Lung Cancer
Volume 69, Issue 3 , Pages 272-278 , September 2010

KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: A meta-analysis of 22 studies

  • Chen Mao

      Affiliations

    • Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
    • The first two authors contributed equally to this work and should be considered as co-first authors.
  • ,
  • Li-Xin Qiu

      Affiliations

    • Department of Medical Oncology, Cancer Hospital, Fudan University, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
    • The first two authors contributed equally to this work and should be considered as co-first authors.
  • ,
  • Ru-Yan Liao

      Affiliations

    • Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
  • ,
  • Fang-Bing Du

      Affiliations

    • Department of Respiratory Medicine, Hefei Second People's Hospital, Hefei, China
  • ,
  • Hong Ding

      Affiliations

    • Longgang Center for Disease Control and Prevention of Shenzhen, Shenzhen, China
  • ,
  • Wan-Chun Yang

      Affiliations

    • Department of Respiratory Medicine, Hefei Second People's Hospital, Hefei, China
  • ,
  • Jin Li

      Affiliations

    • Department of Medical Oncology, Cancer Hospital, Fudan University, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
  • ,
  • Qing Chen

      Affiliations

    • Department of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China
    • Corresponding Author InformationCorresponding author. Tel.: +86 20 61648312.

Received 4 September 2009 ,Revised 25 November 2009 ,Accepted 30 November 2009.

References 

  1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol. 2001;2:533–543
  2. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization classification of lung tumours. Eur Respir J. 2001;18:1059–1068
  3. 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
  4. Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP, 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
  5. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, 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;21:2237–2246
  6. 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 randomized, placebo-controlled, multi-centre study (Iressa survival evaluation in lung cancer). Lancet. 2005;366:1527–1537
  7. Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol. 2004;22:1103–1109
  8. 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
  9. Cortes-Funes H, Gomez C, Rosell R, Valero P, Garcia-Giron C, Velasco A, et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients. Ann Oncol. 2005;16:1081–1086
  10. 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
  11. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, et al. Epidermal growth factor receptor gene mutations and increased copy number predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23:6829–6837
  12. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–144
  13. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, 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
  14. Hirsch FR, Varella-Garcia M, Bunn PA, Franklin WA, Dziadziuszko R, Thatcher N, 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;24:5034–5042
  15. Hirsch FR, Varella-Garcia M, Cappuzzo F, McCoy J, Bemis L, Xavier AC, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 2007;18:752–760
  16. Slebos RJ, Hruban RH, Dalesio O, Mooi WJ, Offerhaus GJ, Rodenhuis S. Relationship between K-ras oncogene activation and smoking in adenocarcinoma of the human lung. J Natl Cancer Inst. 1991;83:1024–1027
  17. 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
  18. 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
  19. Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17
  20. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–129
  21. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748
  22. DerSimonian R, Laird N. .Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188
  23. Egger M, Smith DG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634
  24. Endoh H, Yatabe Y, Kosaka T, Kuwano H, Mitsudomi T. PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients. J Thorac Oncol. 2006;1:629–634
  25. Giaccone G, Gallegos Ruiz M, Le Chevalier T, Thatcher N, Smit E, Rodriguez JA, et al. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res. 2006;12:6049–6055
  26. 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
  27. Cappuzzo F, Ligorio C, Jänne 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
  28. Ichihara S, Toyooka S, Fujiwara Y, Hotta K, Shigematsu H, Tokumo M, et al. The impact of epidermal growth factor receptor gene status on gefitinib-treated Japanese patients with non-small-cell lung cancer. Int J Cancer. 2007;120:1239–1247
  29. Jackman DM, Yeap BY, Lindeman NI, Fidias P, Rabin MS, Temel J, et al. Phase II clinical trial of chemotherapy-naive patients > or =70 years of age treated with erlotinib for advanced non-small-cell lung cancer. J Clin Oncol. 2007;25:760–766
  30. Loprevite M, Tiseo M, Chiaramondia M, Capelletti M, Bozzetti C, Bortesi B, et al. Buccal mucosa cells as in vivo model to evaluate gefitinib activity in patients with advanced non small cell lung cancer. Clin Cancer Res. 2007;13:6518–6526
  31. Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007;13(10):2890–2896
  32. van Zandwijk N, Mathy A, Boerrigter L, Ruijter H, Tielen I, de Jong D, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007;18:99–103
  33. Chang JW, Liu HP, Hsieh MH, Fang YF, Hsieh MS, Hsieh JJ, et al. Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: a chromogenic in situ hybridization study of 182 patients. Lung Cancer. 2008;61:328–339
  34. Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu N, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008;26:4268–4275
  35. Felip E, Rojo F, Reck M, Heller A, Klughammer B, Sala G, et al. A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy. Clin Cancer Res. 2008;14:3867–3874
  36. Miller VA, Riely GJ, Zakowski MF, Li AR, Patel JD, Heelan RT, et al. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol. 2008;26:1472–1478
  37. Sasaki H, Endo K, Okuda K, Kawano O, Kitahara N, Tanaka H, et al. Epidermal growth factor receptor gene amplification and gefitinib sensitivity in patients with recurrent lung cancer. J Cancer Res Clin Oncol. 2008;134:569–577
  38. Schneider CP, Heigener D, Schott-von-Römer K, Gütz S, Laack E, Digel W, et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study. J Thorac Oncol. 2008;3:1446–1453
  39. Zucali PA, Ruiz MG, Giovannetti E, Destro A, Varella-Garcia M, Floor K, et al. Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. Ann Oncol. 2008;19:1605–1612
  40. Varella-Garcia M, Mitsudomi T, Yatabe Y, Kosaka T, Nakajima E, Xavier AC, et al. EGFR and HER2 genomic gain in recurrent non-small cell lung cancer after surgery: impact on outcome to treatment with gefitinib and association with EGFR and KRAS mutations in a Japanese cohort. J Thorac Oncol. 2009;4:318–325
  41. Tiseo M, Rossi G, Capelletti M, Sartori G, Spiritelli E, Marchioni A, et al. Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC): study of a comprehensive panel of molecular markers. Lung Cancer. 2009;
  42. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110(6):669–672
  43. Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol. 2001;2:127
  44. Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, 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
  45. Nelson HH, Christiani DC, Mark EJ, Wiencke JK, Wain JC, Kelsey KT. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst. 1999;91:2032–2038
  46. Keller SM, Vangel MG, Adak S, Wagner H, Schiller JH, Herskovic A, et al. The influence of gender on survival and tumor recurrence following adjuvant therapy of completely resected stages II and IIIa non-small cell lung cancer. Lung Cancer. 2002;37:303–309
  47. Grossi F, Loprevite M, Chiaramondia M, Ceppa P, Pera C, Ratto GB, et al. Prognostic significance of K-ras, p53, bcl-2, PCNA, CD34 in radically resected non-small cell lung cancers. Eur J Cancer. 2003;39:1242–1250
  48. Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Jänne PA, Riely GJ, 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

PII: S0169-5002(09)00632-1

doi: 10.1016/j.lungcan.2009.11.020

Lung Cancer
Volume 69, Issue 3 , Pages 272-278 , September 2010