Molecular pathology of lung cancer: Key to personalized medicine

Modern Pathology

Volumn 25, Issue 3, 2012, Pages 347-369

  Cheng, Liang ^a   Alexander, Riley E ^a   MacLennan, Gregory T ^b   Cummings, Oscar W ^a   Montironi, Rodolfo ^b   Lopez Beltran, Antonio ^c,d   Cramer, Harvey M ^a   Davidson, Darrell D ^a   Zhang, Shaobo ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CASE WESTERN RESERVE UNIVERSITY   (United States)

^c UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

^d UNIVERSITY OF CÓRDOBA   (Spain)

Author keywords

EML4 ALK rearrangement; epidermal growth factor receptor (EGFR); KRAS mutation; lung adenocarcinoma; molecular classification; personalized medicine; targeted therapy

Indexed keywords

B RAF KINASE; CETUXIMAB; CRIZOTINIB; ENDOTHELIAL CELL GROWTH FACTOR; ERLOTINIB; EXCISION REPAIR CROSS COMPLEMENTING PROTEIN 1; GEFITINIB; K RAS PROTEIN; MONOCLONAL ANTIBODY; PANITUMUMAB; PROTEIN TYROSINE KINASE INHIBITOR; SCATTER FACTOR RECEPTOR; TUMOR MARKER; UNCLASSIFIED DRUG; WZ 4002;

ARTICLE; COPY NUMBER VARIATION; DRUG RESISTANCE; GENE AMPLIFICATION; GENE MUTATION; GENE OVEREXPRESSION; GENE REARRANGEMENT; GENETIC ASSOCIATION; HUMAN; LUNG ADENOCARCINOMA; LUNG CANCER; MOLECULAR PATHOLOGY; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); WILD TYPE;

ADENOCARCINOMA; ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; HUMANS; INDIVIDUALIZED MEDICINE; LUNG NEOPLASMS; MOLECULAR DIAGNOSTIC TECHNIQUES; MUTATION; PROTEIN KINASE INHIBITORS; RECEPTOR, EPIDERMAL GROWTH FACTOR; TUMOR MARKERS, BIOLOGICAL;

EID: 84862823259     PISSN: 08933952     EISSN: 15300285     Source Type: Journal    
DOI: 10.1038/modpathol.2011.215     Document Type: Article

References (244)

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90.
2. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212-236.
3. Ettinger DS, AkerleyW, Bepler G, et al. Non-small cell lung cancer: clinical practice guidelines in oncology. J Natl Compr Canc Netw 2011;8:740-801.
4. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6: 244-285.
5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
6. 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;350:2129-2139.
7. 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 USA 2004;101:13306-13311.
8. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in nonsmall-cell lung cancer. Nature 2007;448:561-566.
9. Pao W, Girard N. New driver mutations in non-smallcell lung cancer. Lancet Oncol 2011;12:175-180.
10. Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005;23:8081-8092.
11. 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;23:5900-5909.
12. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-181.
13. Cheng L, Zhang S, Alexander R, et al. The landscape of EGFR pathways and personalized management of nonsmall-cell lung cancer. Future Oncol 2011;7:519-541.
14. Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008;358:1160-1174.
15. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-774.
16. Cheng L, Zhang D. Molecular Genetic Pathology. Humana Press/Springer: New York, New York, 2008.
17. Wang X, Zhang S, MacLennan GT, et al. Epidermal growth factor receptor protein expression and gene amplification in small cell carcinoma of the urinary bladder. Clin Cancer Res 2007;13:953-957.
18. Marks RA, Zhang S, Montironi R, et al. Epidermal growth factor receptor (EGFR) expression in prostatic adenocarcinoma after hormonal therapy: a fluorescence in situ hybridization and immunohistochemical analysis. Prostate 2008;68:919-923.
19. Wang X, Zhang S, Maclennan GT, et al. Epidermal growth factor receptor protein expression and gene amplification in the chemorefractory metastatic embryonal carcinoma. Mod Pathol 2009;22:7-12.
20. Cohen EE, Davis DW, Karrison TG, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 2009;10:247-257.
21. Wang X, Jones TD, Zhang S, et al. Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate. Mod Pathol 2007;20:175-182.
22. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol 2011;29:2121-2127.
23. Sholl LM, Xiao Y, Joshi V, et al. EGFR mutation is a better predictor of response to tyrosine kinase inhibitors in non-small cell lung carcinoma than FISH, CISH, and immunohistochemistry. Am J Clin Pathol 2010;133:922-934.
24. 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;23:2556-2568.
25. 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;97:643-655.
26. Kosaka T, Yatabe Y, Endoh H, et al. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004;64:8919-8923.
27. 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;23:857-865.
28. 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: 2513-2520.
29. 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;23:6829-6837.
30. Hirsch FR, Herbst RS, Olsen C, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008;26:3351-3357.
31. Dahabreh IJ, Linardou H, Siannis F, et al. Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2010;16:291-303.
32. Sholl LM, John Iafrate A, Chou YP, et al. Validation of chromogenic in situ hybridization for detection of EGFR copy number amplification in nonsmall cell lung carcinoma. Mod Pathol 2007;20:1028-1035.
33. Yamamoto H, Toyooka S, Mitsudomi T. Impact of EGFR mutation analysis in non-small cell lung cancer. Lung Cancer 2009;63:315-321.
34. Tamura K, Okamoto I, Kashii T, et al. Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer 2008;98:907-914.
35. Lurje G, Lenz HJ. EGFR signaling and drug discovery. Oncology 2009;77:400-410.
36. Okabe T, Okamoto I, Tamura K, et al. Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res 2007;67:2046-2053.
37. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-2970.
38. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011;29: 2866-2874.
39. 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;23:2493-2501.
40. Reck M. A major step towards individualized therapy of lung cancer with gefitinib: the IPASS trial and beyond. Expert Rev Anticancer Ther 2011;10: 955-965.
41. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957.
42. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008;372:1809-1818.
43. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-742.
44. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with nonsmall-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-128.
45. O'Byrne KJ, Gatzemeier U, Bondarenko I, et al. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011;12:795-805.
46. Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase trial. Lancet Oncol 2010;11:619-626.
47. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 2010;11: 521-529.
48. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-2388.
49. Reiter JL, Threadgill DW, Eley GD, et al. Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms. Genomics 2001;71:1-20.
50. Strausberg RL, Feingold EA, Grouse LH, et al. Generation and initial analysis of more than 15 000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA 2002;99:16899-16903.
51. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-354.
52. Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2-16.
53. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-1043.
54. Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer-is it becoming a reality? Nat Rev Clin Oncol 2010;8:384.
55. Linardou H, Dahabreh IJ, Bafaloukos D, et al. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol 2009;6:352-366.
56. Yoon YK, Kim HP, Han SW, et al. KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: implication for combinatorial approach. Mol Carcinog 2010;49:353-362.
57. 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;97:339-346.
58. Sordella R, Bell DW, Haber DA, et al. Gefitinib-sensitizing EGFR mutations in lung cancer activate antiapoptotic pathways. Science 2004;305:1163-1167.
59. Roberts PJ, Stinchcombe TE, Der CJ, et al. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 2010;28:4769-4777.
60. Singh M, Lima A, Molina R, et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 2010;28:585-593.
61. Benesova L, Minarik M, Jancarikova D, et al. Multiplicity of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors. Anticancer Res 2010;30: 1667-1671.
62. Siena S, Sartore-Bianchi A, Di Nicolantonio F, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 2009;101: 1308-1324.
63. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.
64. Riely GJ, Politi KA, Miller VA, et al. Update on epidermal growth factor receptor mutations in nonsmall cell lung cancer. Clin Cancer Res 2006; 12:7232-7241.
65. Zhou W, Ercan D, Janne PA, et al. Discovery of selective irreversible inhibitors for EGFR-T790M. Bioorg Med Chem Lett 2011;21:638-643.
66. Penzel R, Sers C, Chen Y, et al. EGFR mutation detection in NSCLC-assessment of diagnostic application and recommendations of the German Panel for Mutation Testing in NSCLC. Virchows Arch 2011;458: 95-98.
67. Wu JY, Wu SG, Yang CH, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res 2008;14:4877-4882.
68. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-2449.
69. Kumar A, Petri ET, Halmos B, et al. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol 2008; 26:1742-1751.
70. Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494-6501.
71. Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009;28(Suppl 1):S24-S31.
72. Wang X, Wang M, MacLennan GT, et al. Evidence for common clonal origin of multifocal lung cancers. J Natl Cancer Inst 2009;101:560-570.
73. Weber F, Fukino K, Villalona-Calero M, et al. Limitations of single-strand conformation polymorphism analysis as a high-throughput method for the detection of EGFR mutations in the clinical setting. J Clin Oncol 2005;23:5847-5849.
74. Willmore-Payne C, Holden JA, Layfield LJ. Detection of epidermal growth factor receptor and human epidermal growth factor receptor 2 activating mutations in lung adenocarcinoma by high-resolution melting amplicon analysis: correlation with gene copy number, protein expression, and hormone receptor expression. Hum Pathol 2006;37:755-763.
75. Takano T, Ohe Y, Tsuta K, et al. Epidermal growth factor receptor mutation detection using high-resolution melting analysis predicts outcomes in patients with advanced non small cell lung cancer treated with gefitinib. Clin Cancer Res 2007;13:5385-5390.
76. Fukui T, Ohe Y, Tsuta K, et al. Prospective study of the accuracy of EGFR mutational analysis by highresolution melting analysis in small samples obtained from patients with non-small cell lung cancer. Clin Cancer Res 2008;14:4751-4757.
77. Nomoto K, Tsuta K, Takano T, et al. Detection of EGFR mutations in archived cytologic specimens of nonsmall cell lung cancer using high-resolution melting analysis. Am J Clin Pathol 2006;126:608-615.
78. Hoshi K, Takakura H, Mitani Y, et al. Rapid detection of epidermal growth factor receptor mutations in lung cancer by the SMart-Amplification Process. Clin Cancer Res 2007;13:4974-4983.
79. Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2011;29: (Suppl, abstract CRA 7506).
80. Janne PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 2006; 12:4416s-4420s.
81. Ji H. Mechanistic insights into acquired drug resistance in epidermal growth factor receptor mutationtargeted lung cancer therapy. Cancer Sci 2010;101: 1933-1938.
82. Shih JY, Gow CH, Yang PC. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer. N Engl J Med 2005;353:207-208.
83. Toyooka S, Kiura K, Mitsudomi T. EGFR mutation and response of lung cancer to gefitinib. N Engl J Med 2005;352:2136.
84. Hammerman PS, Janne PA, Johnson BE. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2009;15:7502-7509.
85. Jackman DM, Miller VA, Cioffredi LA, et al. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials. Clin Cancer Res 2009;15:5267-5273.
86. West H, Lilenbaum R, Harpole D, et al. Molecular analysis-based treatment strategies for the management of non-small cell lung cancer. J Thorac Oncol 2009;4:S1029-S1039; quiz S1041-S1042.
87. Rosell R, Taron M, Reguart N, et al. Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clin Cancer Res 2006;12:7222-7231.
88. Pao W, Miller VA, Venkatraman E, et al. Predicting sensitivity of non-small-cell lung cancer to gefitinib: is there a role for P-Akt? J Natl Cancer Inst 2004;96:1117-1119.
89. Sugawa N, Ekstrand AJ, James CD, et al. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci USA 1990;87: 8602-8606.
90. Pedersen MW, Meltorn M, Damstrup L, et al. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anticancer therapy. Ann Oncol 2001;12:745-760.
91. Antonyak MA, Moscatello DK, Wong AJ. Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem 1998;273:2817-2822.
92. Chu CT, Everiss KD, Wikstrand CJ, et al. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 1997;324:855-861.
93. Huang HS, Nagane M, Klingbeil CK, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 1997;272:2927-2935.
94. Frederick L, Wang XY, Eley G, et al. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000;60: 1383-1387.
95. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353: 2012-2024.
96. Li B, Yuan M, Kim IA, et al. Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 2004;23:4594-4602.
97. Sasaki H, Kawano O, Endo K, et al. EGFRvIII mutation in lung cancer correlates with increased EGFR copy number. Oncol Rep 2007;17:319-323.
98. Ji H, Zhao X, Yuza Y, et al. Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. Proc Natl Acad Sci USA 2006;103:7817-7822.
99. Ohtsuka K, Ohnishi H, Fujiwara M, et al. Abnormalities of epidermal growth factor receptor in lung squamous-cell carcinomas, adenosquamous carcinomas, and large-cell carcinomas: tyrosine kinase domain mutations are not rare in tumors with an adenocarcinoma component. Cancer 2007;109:741-750.
100. Li D, Ji H, Zaghlul S, et al. Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant-dependent lung carcinomas. J Clin Invest 2007;117:346-352.
101. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-144.
102. Hirsch FR, Varella-Garcia M, Bunn Jr 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;21:3798-3807.
103. Awaya H, Takeshima Y, Furonaka O, et al. Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung. J Clin Pathol 2005;58:1076-1080.
104. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6:279-286.
105. Hoff K, Jorgensen JT, Muller S, et al. Visualization of FISH Probes by dual-color chromogenic in situ hybridization. Am J Clin Pathol 2010;133:205-211.
106. Scagliotti GV, Selvaggi G, Novello S, et al. The biology of epidermal growth factor receptor in lung cancer. Clin Cancer Res 2004;10:4227s-4232s.
107. Khambata-Ford S, Harbison CT, Hart LL, 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-smallcell lung cancer. J Clin Oncol 2010;28:918-927.
108. Scartozzi M, Bearzi I, Berardi R, et al. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 2004;22:4772-4778.
109. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23:1803-1810.
110. Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 2010;7:493-507.
111. Li AR, Chitale D, Riely GJ, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn 2008; 10:242-248.
112. Endoh H, Ishibashi Y, Yamaki E, et al. Immunohistochemical analysis of phosphorylated epidermal growth factor receptor might provide a surrogate marker of EGFR mutation. Lung Cancer 2009;63: 241-246.
113. Hijiya N, Miyawaki M, Kawahara K, et al. Phosphorylation status of epidermal growth factor receptor is closely associated with responsiveness to gefitinib in pulmonary adenocarcinoma. Hum Pathol 2008;39: 316-323.
114. Yu J, Kane S, Wu J, et al. Mutation-specific antibodies for the detection of EGFR mutations in non-small-cell lung cancer. Clin Cancer Res 2009;15:3023-3028.
115. Brevet M, Arcila M, Ladanyi M. Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. J Mol Diagn 2010;12: 169-176.
116. Zhang Z, Stiegler AL, Boggon TJ, et al. EGFR-mutated lung cancer: a paradigm of molecular oncology. Oncotarget 2010;1:497-514.
117. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
118. Vakiani E, Solit DB. KRAS and BRAF: drug targets and predictive biomarkers. J Pathol 2011;223:219-229.
119. Sun L, Zhang Q, Luan H, et al. Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice. J Exp Clin Cancer Res 2011;30:30.
120. Paez D, Pare L, Espinosa I, et al. Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFRbased therapy? Cancer Sci 2011;101:2048-2053.
121. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2011;69:272-278.
122. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010;17:77-88.
123. Toschi L, Cappuzzo F. Clinical implications of MET gene copy number in lung cancer. Future Oncol 2011;6:239-247.
124. Suda K, Murakami I, Katayama T, et al. Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin Cancer Res 2011;16:5489-5498.
125. McDermott U, Pusapati RV, Christensen JG, et al. Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res 2011;70:1625-1634.
126. Tiseo M, Gelsomino F, Boggiani D, et al. EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011;71:241-243.
127. Murakami S, Yokose T, Saito H, et al. Recurrent EML4-ALK-associated lung adenocarcinoma with a slow clinical course. Lung Cancer 2011;69:361-364.
128. Normant E, Paez G, West KA, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene 2010;30:2581-2586.
129. Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med 2010;363:1734-1739.
130. Barton S, Starling N, Swanton C. Predictive molecular markers of response to epidermal growth factor receptor (EGFR) family-targeted therapies. Curr Cancer Drug Targets 2010;10:799-812.
131. van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One 2011;6:e17791.
132. De Roock W, Claes B, Bernasconi D, 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 2010;11:753-762.
133. Schmid K, Oehl N, Wrba F, et al. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res 2009;15:4554-4560.
134. Nguyen KS, Kobayashi S, Costa DB. Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway. Clin Lung Cancer 2009;10:281-289.
135. Morgillo F, Kim WY, Kim ES, et al. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res 2007;13:2795-2803.
136. Miyamae Y, Shimizu K, Hirato J, et al. Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma. Oncol Rep 2011;25: 921-928.
137. Tochigi N, Dacic S, Nikiforova M, et al. Adenosquamous carcinoma of the lung: a microdissection study of KRAS and EGFR mutational and amplification status in a western patient population. Am J Clin Pathol 2011;135:783-789.
138. Ladanyi M, Pao W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008;21(Suppl 2):S16-S22.
139. Chen C, Jiang XL, Zhang CC, et al. Correlation of genes associated with drug response to prognosis of large cell lung carcinoma. Chin J Cancer 2011;30: 497-504.
140. De Pas TM, Giovannini M, Manzotti M, et al. Largecell neuroendocrine carcinoma of the lung harboring EGFR mutation and responding to Gefitinib. J Clin Oncol 2011;29:e819-e822.
141. Jiang X, Liu Y, Chen C, et al. The value of biomarkers in patients with sarcomatoid carcinoma of the lung: molecular analysis of 33 cases. Clin Lung Cancer2012. (in press).
142. Hammerman P, Sos ML, Ramos A, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 2011;1:78-89.
143. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011;8:381-385.
144. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994;263:1281-1284.
145. Palmer RH, Vernersson E, Grabbe C, et al. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J 2009;420:345-361.
146. Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11-23.
147. Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and nontumor lung tissues. Am J Pathol 2009;174:661-670.
148. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-4253.
149. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol 2009;22:508-515.
150. Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol 2008;3:13-17.
151. Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011;17: 2081-2086.
152. Horn L, Sandler A. Epidermal growth factor receptor inhibitors and antiangiogenic agents for the treatment of non-small cell lung cancer. Clin Cancer Res 2009;15:5040-5048.
153. Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009; 27:4232-4235.
154. Takeuchi K, Choi YL, Togashi Y, et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009;15:3143-3149.
155. Choi YL, Takeuchi K, Soda M, et al. Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer. Cancer Res 2008;68: 4971-4976.
156. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res 2008;14:6618-6624.
157. Polgar D, Leisser C, Maier S, et al. Truncated ALK derived from chromosomal translocation t(2;5) (p23;q35) binds to the SH3 domain of p85-PI3K. Mutat Res 2005;570:9-15.
158. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst 2010;102:672-675.
159. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer 2009;115:1723-1733.
160. Zhang X, Zhang S, Yang X, et al. Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol Cancer 2010;9:188.
161. Sasaki T, Rodig SJ, Chirieac LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010;46:1773-1780.
162. Rodig SJ, Mino-Kenudson M, Dacic S, et al. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 2009;15:5216-5223.
163. McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008;68:3389-3395.
164. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res 2011;71:6051-6060.
165. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in nonsmall cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci USA 2011;108: 7535-7540.
166. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12:1004-1012.
167. Just PA, Cazes A, Audebourg A, et al. Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: a comprehensive study of Caucasian non-smokers. Lung Cancer 2012 (in press).
168. McLeer-Florin A, Moro-Sibilot D, Melis A, et al. Dual IHC and FISH testing for ALK gene rearrangement in lung adenocarcinomas in a routine practice: A French Study. J Thorac Oncol 2012 (in press).
169. Jorissen RN, Walker F, Pouliot N, et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 2003;284:31-53.
170. Nicholas MK, Lukas RV, Jafri NF, et al. Epidermal growth factor receptor-mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res 2006;12:7261-7270.
171. Yang XD, Jia XC, Corvalan JR, et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 1999;59: 1236-1243.
172. Kawamoto T, Sato JD, Le A, et al. 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 USA 1983;80:1337-1341.
173. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
174. Hinoda Y, Sasaki S, Ishida T, et al. Monoclonal antibodies as effective therapeutic agents for solid tumors. Cancer Sci 2004;95:621-625.
175. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445-2459.
176. 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;290:2149-2158.
177. Tam IY, Leung EL, Tin VP, et al. Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations. Mol Cancer Ther 2009;8:2142-2151.
178. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008;359:366-377.
179. Bell DW, Gore I, Okimoto RA, et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005;37:1315-1316.
180. Ercan D, Zejnullahu K, Yonesaka K, et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010;29: 2346-2356.
181. Hopper-Borge EA, Nasto RE, Ratushny V, et al. Mechanisms of tumor resistance to EGFR-targeted therapies. Expert Opin Ther Targets 2009;13:339-362.
182. 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;352:786-792.
183. Eberhard DA, Giaccone G, Johnson BE. Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 2008;26:983-994.
184. Okamoto K, Okamoto I, Okamoto W, et al. Role of survivin in EGFR inhibitor-induced apoptosis in nonsmall cell lung cancers positive for EGFR mutations. Cancer Res 2011;70:10402-10410.
185. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011;17:1616-1622.
186. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyro-sine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2008;14:2895-2899.
187. Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol 2010;28:357-360.
188. Govindan R. A review of epidermal growth factor receptor/HER2 inhibitors in the treatment of patients with non-small-cell lung cancer. Clin Lung Cancer 2010;11:8-12.
189. Ogino S, Meyerhardt JA, Irahara N, et al. KRAS mutation in stage III colon cancer and clinical outcome following intergroup trial CALGB 89803. Clin Cancer Res 2009;15:7322-7329.
190. Mink SR, Vashistha S, Zhang W, et al. Cancerassociated fibroblasts derived from EGFR-TKI-resistant tumors reverse EGFR pathway inhibition by EGFR-TKIs. Mol Cancer Res 2010;8:809-820.
191. Wang W, Li Q, Yamada T, et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin Cancer Res 2009;15:6630-6638.
192. Lemos C, Jansen G, Peters GJ. Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors. Br J Cancer 2008;98:857-862.
193. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006;24:3340-3346.
194. Krumbach R, Schuler J, Hofmann M, et al. Primary resistance to cetuximab in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. Eur J Cancer 2011;47: 1231-1243.
195. Greulich H, Chen TH, Feng W, et al. Oncogenic transformation by inhibitor-sensitive and-resistant EGFR mutants. PLoS Med 2005;2:e313.
196. 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;12:1647-1653.
197. Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 2006;54:209-215.
198. Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 2009;69:3256-3261.
199. Vivanco I, Rohle D, Versele M, et al. The phosphatase and tensin homolog regulates epidermal growth factor receptor (EGFR) inhibitor response by targeting EGFR for degradation. Proc Natl Acad Sci USA 2010;107:6459-6464.
200. Yamamoto C, Basaki Y, Kawahara A, et al. Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Res 2010;70:8715-8725.
201. Kohno T, Takahashi M, Manda R, et al. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers. Genes Chromosomes Cancer 1998;22:152-156.
202. Soria JC, Lee HY, Lee JI, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002;8:1178-1184.
203. Ellis LM, Hicklin DJ. Resistance to targeted therapies: refining anticancer therapy in the Era of molecular oncology. Clin Cancer Res 2009;15:7471-7478.
204. Harris TJ, McCormick F. The molecular pathology of cancer. Nat Rev Clin Oncol 2010;7:251-265.
205. Thomas RK, Baker AC, Debiasi RM, et al. Highthroughput oncogene mutation profiling in human cancer. Nat Genet 2007;39:347-351.
206. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-1075.
207. Linardou H, Dahabreh IJ, Kanaloupiti D, et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008;9: 962-972.
208. 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:e73.
209. Santis G, Angell R, Nickless G, et al. Screening for EGFR and KRAS mutations in endobronchial ultrasound derived transbronchial needle aspirates in non-small cell lung cancer using COLD-PCR. PLoS One 2010;6:e25191.
210. Reinersman JM, Johnson ML, Riely GJ, et al. Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans. J Thorac Oncol 2011;6: 28-31.
211. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-262.
212. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417: 949-954.
213. Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011;29: 2046-2051.
214. Leicht DT, Balan V, Kaplun A, et al. Raf kinases: function, regulation and role in human cancer. Biochem Biophys Acta 2007;1773:1196-1212.
215. Di Nicolantonio F, Martini M, Molinari F, et al. Wildtype BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 2008;26:5705-5712.
216. Yoon J, Koo KH, Choi KY. MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy. Cancer Res 2011;71:445-453.
217. Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol 2008;32:1317-1321.
218. De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol 2009;131:694-700.
219. Qi J, McTigue MA, Rogers A, et al. Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res 2011;71:1081-1091.
220. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2: 127-137.
221. Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003;22:2812-2822.
222. She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 30-kinase/Akt pathway signaling. Clin Cancer Res 2003;9:4340-4346.
223. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359:1757-1765.
224. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-1380.
225. Engelman JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest 2006;116:2695-2706.
226. Yatabe Y, Matsuo K, Mitsudomi T. Heterogeneous distribution of EGFR mutations is extremely rare in lung adenocarcinoma. J Clin Oncol 2010;29: 2972-2977.
227. Zhou Q, Zhang XC, Chen ZH, et al. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol 2011;29:3316-3321.
228. Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010;141:69-80.
229. Costa DB, Nguyen KS, Cho BC, et al. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res 2008;14:7060-7067.
230. Seki T, Hagiya M, Shimonishi M, et al. Organization of the human hepatocyte growth factor-encoding gene. Gene 1991;102:213-219.
231. Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 2009;27:1667-1674.
232. Beau-Faller M, Ruppert AM, Voegeli AC, et al. MET gene copy number in non-small cell lung cancer: molecular analysis in a targeted tyrosine kinase inhibitor naive cohort. J Thorac Oncol 2008;3: 331-339.
233. Longati P, Bardelli A, Ponzetto C, et al. Tyrosines1234-1235. are critical for activation of the tyrosine kinase encoded by the MET proto-oncogene (HGF receptor). Oncogene 1994;9:49-57.
234. Eder JP, Vande Woude GF, Boerner SA, et al. Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 2009;15:2207-2214.
235. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006;355:983-991.
236. Simon GR, Sharma S, Cantor A, et al. ERCC1 expression is a predictor of survival in resected patients with nonsmall cell lung cancer. Chest 2005;127:978-983.
237. Gandara DR, Grimminger P, Mack PC, et al. Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell lung cancer. J Thorac Oncol 2010;5: 1933-1938.
238. Lee KH, Min HS, Han SW, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer. Lung Cancer 2008;60:401-407.
239. Joerger M, deJong D, Burylo A, et al. Tubuline, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy. Lung Cancer 2011;74:310-317.
240. Gomez-Roca C, Raynaud CM, Penault-Llorca F, et al. Differential expression of biomarkers in primary nonsmall cell lung cancer and metastatic sites. J Thorac Oncol 2009;4:1212-1220.
241. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-132.
242. Yang CH, Yu CJ, Shih JY, et al. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol 2008;26:2745-2753.
243. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005;102:7665-7670.
244. Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res 2011;17:1169-1180.