Food and Drug Administration. In: www.fda.gov.
  32. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non–small-cell lung cancer. N Engl J Med. 2005;353(2):123–132
  33. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non–small-cell lung cancer: a phase III trial—INTACT 1. J Clin Oncol. 2004;22(5):777–784
  34. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non–small-cell lung cancer. J Clin Oncol. 2005;23(25):5892–5899
  35. Kris MG, Natale RB, Herbst RS, et al. 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. 2003;290(16):2149–2158
  36. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non–small-cell lung cancer (The IDEAL 1 Trial). [corrected] J Clin Oncol. 2003;21(12):2237–2246
  37. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol. 2004;22(16):3238–3247
  38. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non–small-cell lung cancer. J Clin Oncol. 2004;22(6):1103–1109
  39. Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60(5):1383–1387
  40. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–346
  41. Yatabe Y, Kosaka T, Takahashi T, Mitsudomi T. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol. 2005;29(5):633–639
  42. Huang SF, Liu HP, Li LH, et al. 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. 2004;10(24):8195–8203
  43. Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 2004;64(24):8919–8923
  44. Tokumo M, Toyooka S, Kiura K, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non–small cell lung cancers. Clin Cancer Res. 2005;11(3):1167–1173
  45. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst. 2005;97(9):643–655
  46. Sonobe M, Manabe T, Wada H, Tanaka F. Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer. 2005;93(3):355–363
  47. Sasaki H, Endo K, Konishi A, et al. EGFR mutation status in Japanese lung cancer patients: genotyping analysis using LightCycler. Clin Cancer Res. 2005;11(8):2924–2929
  48. Yang SH, Mechanic LE, Yang P, et al. Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non–small cell lung cancer. Clin Cancer Res. 2005;11(6):2106–2110
  49. Mu XL, Li LY, Zhang XT, et al. Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non–small cell lung cancer. Clin Cancer Res. 2005;11(12):4289–4294
  50. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133–144
  51. Mitsudomi T, Kosaka T, Endoh H, et al. 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. 2005;23(11):2513–2520
  52. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer. 2006;118(2):257–262
  53. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non–small-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005;23(11):2556–2568
  54. Dowell JE. Epidermal growth factor receptor mutations in non–small cell lung cancer: a basic science discovery with immediate clinical impact. Am J Med Sci. 2006;331(3):139–149
  55. Johnson BE, Janne PA. Epidermal growth factor receptor mutations in patients with non–small cell lung cancer. Cancer Res. 2005;65(17):7525–7529
  56. Gazdar AF, Shigematsu H, Herz J, Minna JD. Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers?. Trends Mol Med. 2004;10(10):481–486
  57. Sordella R, Bell DW, Haber DA, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004;305(5687):1163–1167
  58. Tam IY, Chung LP, Suen WS, et al. Distinct epidermal growth factor receptor and KRAS mutation patterns in non–small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res. 2006;12(5):1647–1653
  59. Toyooka S, Tokumo M, Shigematsu H, et al. Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers. Cancer Res. 2006;66(3):1371–1375
  60. Tsao AS, Tang X, Sabloff B, et al. Clinical-pathological characteristics of the EGFR gene mutation in non–small cell lung cancer. J Thoracic Oncol. 2006;1:231–239
  61. Toyooka S, Yatabe Y, Tokumo M, et al. Mutations of epidermal growth factor receptor and K-ras genes in adenosquamous carcinoma of the lung. Int J Cancer. 2006;118(6):1588–1590
  62. Pao W, Miller V, Zakowski M, et al. 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. 2004;101(36):13306–13311
  63. Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol. 2005;23(14):3279–3287
  64. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Tumours of the lung. In:  Travis WD,  Brambilla E,  Muller-Hermelink HK,  Harris CC editor. Pathology and genetics: tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004;p. 9–124
  65. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non–small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12(31):839–844
  66. Tidow N, Boecker A, Schmidt H, et al. Distinct amplification of an untranslated regulatory sequence in the egfr gene contributes to early steps in breast cancer development. Cancer Res. 2003;63(6):1172–1178
  67. Gebhardt F, Zanker KS, Brandt B. Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem. 1999;274(19):13176–13180
  68. Ahrendt SA, Decker PA, Alawi EA, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer. 2001;92(6):1525–1530
  69. Keohavong P, Mady HH, Gao WM, Siegfried JM, Luketich JD, Melhem MF. Topographic analysis of K-ras mutations in histologically normal lung tissues and tumours of lung cancer patients. Br J Cancer. 2001;85(2):235–241
  70. Westra WH, Slebos RJ, Offerhaus GJ, et al. K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer. 1993;72(2):432–438
  71. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):e17
  72. Tomizawa Y, Iijima H, Sunaga N, et al. Clinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non–small cell lung cancer. Clin Cancer Res. 2005;11(19 Pt 1):6816–6822
  73. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non–small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005;23(11):2493–2501
  74. Taron M, Ichinose Y, Rosell R, et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res. 2005;11(16):5878–5885
  75. Takano T, Ohe Y, Sakamoto H, et al. 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. 2005;23(28):6829–6837
  76. Hirsch FR, Varella-Garcia M, McCoy J, et al. 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. 2005;23(28):6838–6845
  77. Sequist LV, Haber DA, Lynch TJ. Epidermal growth factor receptor mutations in non–small cell lung cancer: predicting clinical response to kinase inhibitors. Clin Cancer Res. 2005;11(16):5668–5670
  78. Amann J, Kalyankrishna S, Massion PP, et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res. 2005;65(1):226–235
  79. Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson BE, Janne PA. Gefitinib induces apoptosis in the EGFRL858R non–small-cell lung cancer cell line H3255. Cancer Res. 2004;64(20):7241–7244
  80. Janne PA, Borras AM, Kuang Y, et al. A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res. 2006;12(3 Pt 1):751–758
  81. Eberhard DA, Johnson BE, Amler LC, et al. 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. 2005;23(25):5900–5909
  82. Pao W, Miller VA, Venkatraman E, Kris MG. Predicting sensitivity of non–small-cell lung cancer to gefitinib: is there a role for P-Akt?. J Natl Cancer Inst. 2004;96(15):1117–1119
  83. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73
  84. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786–792
  85. Marchetti A, Martella C, Felicioni L, et al. 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. 2005;23(4):857–865
  86. Soung YH, Lee JW, Kim SY, et al. Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch. 2005;446(5):483–488
  87. Sugio K, Uramoto H, Ono K, et al. Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking. Br J Cancer. 2006;94(6):896–903

 This study was supported by grant W81XWU-04-1-0142 (IW) from the US Department of Defense.

PII: S1092-9134(06)00083-9

doi: 10.1016/j.anndiagpath.2006.06.011

Annals of Diagnostic Pathology
Volume 10, Issue 5 , Pages 306-315 , October 2006