Skip to main content

Advertisement

SpringerLink
Log in

Biological and clinical implications of EGFR mutations in lung cancer

  • REVIEW ARTICLE
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Patients with non-small-cell lung cancer sometimes show a dramatic clinical response to gefitinib or erlotinib, small-molecule tyrosine kinase inhibitors (TKI) specific for the epidermal growth factor receptor (EGFR). However, until April 2004, it was unclear how to identify patients who would benefit from these drugs. Then, two groups from Boston reported that EGFR gene mutations in the kinase domain are strongly associated with gefitinib sensitivity. EGFR mutations are more frequent in Asians, females, nonsmokers, and adenocarcinomas than in their counterparts. These populations precisely coincide with those populations with higher response rates to TKIs. We and others subsequently confirmed and extended these findings.

Methods

We reviewed recent literatures on EGFR mutations and EGFR-TKIs. We discuss topics including the molecular epidemiology and biology of EGFR mutations in relation to EGFR-TKIs, the controversy about whether EGFR mutations account for all the clinical activity of EGFR-TKIs, and the mechanisms of acquired resistance to gefitinib or erlotinib.

Results

The discovery of EGFR mutations has great biologic and clinical implications in lung cancer. However, all but one phase III trials have so far failed to show a survival advantage of the treatment arm involving EGFR-TKIs.

Conclusion

It would be possible to individualize EGFR-TKI treatment of lung cancer by selecting patients according to EGFR mutational status and other biomarkers.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. JH Schiller D Harrington CP Belani et al. (2002) ArticleTitleComparison of four chemotherapy regimens for advanced non-small-cell lung cancer N Engl J Med 346 92–98 Occurrence Handle11784875 Occurrence Handle1:CAS:528:DC%2BD38Xkt1OlsQ%3D%3D Occurrence Handle10.1056/NEJMoa011954

    Article  PubMed  CAS  Google Scholar 

  2. CL Arteaga (2002) ArticleTitleOverview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia Semin Oncol 29 3–9 Occurrence Handle12422308 Occurrence Handle1:CAS:528:DC%2BD38XoslWitbg%3D

    PubMed  CAS  Google Scholar 

  3. F Ciardiello G Tortora (2001) ArticleTitleA novel approach in the treatment of cancer: targeting the epidermal growth factor receptor Clin Cancer Res 7 2958–2970 Occurrence Handle11595683 Occurrence Handle1:CAS:528:DC%2BD3MXnvF2ktbk%3D

    PubMed  CAS  Google Scholar 

  4. M Fukuoka S Yano G Giaccone et al. (2003) ArticleTitleMulti-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer J Clin Oncol 21 2237–2246 Occurrence Handle12748244 Occurrence Handle1:CAS:528:DC%2BD2cXpsVGqu7w%3D Occurrence Handle10.1200/JCO.2003.10.038

    Article  PubMed  CAS  Google Scholar 

  5. MG Kris RB Natale RS Herbst et al. (2003) ArticleTitleEfficacy 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 Occurrence Handle14570950 Occurrence Handle1:CAS:528:DC%2BD3sXosVOnsbo%3D Occurrence Handle10.1001/jama.290.16.2149

    Article  PubMed  CAS  Google Scholar 

  6. VA Miller MG Kris N Shah et al. (2004) ArticleTitleBronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer J Clin Oncol 22 1103–1109 Occurrence Handle15020612 Occurrence Handle1:CAS:528:DC%2BD2cXptlCku7g%3D Occurrence Handle10.1200/JCO.2004.08.158

    Article  PubMed  CAS  Google Scholar 

  7. F Cappuzzo V Gregorc E Rossi et al. (2003) ArticleTitleGefitinib 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 Occurrence Handle12860941 Occurrence Handle1:CAS:528:DC%2BD2cXptlCktL0%3D Occurrence Handle10.1200/JCO.2003.01.039

    Article  PubMed  CAS  Google Scholar 

  8. T Suzuki T Nakagawa H Endo et al. (2003) ArticleTitleThe sensitivity of lung cancer cell lines to the EGFR-selective tyrosine kinase inhibitor ZD1839 ("Iressa") is not related to the expression of EGFR or HER-2 or to K-ras gene status Lung Cancer 42 35–41 Occurrence Handle14512185 Occurrence Handle10.1016/S0169-5002(03)00278-2

    Article  PubMed  Google Scholar 

  9. JG Paez PA Janne JC Lee et al. (2004) ArticleTitleEGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 304 1497–1500 Occurrence Handle15118125 Occurrence Handle1:CAS:528:DC%2BD2cXksVGmsbs%3D Occurrence Handle10.1126/science.1099314

    Article  PubMed  CAS  Google Scholar 

  10. TJ Lynch DW Bell R Sordella et al. (2004) ArticleTitleActivating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib N Engl J Med 350 2129–2139 Occurrence Handle15118073 Occurrence Handle1:CAS:528:DC%2BD2cXktF2js7c%3D Occurrence Handle10.1056/NEJMoa040938

    Article  PubMed  CAS  Google Scholar 

  11. R Sordella DW Bell DA Haber et al. (2004) ArticleTitleGefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways Science 305 1163–1167 Occurrence Handle15284455 Occurrence Handle1:CAS:528:DC%2BD2cXmslCmur8%3D Occurrence Handle10.1126/science.1101637

    Article  PubMed  CAS  Google Scholar 

  12. H Suzuki T Takahashi T Kuroishi et al. (1992) ArticleTitlep53 mutations in non-small cell lung cancer in Japan: Association between mutations and smoking Cancer Res 52 734–736 Occurrence Handle1310070 Occurrence Handle1:CAS:528:DyaK38XhtVemtr4%3D

    PubMed  CAS  Google Scholar 

  13. SA Ahrendt PA Decker EA Alawi et al. (2001) ArticleTitleCigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung Cancer 92 1525–1530 Occurrence Handle11745231 Occurrence Handle1:CAS:528:DC%2BD3MXnvVygsr0%3D Occurrence Handle10.1002/1097-0142(20010915)92:6<1525::AID-CNCR1478>3.0.CO;2-H

    Article  PubMed  CAS  Google Scholar 

  14. T Mitsudomi T Oyama K Nishida et al. (1996) ArticleTitleLoss of heterozygosity at 3p in non-small cell lung cancer and its prognostic implication Clin Cancer Res 2 1185–1189 Occurrence Handle9816286 Occurrence Handle1:STN:280:DyaK1M%2FjsFWgtg%3D%3D

    PubMed  CAS  Google Scholar 

  15. T Kosaka Y Yatabe H Endoh et al. (2004) ArticleTitleMutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications Cancer Res 64 8919–8923 Occurrence Handle15604253 Occurrence Handle1:CAS:528:DC%2BD2cXhtVOmsL3P Occurrence Handle10.1158/0008-5472.CAN-04-2818

    Article  PubMed  CAS  Google Scholar 

  16. NL Kobrinsky MG Klug PJ Hokanson et al. (2003) ArticleTitleImpact of smoking on cancer stage at diagnosis J Clin Oncol 21 907–913 Occurrence Handle12610192 Occurrence Handle10.1200/JCO.2003.05.110

    Article  PubMed  Google Scholar 

  17. W Liu F Innocenti P Chen et al. (2003) ArticleTitleInterethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism Clin Cancer Res 9 1009–1012 Occurrence Handle12631599 Occurrence Handle1:CAS:528:DC%2BD3sXhvFKit7o%3D

    PubMed  CAS  Google Scholar 

  18. F Gebhardt KS Zanker B Brandt (1999) ArticleTitleModulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1 J Biol Chem 274 13176–13180 Occurrence Handle10224073 Occurrence Handle1:CAS:528:DyaK1MXjtFOls7k%3D Occurrence Handle10.1074/jbc.274.19.13176

    Article  PubMed  CAS  Google Scholar 

  19. Y Yatabe T Kosaka T Takahashi et al. (2005) ArticleTitleEGFR mutation is specific for terminal respiratory unit type adenocarcinoma Am J Surg Pathol 29 633–639 Occurrence Handle15832087 Occurrence Handle10.1097/01.pas.0000157935.28066.35

    Article  PubMed  Google Scholar 

  20. A Marchetti C Martella L Felicioni et al. (2005) ArticleTitleEGFR 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 Occurrence Handle15681531 Occurrence Handle1:CAS:528:DC%2BD2MXitVKit7o%3D Occurrence Handle10.1200/JCO.2005.08.043

    Article  PubMed  CAS  Google Scholar 

  21. H Shigematsu L Lin T Takahashi et al. (2005) ArticleTitleClinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers J Natl Cancer Inst 97 339–346 Occurrence Handle15741570 Occurrence Handle1:CAS:528:DC%2BD2MXitV2jsb4%3D Occurrence Handle10.1093/jnci/dji055

    Article  PubMed  CAS  Google Scholar 

  22. H Shigematsu AF Gazdar (2006) ArticleTitleSomatic mutations of epidermal growth factor receptor signaling pathway in lung cancers Int J Cancer 118 257–262 Occurrence Handle16231326 Occurrence Handle1:CAS:528:DC%2BD2MXhtlWqs7bF Occurrence Handle10.1002/ijc.21496

    Article  PubMed  CAS  Google Scholar 

  23. T Mitsudomi T Kosaka H Endoh et al. (2005) ArticleTitleMutations 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 Occurrence Handle15738541 Occurrence Handle1:CAS:528:DC%2BD2MXjvVyktLs%3D Occurrence Handle10.1200/JCO.2005.00.992

    Article  PubMed  CAS  Google Scholar 

  24. SW Han TY Kim PG Hwang et al. (2005) ArticleTitlePredictive 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 Occurrence Handle15710947 Occurrence Handle1:CAS:528:DC%2BD2MXjvVyktL0%3D Occurrence Handle10.1200/JCO.2005.01.388

    Article  PubMed  CAS  Google Scholar 

  25. KS Kim JY Jeong YC Kim et al. (2005) ArticleTitlePredictors of the response to gefitinib in refractory non-small cell lung cancer Clin Cancer Res 11 2244–2251 Occurrence Handle15788673 Occurrence Handle1:CAS:528:DC%2BD2MXisFaju74%3D Occurrence Handle10.1158/1078-0432.CCR-04-2081

    Article  PubMed  CAS  Google Scholar 

  26. H Cortes-Funes C Gomez R Rosell et al. (2005) ArticleTitleEpidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients Ann Oncol 16 1081–1086 Occurrence Handle15851406 Occurrence Handle1:STN:280:DC%2BD2MzhsV2qtA%3D%3D Occurrence Handle10.1093/annonc/mdi221

    Article  PubMed  CAS  Google Scholar 

  27. M Taron Y Ichinose R Rosell et al. (2005) ArticleTitleActivating 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 11 5878–5885 Occurrence Handle16115929 Occurrence Handle1:CAS:528:DC%2BD2MXos1Cjur0%3D Occurrence Handle10.1158/1078-0432.CCR-04-2618

    Article  PubMed  CAS  Google Scholar 

  28. T Takano Y Ohe H Sakamoto et al. (2005) ArticleTitleEpidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer J Clin Oncol 23 6829–6837 Occurrence Handle15998907 Occurrence Handle1:CAS:528:DC%2BD2MXhtFCrsb3P Occurrence Handle10.1200/JCO.2005.01.0793

    Article  PubMed  CAS  Google Scholar 

  29. GJ Riely W Pao D Pham et al. (2006) ArticleTitleClinical 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 12 839–844 Occurrence Handle16467097 Occurrence Handle1:CAS:528:DC%2BD28XhtFeiurk%3D Occurrence Handle10.1158/1078-0432.CCR-05-1846

    Article  PubMed  CAS  Google Scholar 

  30. H Greulich T-H Chen W Feng et al. (2005) ArticleTitleOncogenic transformation by inhibitor-sensitive and resistant EGFR mutations PLoS Med 2 e313 Occurrence Handle16187797 Occurrence Handle10.1371/journal.pmed.0020313 Occurrence Handle1:CAS:528:DC%2BD28XktVeh

    Article  PubMed  CAS  Google Scholar 

  31. F Cappuzzo FR Hirsch E Rossi et al. (2005) ArticleTitleEpidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small cell lung cancer J Natl Cancer Inst 97 643–655 Occurrence Handle15870435 Occurrence Handle1:CAS:528:DC%2BD2MXjvFymt70%3D Occurrence Handle10.1093/jnci/dji112

    Article  PubMed  CAS  Google Scholar 

  32. MS Tsao A Sakurada JC Cutz et al. (2005) ArticleTitleErlotinib in lung cancer – molecular and clinical predictors of outcome N Engl J Med 353 133–144 Occurrence Handle16014883 Occurrence Handle1:CAS:528:DC%2BD2MXmtFejt70%3D Occurrence Handle10.1056/NEJMoa050736

    Article  PubMed  CAS  Google Scholar 

  33. T Shibata S Uryu A Kokubu et al. (2005) ArticleTitleGenetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: its association with clinicopathologic features Clin Cancer Res 11 6177–6185 Occurrence Handle16144918 Occurrence Handle1:CAS:528:DC%2BD2MXpslans7w%3D Occurrence Handle10.1158/1078-0432.CCR-05-0293

    Article  PubMed  CAS  Google Scholar 

  34. F Cappuzzo E Magrini GL Ceresoli et al. (2004) ArticleTitleAkt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer J Natl Cancer Inst 96 1133–1141 Occurrence Handle15292385 Occurrence Handle1:CAS:528:DC%2BD2cXntFamsbg%3D Occurrence Handle10.1093/jnci/djh217

    Article  PubMed  CAS  Google Scholar 

  35. F Cappuzzo M Varella-Garcia H Shigematsu et al. (2005) ArticleTitleIncreased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients J Clin Oncol 23 5007–5018 Occurrence Handle16051952 Occurrence Handle1:CAS:528:DC%2BD2MXpsFWmtLo%3D Occurrence Handle10.1200/JCO.2005.09.111

    Article  PubMed  CAS  Google Scholar 

  36. W Pao TY Wang GJ Riely et al. (2005) ArticleTitleKRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib PLoS Med 2 e17 Occurrence Handle15696205 Occurrence Handle10.1371/journal.pmed.0020017 Occurrence Handle1:CAS:528:DC%2BD2MXit1ygtL4%3D

    Article  PubMed  CAS  Google Scholar 

  37. S Kobayashi TJ Boggon T Dayaram et al. (2005) ArticleTitleEGFR mutation and resistance of non-small-cell lung cancer to gefitinib N Engl J Med 352 786–792 Occurrence Handle15728811 Occurrence Handle1:CAS:528:DC%2BD2MXhsFCiurk%3D Occurrence Handle10.1056/NEJMoa044238

    Article  PubMed  CAS  Google Scholar 

  38. W Pao VA Miller KA Politi et al. (2005) ArticleTitleAcquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain PLoS Med 2 e73 Occurrence Handle15737014 Occurrence Handle10.1371/journal.pmed.0020073 Occurrence Handle1:CAS:528:DC%2BD2MXjtFyhsLo%3D

    Article  PubMed  CAS  Google Scholar 

  39. NP Shah JM Nicoll B Nagar et al. (2002) ArticleTitleMultiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia Cancer Cell 2 117–125 Occurrence Handle12204532 Occurrence Handle1:CAS:528:DC%2BD38XmslSks7c%3D Occurrence Handle10.1016/S1535-6108(02)00096-X

    Article  PubMed  CAS  Google Scholar 

  40. ME Gorre M Mohammed K Ellwood et al. (2001) ArticleTitleClinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 293 876–880 Occurrence Handle11423618 Occurrence Handle1:CAS:528:DC%2BD3MXlvVKrsbs%3D Occurrence Handle10.1126/science.1062538

    Article  PubMed  CAS  Google Scholar 

  41. S Blencke A Ullrich H Daub (2003) ArticleTitleMutation of threonine 766 in the epidermal growth factor receptor reveals a hotspot for resistance formation against selective tyrosine kinase inhibitors J Biol Chem 278 15435–15440 Occurrence Handle12594213 Occurrence Handle1:CAS:528:DC%2BD3sXjtVClt7Y%3D Occurrence Handle10.1074/jbc.M211158200

    Article  PubMed  CAS  Google Scholar 

  42. TA Carter LM Wodicka NP Shah et al. (2005) ArticleTitleInhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases Proc Natl Acad Sci USA 102 11011–11016 Occurrence Handle16046538 Occurrence Handle1:CAS:528:DC%2BD2MXnvVWjurg%3D Occurrence Handle10.1073/pnas.0504952102

    Article  PubMed  CAS  Google Scholar 

  43. RS Herbst D Prager R Hermann et al. (2005) ArticleTitleTRIBUTE: 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 23 5892–5899 Occurrence Handle16043829 Occurrence Handle1:CAS:528:DC%2BD2MXhtVKgtbzN Occurrence Handle10.1200/JCO.2005.02.840

    Article  PubMed  CAS  Google Scholar 

  44. FA Shepherd J Rodrigues Pereira T Ciuleanu et al. (2005) ArticleTitleErlotinib in previously treated non-small-cell lung cancer N Engl J Med 353 123–132 Occurrence Handle16014882 Occurrence Handle1:CAS:528:DC%2BD2MXmtFaksbo%3D Occurrence Handle10.1056/NEJMoa050753

    Article  PubMed  CAS  Google Scholar 

  45. Thatcher N, Chang A, Parikh P (2005) Results of a Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-cmall-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proc Am Assoc Cancer Res 46 (suppl): Abstract# LB-6

  46. T Takano Y Ohe M Kusumoto et al. (2004) ArticleTitleRisk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib Lung Cancer 45 93–104 Occurrence Handle15196739 Occurrence Handle10.1016/j.lungcan.2004.01.010

    Article  PubMed  Google Scholar 

  47. DW Bell TJ Lynch SM Haserlat et al. (2005) ArticleTitleEpidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials J Clin Oncol 23 8081–8092 Occurrence Handle16204011 Occurrence Handle1:CAS:528:DC%2BD2MXht1CqsLzM Occurrence Handle10.1200/JCO.2005.02.7078

    Article  PubMed  CAS  Google Scholar 

  48. FR Hirsch M Varella-Garcia J McCoy et al. (2005) ArticleTitleIncreased 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 23 6838–6845 Occurrence Handle15998906 Occurrence Handle1:CAS:528:DC%2BD2MXhtFCrsb3K Occurrence Handle10.1200/JCO.2005.01.2823

    Article  PubMed  CAS  Google Scholar 

  49. G Giaccone RS Herbst C Manegold et al. (2004) ArticleTitleGefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 1 J Clin Oncol 22 777–784 Occurrence Handle14990632 Occurrence Handle1:CAS:528:DC%2BD2cXpsVKjur4%3D Occurrence Handle10.1200/JCO.2004.08.001

    Article  PubMed  CAS  Google Scholar 

  50. RS Herbst G Giaccone JH Schiller et al. (2004) ArticleTitleGefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 2 J Clin Oncol 22 785–794 Occurrence Handle14990633 Occurrence Handle1:CAS:528:DC%2BD2cXpsVKjur0%3D Occurrence Handle10.1200/JCO.2004.07.215

    Article  PubMed  CAS  Google Scholar 

  51. N Thatcher A Chang P Parikh et al. (2005) ArticleTitleGefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) Lancet 366 1527–1537 Occurrence Handle16257339 Occurrence Handle1:CAS:528:DC%2BD2MXhtFKhsbfP Occurrence Handle10.1016/S0140-6736(05)67625-8

    Article  PubMed  CAS  Google Scholar 

  52. R Perez-Soler (2004) ArticleTitlePhase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer Clin Lung Cancer 6 IssueIDSuppl 1 S20–S23 Occurrence Handle15638953 Occurrence Handle1:CAS:528:DC%2BD2MXhtFalt74%3D Occurrence Handle10.3816/CLC.2004.s.010

    Article  PubMed  CAS  Google Scholar 

  53. H Kaneda K Tamura T Kurata et al. (2004) ArticleTitleRetrospective analysis of the predictive factors associated with the response and survival benefit of gefitinib in patients with advanced non-small-cell lung cancer Lung Cancer 46 247–254 Occurrence Handle15474673 Occurrence Handle10.1016/j.lungcan.2004.04.032

    Article  PubMed  Google Scholar 

  54. SF Huang HP Liu LH Li et al. (2004) ArticleTitleHigh 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 Occurrence Handle15623594 Occurrence Handle1:CAS:528:DC%2BD2cXhtFGjsrjK Occurrence Handle10.1158/1078-0432.CCR-04-1245

    Article  PubMed  CAS  Google Scholar 

  55. Kris MG, Sandler A, Miller V, et al. (2004) Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). J Clin Oncol 22:Abstract# 7062

    Google Scholar 

  56. ST Lim EH Wong KL Chuah et al. (2005) ArticleTitleGefitinib is more effective in never-smokers with non-small-cell lung cancer: experience among Asian patients Br J Cancer 93 23–28 Occurrence Handle15942627 Occurrence Handle1:CAS:528:DC%2BD2MXlsl2itL4%3D Occurrence Handle10.1038/sj.bjc.6602652

    Article  PubMed  CAS  Google Scholar 

  57. DH Lee JY Han HG Lee et al. (2005) ArticleTitleGefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers Clin Cancer Res 11 3032–3037 Occurrence Handle15837758 Occurrence Handle1:CAS:528:DC%2BD2MXjtlejtLc%3D Occurrence Handle10.1158/1078-0432.CCR-04-2149

    Article  PubMed  CAS  Google Scholar 

  58. XT Zhang LY Li XL Mu et al. (2005) ArticleTitleThe EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer Ann Oncol 16 1334–1342 Occurrence Handle15956035 Occurrence Handle10.1093/annonc/mdi340

    Article  PubMed  Google Scholar 

  59. M Tokumo S Toyooka K Kiura et al. (2005) ArticleTitleThe relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers Clin Cancer Res 11 1167–1173 Occurrence Handle15709185 Occurrence Handle1:CAS:528:DC%2BD2MXht1ynt7c%3D

    PubMed  CAS  Google Scholar 

  60. W Pao V Miller M Zakowski et al. (2004) ArticleTitleEGF 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 USA 101 13306–13311 Occurrence Handle15329413 Occurrence Handle1:CAS:528:DC%2BD2cXnvFems70%3D Occurrence Handle10.1073/pnas.0405220101

    Article  PubMed  CAS  Google Scholar 

  61. SH Yang LE Mechanic P Yang et al. (2005) ArticleTitleMutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer Clin Cancer Res 11 2106–2110 Occurrence Handle15788655 Occurrence Handle1:CAS:528:DC%2BD2MXisFajtbw%3D Occurrence Handle10.1158/1078-0432.CCR-04-1853

    Article  PubMed  CAS  Google Scholar 

  62. YH Soung JW Lee SY Kim et al. (2005) ArticleTitleMutational analysis of EGFR and K-RAS genes in lung adenocarcinomas Virchows Arch 446 483–488 Occurrence Handle15815931 Occurrence Handle1:CAS:528:DC%2BD2MXksl2gsro%3D Occurrence Handle10.1007/s00428-005-1254-y

    Article  PubMed  CAS  Google Scholar 

  63. BM Qin X Chen JD Zhu et al. (2005) ArticleTitleIdentification of EGFR kinase domain mutations among lung cancer patients in China: implication for targeted cancer therapy Cell Res 15 212–217 Occurrence Handle15780185 Occurrence Handle1:CAS:528:DC%2BD2MXksFynsr8%3D Occurrence Handle10.1038/sj.cr.7290289

    Article  PubMed  CAS  Google Scholar 

  64. TY Chou CH Chiu LH Li et al. (2005) ArticleTitleMutation 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 Occurrence Handle15897572 Occurrence Handle1:CAS:528:DC%2BD2MXktFyrtLc%3D Occurrence Handle10.1158/1078-0432.CCR-04-1981

    Article  PubMed  CAS  Google Scholar 

  65. M Sonobe T Manabe H Wada et al. (2005) ArticleTitleMutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma Br J Cancer 93 355–363 Occurrence Handle16052218 Occurrence Handle1:CAS:528:DC%2BD2MXmvFensLY%3D Occurrence Handle10.1038/sj.bjc.6602707

    Article  PubMed  CAS  Google Scholar 

  66. XL Mu LY Li XT Zhang et al. (2005) ArticleTitleGefitinib-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 Occurrence Handle15958609 Occurrence Handle1:CAS:528:DC%2BD2MXltFelurY%3D Occurrence Handle10.1158/1078-0432.CCR-04-2506

    Article  PubMed  CAS  Google Scholar 

  67. Y Tomizawa H Iijima N Sunaga et al. (2005) ArticleTitleClinicopathologic significance of the mutations of the epidermal growth factor receptor gene in patients with non-small cell lung cancer Clin Cancer Res 11 6816–6822 Occurrence Handle16203769 Occurrence Handle1:CAS:528:DC%2BD2MXhtVKiur3K Occurrence Handle10.1158/1078-0432.CCR-05-0441

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery and Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Tetsuya Mitsudomi, Takayuki Kosaka & Yasushi Yatabe

Authors
  1. Tetsuya Mitsudomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayuki Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasushi Yatabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuya Mitsudomi.

About this article

Cite this article

Mitsudomi, T., Kosaka, T. & Yatabe, Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 11, 190–198 (2006). https://doi.org/10.1007/s10147-006-0583-4

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-006-0583-4

Key words

Search

Navigation