Summary
Introduction In patients with non-small cell lung cancer (NSCLC), the predictive value of rare epidermal growth factor receptor (EGFR) exon 20 mutations in determining a patient’s response to EGFR tyrosine kinase inhibitor (TKI) treatment is unclear. Patients and Methods We reviewed data for NSCLC patients harboring EGFR exon 20 mutations from two hospitals in Korea. EGFR mutations were analyzed using directional sequencing. Results We identified eight patients carrying EGFR exon 20 mutations, seven of whom had insertional mutations. Three patients carried previously unreported insertional mutations. Among six patients who were treated with EGFR TKI, one showed stable disease and three showed primary resistance. Response evaluations were not performed for the other two patients because of their clinical deterioration. Conclusions EGFR exon 20 insertional mutations, including three that were previously unreported, were associated with the poor response of patients to TKI treatment.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500. doi:10.1126/science.1099314
Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362(25):2380–2388. doi:10.1056/NEJMoa0909530
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M (2010) 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 11(2):121–128. doi:10.1016/S1470-2045(09)70364-X
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13(3):239–246. doi:10.1016/S1470-2045(11)70393-X
Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31(27):3327–3334. doi:10.1200/JCO.2012.44.2806
Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, You C (2011) 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 12(8):735–742. doi:10.1016/S1470-2045(11)70184-X
Murray S, Dahabreh IJ, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P (2008) 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 Off Publ Int Assoc Study Lung Cancer 3(8):832–839. doi:10.1097/JTO.0b013e31818071f3
Beau-Faller M, Prim N, Ruppert AM, Nanni-Metellus I, Lacave R, Lacroix L, Escande F, Lizard S, Pretet JL, Rouquette I, de Cremoux P, Solassol J, de Fraipont F, Bieche I, Cayre A, Favre-Guillevin E, Tomasini P, Wislez M, Besse B, Legrain M, Voegeli AC, Baudrin L, Morin F, Zalcman G, Quoix E, Blons H, Cadranel J (2014) Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol Off J Eur Soc Med Oncol 25(1):126–131. doi:10.1093/annonc/mdt418
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC (2011) Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res Off J Am Assoc Cancer Res 17(11):3812–3821. doi:10.1158/1078-0432.CCR-10-3408
Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, Zakowski MF, Kris MG, Ladanyi M (2013) EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 12(2):220–229. doi:10.1158/1535-7163.MCT-12-0620
Oxnard GR, Lo PC, Nishino M, Dahlberg SE, Lindeman NI, Butaney M, Jackman DM, Johnson BE, Janne PA (2013) Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 8(2):179–184. doi:10.1097/JTO.0b013e3182779d18
Yasuda H, Kobayashi S, Costa DB (2012) EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 13(1):e23–e31. doi:10.1016/S1470-2045(11)70129-2
Travis WD (2011) Pathology of lung cancer. Clin Chest Med 32(4):669–692. doi:10.1016/j.ccm.2011.08.005
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216
Wu JY, Wu SG, Yang CH, Gow CH, Chang YL, Yu CJ, Shih JY, Yang PC (2008) Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Cancer Res Off J Am Assoc Cancer Res 14(15):4877–4882. doi:10.1158/1078-0432.CCR-07-5123
Huang SF, Liu HP, Li LH, Ku YC, Fu YN, Tsai HY, Chen YT, Lin YF, Chang WC, Kuo HP, Wu YC, Chen YR, Tsai SF (2004) High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res Official J Am Assoc Cancer Res 10(24):8195–8203. doi:10.1158/1078-0432.CCR-04-1245
Sasaki H, Endo K, Takada M, Kawahara M, Kitahara N, Tanaka H, Okumura M, Matsumura A, Iuchi K, Kawaguchi T, Kawano O, Yukiue H, Yokoyama T, Yano M, Fujii Y (2007) EGFR exon 20 insertion mutation in Japanese lung cancer. Lung Cancer 58(3):324–328. doi:10.1016/j.lungcan.2007.06.024
Sequist LV, Bell DW, Lynch TJ, Haber DA (2007) Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol 25(5):587–595. doi:10.1200/JCO.2006.07.3585
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, Roth JA, Herz J, Minna JD, Gazdar AF (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97(5):339–346. doi:10.1093/jnci/dji055
Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, Ince WL, Janne PA, Januario T, Johnson DH, Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, Stinson JA, Zhang YR, Seshagiri S, Hillan KJ (2005) 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 Clinical Oncol Off J Am Soc Clin Oncol 23(25):5900–5909. doi:10.1200/JCO.2005.02.857
Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, Joshi VA, McCollum D, Evans TL, Muzikansky A, Kuhlmann GL, Han M, Goldberg JS, Settleman J, Iafrate AJ, Engelman JA, Haber DA, Johnson BE, Lynch TJ (2008) First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol Off J Am Soc Clin Oncol 26(15):2442–2449. doi:10.1200/JCO.2007.14.8494
Conflicts of interest
There are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Hyun Sun Woo and Hee Kyung Ahn contributed equally to this work.
Rights and permissions
About this article
Cite this article
Woo, H.S., Ahn, H.K., Lee, H.Y. et al. Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors. Invest New Drugs 32, 1311–1315 (2014). https://doi.org/10.1007/s10637-014-0146-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-014-0146-x