Advertisement

EGFR: How Important Is EGFR Mutation Status in the Management of Lung Cancer?

  • Mizuki Haraguchi
  • Kazuhisa Takahashi
Chapter
Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)

Abstract

The underlying basis of the cancer phenotype is caused by the alteration of genes that regulate cell growth, differentiation, proliferation, and programmed cell death. Along with the molecular biology of the cell, over the last several decades, numerous other important factors that contribute to cell growth, differentiation, and proliferation processes have been found. In contrast to normal cells, cancer cells have the capacity to proliferate without external stimuli, usually as a consequence of gene mutations. The human epidermal growth factor receptor (EGFR) is overexpressed or dysfunctional in many human malignancies. EGFR is one of the human epidermal growth factor receptor (HER) family proteins, and signaling intermediated by EGFR has received intense focus, resulting in the emergence of attractive candidates for anticancer therapy, especially in lung cancer. In this section, we focus on the signaling cascade via EGFR and overview the therapeutic approach against EGFR.

Keywords

Epidermal growth factor receptor (EGFR) Driver mutation EGFR-tyrosine kinase inhibitor Resistance 

References

  1. 1.
    Vinay K, Abul KA, Jon CA. Neoplasia. In: Robbins and cotran pathologic basis of disease. 9th ed. Philadelphia: Saunders, An Imprint of Elsevier Inc; 2015. p. 265–340.Google Scholar
  2. 2.
    Oxnard GR, Binder A, Jänne PA. New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 2013;31(8):1097–104.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Aphrothiti H, Gopa L, David S. Intracellular signaling. In: John EN, James OA, Joel ET, editors. Abeloff's clinical oncology. 5th ed. Philadelphia: Elsevier; 2014. p. 22–39.Google Scholar
  4. 4.
    Weinstein IB. Cancer. Addiction to oncogenes-the Achilles heal of cancer. Science. 2002;297(5578):63–4.CrossRefPubMedGoogle Scholar
  5. 5.
    Sharma SV, Bell DW, Haber DA, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer. 2007;7(3):169–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–87.CrossRefPubMedGoogle Scholar
  7. 7.
    Normanno N, De Luca A, Salomon DS, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;366(1):2–16.CrossRefPubMedGoogle Scholar
  8. 8.
    Linardou H, Dahabreh IJ, Murray S, et al. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol. 2009;6(6):352–66.CrossRefPubMedGoogle Scholar
  9. 9.
    Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 2014;25(3):282–303.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Siegelin MD, Borczuk AC. Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab Investig. 2014;94(2):129–37.CrossRefPubMedGoogle Scholar
  11. 11.
    Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16.CrossRefPubMedGoogle Scholar
  12. 12.
    Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5(5):341–54.CrossRefGoogle Scholar
  13. 13.
    Yewale C, Baradia D, Misra A, et al. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials. 2013;34(34):8690–707.CrossRefPubMedGoogle Scholar
  14. 14.
    Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol. 2007;19(2):124–34.CrossRefPubMedGoogle Scholar
  15. 15.
    Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer. 2013;13(9):663–73.CrossRefPubMedGoogle Scholar
  16. 16.
    Olayioye MA, Neve RM, Hynes NE, et al. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19(13):3159–67.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chang L, Karin M. Mammalian MAP kinase signalling cascades. Nature. 2001;410(6824):37–40.CrossRefPubMedGoogle Scholar
  18. 18.
    Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003;3(6):459–65.CrossRefPubMedGoogle Scholar
  19. 19.
    Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22.CrossRefGoogle Scholar
  20. 20.
    Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9(7):517–31.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489–501.CrossRefPubMedGoogle Scholar
  22. 22.
    Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6(9):729–34.CrossRefPubMedGoogle Scholar
  23. 23.
    Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol. 2012;13(3):195–203.CrossRefGoogle Scholar
  24. 24.
    Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer. 2004;4(5):361–70.CrossRefPubMedGoogle Scholar
  25. 25.
    Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012;12(8):553–63.CrossRefPubMedGoogle Scholar
  26. 26.
    Midha A, Dearden S, McCormack R, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015;5(9):2892–911.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Kobayashi Y, Mitsudomi T. Not all epidermal growth factor receptor mutations in lung cancer are created equal: perspectives for individualized treatment strategy. Cancer Sci. 2016;107(9):1179–86.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kohno T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18:375–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Serizawa M, et al. Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays. Cancer. 2014;120:1471–81.CrossRefPubMedGoogle Scholar
  30. 30.
    Lopez-Rios F, Angulo B, Gomez B, Mair D, et al. Comparison of molecular testing methods for the detection of EGFR mutations in formalin-fixed paraffin-embedded tissue specimens of non-small cell lung cancer. J Clin Pathol. 2013;66(5):381–5.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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(5):1169–80.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sherwood JL, Müller S, Orr MC, et al. Panel based MALDI-TOF tumour profiling is a sensitive method for detecting mutations in clinical non small cell lung cancer tumour. PLoS One. 2014;9(6):e100566.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Young EC, Owens MM, Adebiyi I, et al. A comparison of methods for EGFR mutation testing in non-small cell lung cancer. Diagn Mol Pathol. 2013;22(4):190–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Dias-Santagata D, Akhavanfard S, David SS, et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med. 2010;2(5):146–58.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Jänne PA, Borras AM, Kuang Y, et al. A rapid and sensitive enzymatic method for epidermal growth factor receptor mutation screening. Clin Cancer Res. 2006;12(3 Pt 1):751–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Uchida J, Kato K, Kukita Y, et al. Diagnostic accuracy of noninvasive genotyping of EGFR in lung cancer patients by deep sequencing of plasma cell-free DNA. Clin Chem. 2015;61(9):1191–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Costa C, Molina MA, Drozdowskyj A, et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res. 2014;20(7):2001–10.CrossRefPubMedGoogle Scholar
  38. 38.
    Forshew T, Murtaza M, Parkinson C, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68.CrossRefPubMedGoogle Scholar
  39. 39.
    Taniguchi K, Uchida J, Nishino K, et al. Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res. 2011;17(24):7808–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Watanabe M, Kawaguchi T, Isa S, et al. Ultra-sensitive detection of the pretreatment EGFR T790M mutation in non-small cell lung cancer patients with an EGFR-activating mutation using droplet digital PCR. Clin Cancer Res. 2015;21(15):3552–60.CrossRefPubMedGoogle Scholar
  41. 41.
    Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548–54.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Beau-Faller M, Prim N, Ruppert AM, Nanni-Metéllus I, et al. 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. 2014;25(1):126–31.CrossRefPubMedGoogle Scholar
  43. 43.
    Naidoo J, Sima CS, Rodriguez K, et al. Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: clinical outcomes and response to erlotinib. Cancer. 2015;121(18):3212–20.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yasuda H, Park E, Yun CH, Sng NJ, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013;5(216):216ra177.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Voon PJ, Tsui DW, Rosenfeld N, et al. EGFR exon 20 insertion A763-Y764insFQEA and response to erlotinib—letter. Mol Cancer Ther. 2013;12(11):2614–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Woo HS, Ahn HK, Lee HY, et al. Epidermal growth factor receptor (EGFR) exon 20 mutations in non-small-cell lung cancer and resistance to EGFR-tyrosine kinase inhibitors. Investig New Drugs. 2014;32(6):1311–5.CrossRefGoogle Scholar
  47. 47.
    Yasuda H, Kobayashi S, Costa DB, et al. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 2012;13(1):e23–31.CrossRefPubMedGoogle Scholar
  48. 48.
    Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015;16(7):830–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Maemondo M, et al. Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Mitsudomi T, 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.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhou C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42.CrossRefPubMedGoogle Scholar
  52. 52.
    Rosell R, et al. 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. 2010;13:239–46.CrossRefGoogle Scholar
  53. 53.
    Urata Y, et al. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG5108L. J Clin Oncol. 2016;34:3248–57.CrossRefPubMedGoogle Scholar
  54. 54.
    Yang JJ, et al. A randomized controlled trial of erlotinib versus gefitinib in advanced non-small-cell lung cancer harboring EGFR mutations (CTONG0901). J Thorac Oncol. 2015;10:S321(abstr).Google Scholar
  55. 55.
    Sequist LV, et al. Phase III study of afatinib of cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–34.CrossRefPubMedGoogle Scholar
  56. 56.
    Wu YL, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–22.CrossRefPubMedGoogle Scholar
  57. 57.
    Paz-Ares L, et al. Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Ann Oncol. 2017;28:270–7.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Takeda M, Okamoto I, Nakagawa K. Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer. Lung Cancer. 2015;88(1):74–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013;14(8):777–86.CrossRefPubMedGoogle Scholar
  60. 60.
    Sugawara S, Oizumi S, Minato K, et al. Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol. 2015;26(5):888–94.CrossRefPubMedGoogle Scholar
  61. 61.
    Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236–44.CrossRefPubMedGoogle Scholar
  62. 62.
    Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yu HA, Maria E, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR TKI therapy in 155 patients with EGFR mutant lung cancers. Clin Cancer Res. 2013;19(8):2240–7.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Mok TS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Respiratory Medicine, Graduate School of MedicineJuntendo UniversityBukyo-ku, TokyoJapan

Personalised recommendations