The pharmacogenetic rescue of side-lined anticancer drugs to the front-line: Gefitinib as a case example

Annals of Pharmacotherapy

Volumn 45, Issue 2, 2011, Pages 263-275

  Li Wan Po, Alain ^a   Farndon, Peter A ^b   Kobayashi, Susumu ^c   Mitsudomi, Tetsuya ^d   Potter, Vanessa A ^e,f  

^a BIRMINGHAM WOMEN S HOSPITAL   (United Kingdom)

^b National Genetics Education and Development Centre   (United States)

^c HARVARD MEDICAL SCHOOL   (United States)

^d AICHI CANCER CENTER HOSPITAL   (Japan)

^e City Hospital   (United States)

^f NOTTINGHAM UNIVERSITY HOSPITALS NHS TRUST   (United Kingdom)

Author keywords

Non small cell lung cancer; Personalized medicine; Pharmacogenomics; Stratified medicine; Targeted therapy

Indexed keywords

CARBOPLATIN; CISPLATIN; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR; ETOPOSIDE; GEFITINIB; GEMCITABINE; IMATINIB; PACLITAXEL; PROTEIN TYROSINE KINASE INHIBITOR; ANTINEOPLASTIC AGENT; EGFR PROTEIN, HUMAN; QUINAZOLINE DERIVATIVE;

ACNE; ADVANCED CANCER; ANEMIA; ANOREXIA; ASTHENIA; CANCER COMBINATION CHEMOTHERAPY; CANCER RADIOTHERAPY; CANCER SURVIVAL; CLINICAL PRACTICE; DIARRHEA; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG ERUPTION; DRUG MARKETING; DRUG TARGETING; GASTROINTESTINAL STROMAL TUMOR; GENE MUTATION; GENETIC TRANSCRIPTION; HUMAN; INTERSTITIAL LUNG DISEASE; LEUKOPENIA; LUNG NON SMALL CELL CANCER; MEDLINE; MYELOID LEUKEMIA; NAUSEA; NEUROPATHY; NEUTROPENIA; PHARMACOGENETICS; PRESCRIPTION; PRIORITY JOURNAL; PROSPECTIVE STUDY; RETROSPECTIVE STUDY; REVIEW; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; VOMITING; ANTAGONISTS AND INHIBITORS; CARCINOMA, NON-SMALL-CELL LUNG; DRUG RESISTANCE; GENETICS; LUNG NEOPLASMS; MUTATION; PHASE 3 CLINICAL TRIAL (TOPIC); RISK ASSESSMENT; TECHNOLOGY;

ANTINEOPLASTIC AGENTS; CARCINOMA, NON-SMALL-CELL LUNG; CLINICAL TRIALS, PHASE III AS TOPIC; DRUG RESISTANCE, NEOPLASM; HUMANS; LUNG NEOPLASMS; MUTATION; PROSPECTIVE STUDIES; QUINAZOLINES; RECEPTOR, EPIDERMAL GROWTH FACTOR; RETROSPECTIVE STUDIES; RISK ASSESSMENT; TECHNOLOGY TRANSFER;

EID: 79951933598     PISSN: 10600280     EISSN: None     Source Type: Journal    
DOI: 10.1345/aph.1P496     Document Type: Review

References (103)

1. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593-603. (Pubitemid 35315841)
2. Croce CM. Oncogenes and cancer. N Engl J Med 2008;358:502-11. (Pubitemid 351185806)
3. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-17. (Pubitemid 44903745)
4. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001;344:1038-42. (Pubitemid 32267973)
5. Novartis Annual Report, Basel, Switzerland, 20-F-2009.
6. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711-5.
7. Service RF. Surviving the blockbuster syndrome. Science 2004;303:1796-9. (Pubitemid 38374862)
8. Thatcher N, Chang A, Parikh P, et al. Gefitinib 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 2005;366:1527-37. (Pubitemid 41540110)
9. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962;237:1555-62.
10. Sporn MB, Todaro GJ. Autocrine secretion and malignant transformation of cells. N Engl J Med 1980;303:878-80.
11. Cohen S, Carpenter G, King L Jr. Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J Biol Chem 1980;255:4834-42.
12. Yarden Y, Schlessinger J. Self-phosphorylation of epidermal growth factor receptor: evidence for a model of intermolecular allosteric activation. Biochemistry 1987;26:1434-1442. (Pubitemid 17045874)
13. Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 2006;125:1137-49. (Pubitemid 43866200)
14. Jura N, Endres NF, Engel K, et al. Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell 2009;137:1293-307.
15. Hubbard SR. The juxtamembrane region of EGFR takes center stage. Cell 2009;137:1181-83.
16. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A 2010;107:7692-7.
17. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev 2010;29:37-48.
18. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70. (Pubitemid 30046295)
19. Mendelsohn J. Blockade of receptors for growth factors: an anticancer therapy - the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res 2000;6:747-53. (Pubitemid 30159326)
20. Herbst RS, Fukuoka M, Baselga J. Gefitinib - a novel targeted approach to treating cancer. Nat Rev Cancer 2004;4:956-65. (Pubitemid 39626219)
21. Blackledge G, Averbuch S. Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer 2004;90:566-72. (Pubitemid 38297191)
22. 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;21:2237-46. (Pubitemid 46621858)
23. 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;290:2149-58. (Pubitemid 37432975)
24. 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;22:777-84. (Pubitemid 41103588)
25. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial - INTACT 2. J Clin Oncol 2004;22:785-94. (Pubitemid 41103589)
26. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003;361:137-9. (Pubitemid 36092019)
27. Approval package for application number 21-399 Approval letter. Rockville, MD: Food and Drug Administration, Center for Drug Evaluation and Research, May 5, 2003.
28. AstraZeneca. ODAC briefing document Iressa (gefitinib) tablets. January 31, 2005.
29. Report of the Oncologic Drugs Advisory Committee meeting. Rockville, MD: Food and Drug Administration, March 4, 2005.
30. 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;350:2129-39. (Pubitemid 38637993)
31. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. (Pubitemid 38720929)
32. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-44. (Pubitemid 41058345)
33. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32. (Pubitemid 41058344)
34. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 2006;24:5034-42. (Pubitemid 46631407)
35. 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;372:1809-18.
36. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957.
37. European Medicines Agency. Assessment report for Iressa EMEA/H/C/001016. London 2009.
38. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744-52.
39. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
40. European Medicines Agency. Iressa gefitinib EPAR summary for the public EMEA/280173/2009 EMEA/H/C/1016 2009.
41. Kobayashi K, Inoue A, Maemondo M, et al. First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: a phase III study (002) by North East Japan Gefitinib Study Group. J Clin Oncol 2009;27:15s.
42. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;118:257-62. (Pubitemid 41779062)
43. Riely GJ, Politi KA, Miller VA, Pao W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res 2006;12:7232-41. (Pubitemid 46095394)
44. 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;352:786-92. (Pubitemid 40271173)
45. 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.
46. 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;12:6494-501. (Pubitemid 44799723)
47. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 2006;12:5764-9. (Pubitemid 44629607)
48. Fukui T, Mitsudomi T. Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancers. Gen Thorac Cardiovasc Surg 2008;56:97-103. (Pubitemid 351419126)
49. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-51.
50. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet 2007;370:342-50. (Pubitemid 47094995)
51. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet 2007;369:1731-41. (Pubitemid 46778870)
52. Bean J, Riely GJ, Balak M, et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 2008;14:7519-25.
53. Toyooka S, Date H, Uchida A, Kiura K, Takata M. The epidermal growth factor receptor D761Y mutation and effect of tyrosine kinase inhibitor (letter). Clin Cancer Res 2007;13:3431; author reply 3431-2.
54. Tokumo M, Toyooka S, Ichihara S, et al. Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. Lung Cancer 2006;53:117-21. (Pubitemid 43831366)
55. Costa DB, Schumer ST, Tenen DG, Kobayashi S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol 2008;26:1182-4; author reply 1184-6.
56. 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;10:281-9.
57. 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;26:2442-9.
58. Maheswaran S, Sequist LV, Nagrath S, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 2008;359:366-77.
59. Toyooka S, Kiura K, Mitsudomi T. EGFR mutation and response of lung cancer to gefitinib. N Engl J Med 2005;352:2136. (Pubitemid 40664319)
60. Ushiki A, Koizumi T, Kobayashi N, et al. Genetic heterogeneity of EGFR mutation in pleomorphic carcinoma of the lung: response to gefitinib and clinical outcome. Jpn J Clin Oncol 2009;39:267-70.
61. Mahadevan D, Cooke L, Riley C, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 2007;26:3909-19.
62. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43. (Pubitemid 46799492)
63. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 2007;104:20932-7.
64. Guo A, Villen J, Kornhauser J, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A 2008;105:692-7. (Pubitemid 351171770)
65. 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.
66. Murray S, Dahabreh IJ, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P. Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol 2008;3:832-9.
67. 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;64:8919-23. (Pubitemid 39665498)
68. Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-75.
69. Suda K, Tomizawa K, Mitsudomi T. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev 2010;29:49-60.
70. Liu G, Gurubhagavatula S, Zhou W, et al. Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib. Pharmacogenomics J 2007;8:129-38.
71. Carlson JJ, Garrison LP, Ramsey SD, Veenstra DL. Epidermal growth factor receptor genomic variation in NSCLC patients receiving tyrosine kinase inhibitor therapy: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2009;135:1483-93.
72. Higgins JP. Commentary: heterogeneity in meta-analysis should be expected and appropriately quantified. Int J Epidemiol 2008;37:1158-60.
73. Higgins J, Thompson S, Deeks J, Altman D. Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. J Health Serv Res Policy 2002;7:51-61. (Pubitemid 34041777)
74. Nomura M, Shigematsu H, Li L, et al. Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers. PLoS Med 2007;4:e125.
75. Liu W, Innocenti F, Chen P, Das S, Cook EH Jr, Ratain MJ. Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. Clin Cancer Res 2003;9:1009-12. (Pubitemid 36323704)
76. 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;274:13176-80.
77. 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;37:1315-6. (Pubitemid 41722184)
78. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8.
79. Wheatley-Price P, Shepherd FA. Epidermal growth factor receptor inhibitors in the treatment of lung cancer: reality and hopes. Curr Opin Oncol 2008;20:162-75. (Pubitemid 351317404)
80. Tsurutani JMT, Mori S, Okamoto I, Nozaki K, Tada H. A phase III, firstline trial of gefitinib versus cisplatin plus docetaxel for patients with advanced or recurrent non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growth factor receptor (EGFR) gene: a preliminary result of WJTOG 3405 (abstract O -9002). Eur J Cancer 2009;7(suppl):505.
81. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist 2009;14:253-63.
82. Marks JL, Broderick S, Zhou Q, et al. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol 2008;3:111-6. (Pubitemid 351323183)
83. 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;23:2513-20. (Pubitemid 47050841)
84. Shepherd FA, Tsao MS. Epidermal growth factor receptor biomarkers in non-small-cell lung cancer: a riddle, wrapped in a mystery, inside an enigma. J Clin Oncol 2010;28:903-5.
85. Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 2009;28:3801-13.
86. Huo L, Wang YN, Xia W, et al. RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 2010;107:16125-30.
87. Xia W, Wei Y, Du Y, et al. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer. Mol Carcinog 2009;48:610-17.
88. Mosesson Y, Mills GB, Yarden Y. Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 2008;8:835-50.
89. Public Citizen. Petition to the FDA to remove the cancer drug gefitinib (IRESSA) from the market (HRG Publication #1728). http://www.citizen.org/Page. aspx?pid=3145. 2005 March 4 (accessed 2011 Feb 3).
90. Public Citizen. Letter to FDA expressing concerns about the pending approval of the cancer drug gefitinib (IRESSA) (HRG Publication #1665). http://www.citizen.org/hrg1665. 2003 May 1 (accessed 2011 Feb 3).
91. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26:2450-6.
92. National Cancer Institute. Clinical trial of gefitinib for advanced lung cancer closes early. http://www.cancer.gov/newscenter/pressreleases/2005/ gefitinibNSCLC. 2005 April 18 (accessed 2011 Feb 3).
93. Public Citizen. Supplement to petition to the FDA to withdraw the lung cancer drug gefitinib (Iressa) from the market (HRG Publication #1739). http://www.citizen.org/hrg1739. 2005 April 28 (accessed 2011 Feb 3).
94. Washington Legal Foundation. Comments of the Washington Legal Foundation, Abigail Alliance for better access to developmental drugs, and Lorenzen Cancer Foundation. http://www.fda.gov/ohrms/dockets/dockets/05p0094/05P-0094-emc- 000002-01.pdf. 2005 April 20 (accessed 2011 Feb 3).
95. Prescrire. Toujours pas de resultat probant dans le cancer du poumon non a petites cellules. La Revure Prescrire 2010;30:175-6.
96. Shepherd FA, Tsao MS. Epidermal growth factor receptor biomarkers in non-small-cell lung cancer: a riddle, wrapped in a mystery, inside an enigma. J Clin Oncol 2010;28:903-5.
97. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer 2009;9:463-75.
98. Li Wan Po A. Personalised medicine: who is an Asian? Lancet 2007; 369: 1770-1.
99. National Institute for Health and Clinical Excellence. Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer. London: NICE, July 2010.
100. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol 2001;19:1734-42. (Pubitemid 32230875)
101. Takano T, Ohe Y, Kusumoto M, et al. Risk 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 2004;45:93-104. (Pubitemid 38757837)
102. Varmus H. Ten years on - the human genome and medicine. N Engl J Med 2010;362:2028-9.
103. Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market? Pharmacogenomics 2006;7:889-908.