Mutations in the epidermal growth factor receptor gene and effects of EGFR-tyrosine kinase inhibitors on lung cancers
Current Topics Review Article
First Online: 14 March 2008 Received: 20 September 2007 DOI:
10.1007/s11748-007-0193-8 Cite this article as: Fukui, T. & Mitsudomi, T. Gen Thorac Cardiovasc Surg (2008) 56: 97. doi:10.1007/s11748-007-0193-8 Abstract
Epidermal growth factor receptor (
EGFR) gene mutations are frequent in lung cancer arising in patients of Asian ethnicity, female sex, nonsmokers, and adenocarcinoma histology. About 70% of the patients with EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, whereas only 10% of those without the mutations do so. Therefore, EGFR mutation is being recognized as one of the most reliable predictive factors for treatment using EGFR-TKIs. Another important issue in clinical practice is the fatal interstitial lung disease (ILD) that can develop in patients with gefitinib treatment, especially Asian patients. A nested case-control study recently conducted in Japan identified some risk factors that cause ILD, including age ≥ 55 years, a history of smoking, preexisting ILD, poor performance status, short duration since diagnosis of lung cancer, reduced extent of normal lung on computed tomography, and concurrent cardiac disease. About half of the acquired resistance to EGFR-TKIs that almost always occurs during the course of treatment is caused by a secondary mutation at codon 790 (T790M). EGFR-TKIs are not universally effective for treating lung cancers but are effective in patients with particular genotypes. Therefore, patients who would benefit from EGFR-TKIs therapy should be concentrated in clinical trials. Based on this concept, Phase III clinical trials comparing gefitinib monotherapy with standard platinum-based chemotherapy are currently ongoing for patients with EGFR mutations and lung cancer. Key words Molecular targeted therapy Gefitinib Interstitial lung disease
This review was submitted at the invitation of the editorial committee.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92–98.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 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.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.
Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 2006;11:190–198.
Suzuki H, Takahashi T, Kuroishi T, Suyama M, Ariyoshi Y, Takahashi T, et al. p53 mutations in non-small cell lung cancer in Japan: association between mutations and smoking. Cancer Res 1992;52:734–736.
Ahrendt SA, Decker PA, Alawi EA, Zhu Yr YR, Sanchez-Cespedes M, Yang SC, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001;92:1525–1530.
Mitsudomi T, Oyama T, Nishida K, Ogami A, Osaki T, Sugio K, et al. Loss of heterozygosity at 3p in non-small cell lung cancer and its prognostic implication. Clin Cancer Res 1996;2:1185–1189.
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;64:8919–8923.
Mitsudomi T, Kosaka T, Endoh H, Horio Y, Hida T, Mori S, 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.
Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, 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.
Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, 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.
Okamoto I, Kashii T, Urata Y, Hirashima T, Kudoh S, Ichinose Y, et al. EGFR mutation-based phase II multicenter trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): results of West Japan Thoracic Oncology Group trial (WJTOG0403). J Clin Oncol 2006;7073.
Sutani A, Nagai Y, Udagawa K, Uchida Y, Murayama Y, Tanaka T, et al. Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp. J Clin Oncol 2006;7076.
Inoue A, Suzuki T, Fukuhara T, Maemondo M, Kimura Y, Morikawa N, 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.
Sunaga N, Yanagitani N, Kaira K, Tomizawa Y, Iijima H, Otani Y, et al. Phase II study of the efficacy of gefitinib in patients with non-small cell lung cancer with the EGFR mutations. J Clin Oncol 2006;7183.
Asahina H, Yamazaki K, Kinoshita I, Sukoh N, Harada M, Yokouchi H, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer 2006;95:998–1004.
Paz-Ares L, Sanchez J, García-Velasco A, Massuti B, López-Vivanco G, Provencio M, et al. A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). J Clin Oncol 2006;7020.
Sequist L, Martins R, Spigel D, Grunberg S, Jänne P, McCollum D, et al. iTARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors. J Clin Oncol 2007;7504.
Yoshida K, Yatabe Y, Park JY, Shimizu J, Horio Y, Matsuo K, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol 2007;2:22–28.
Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908–3914.
Han SW, Kim TY, Jeon YK, Hwang PG, Im SA, Lee KH, et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;12:2538–2544.
Cappuzzo F, Ligorio C, Janne PA, Toschi L, Rossi E, Trisolini R, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol 2007;25:2248–2255.
Satouchi M, Negoro S, Funada Y, Urata Y, Shimada T, Yoshimura S, et al. Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib. Br J Cancer 2007;96:1191–1196.
Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, 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.
Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, Brannigan BW, 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.
Kosaka T, Yatabe Y, Onozato R, Mitsudomi T. Prognostic implication of the EGFR gene mutations in a large cohort of Japanese patients with early stage lung adenocarcinoma. J Clin Oncol 2007;7574.
Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, 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.
Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.
Kosaka T, Yatabe Y, Endoh H, Yoshida K, Hida T, Tsuboi M, 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;12:5764–5769.
Toyooka S, Kiura K, Mitsudomi T. EGFR mutation and response of lung cancer to gefitinib. N Engl J Med 2005;352:2136.
Inukai M, Toyooka S, Ito S, Asano H, Ichihara S, Soh J, et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res 2006;66:7854–7858.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039–1043.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–132.
Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, 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;366:1527–1537.
Douilard J, Kim E, Hirsh V, Mok T, Socinski M, Gervais R, et al. Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer pretreated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). J Thorac Oncol 2007;2:S305–S306.
Niho S, Ichinose Y, Tamura T, Yamamoto N, Tsuboi M, K. N, et al. Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small-cell lung cancer who failed one or two chemotherapy regimens. J Clin Oncol 2007;LBA7509.
Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Suga M, et al. A cohort and nested case-control study to quantify the risk of interstitial lung disease (ILD) in Japanese patients with NSCLC treated with gefitinib or chemotherapy. J Clin Oncol 2007;A148.
© The Japanese Association for Thoracic Surgery 2008