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01-12-2014 | Translational Research and Biomarkers

Prevalence, Clinicopathologic Characteristics, and Molecular Associations of EGFR Exon 20 Insertion Mutations in East Asian Patients with Lung Adenocarcinoma

Authors: Yunjian Pan, MD, Yang Zhang, MD, Yuan Li, MD, Haichuan Hu, MD, Lei Wang, MD, Hang Li, MD, Rui Wang, MD, Ting Ye, MD, Xiaoyang Luo, MD, Yiliang Zhang, MD, Bin Li, MD, Deng Cai, MD, Lei Shen, MD, Yihua Sun, MD, Haiquan Chen, MD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

Abstract

Purpose

To define the prevalence, clinicopathologic characteristics and molecular associations of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in East Asian lung adenocarcinoma patients.

Methods

A total of 1,086 lung adenocarcinomas were sequenced for EGFR mutations. EGFR and HER2 copy number variations; total and phosphorylated (p) protein expression of ErbB family members including EGFR, HER2, and HER3; phosphorylated protein expression of downstream signaling molecules including Akt and Erk; and clinicopathologic features in lung adenocarcinomas with EGFR exon 20 insertion mutations were all investigated.

Results

EGFR exon 20 insertion mutations were present in 2.9 % of lung adenocarcinomas and 4.7 % of all the EGFR mutations. Compared to those with classic activating EGFR mutations, lung adenocarcinomas with exon 20 insertion mutations were characterized by significantly younger age at diagnosis (P = 0.032 for exon 20 insertions vs. L858R) and shorter relapse-free survival [P = 0.045 for exon 20 insertions versus (vs) exon 19 deletions]. Molecularly, samples harboring exon 20 insertion mutations had lower expression of phosphorylated (p)-EGFR (P < 0.001) and HER3 (P = 0.016). In addition, higher expression of p-Akt (P = 0.007) and lower expression of p-Erk (P = 0.009) were observed in tumors with exon 20 insertion mutations.

Conclusions

Lung adenocarcinomas with EGFR exon 20 insertion mutations were present in a substantial proportion. This subset showed distinct clinicopathologic features, less dependence on EGFR molecularly, and different pathway activation patterns compared to those with classic EGFR activating mutations.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRef

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.PubMedCrossRef

Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500.PubMedCrossRef

Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–13311.PubMedCentralPubMedCrossRef

Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol. 2012;13:e23–e31.PubMedCrossRef

Wu JY, Wu SG, Yang CH, et al. Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response. Clin Canc Res. 2008;14:4877–4882.CrossRef

Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Canc Res.2011;17:3812–3821.CrossRef

Yasuda HSN, Yeo W, Figueiredo-Pontes L, Kobayashi S, Costa D. Sensitivity of EGFR exon 20 insertion mutations to EGFR inhibitors is determined by their location within the tyrosine kinase domain of EGFR. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. Canc Res. 2012;72(8 Suppl):23.

Hirsch FR, Varella-Garcia M, Cappuzzo F, 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.PubMedCrossRef

10.

Cappuzzo F, Ligorio C, Janne PA, 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.PubMedCrossRef

11.

Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 2005;23:6838–6845.PubMedCrossRef

12.

Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–354.PubMedCrossRef

13.

Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110:669–672.PubMedCrossRef

14.

Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–1043.PubMedCrossRef

15.

Cappuzzo F, Varella-Garcia M, Shigematsu H, et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. J Clin Oncol. 2005;23:5007–5018.PubMedCrossRef

16.

Engelman JA, Janne PA, Mermel C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA. 2005;102:3788–3793.PubMedCentralPubMedCrossRef

17.

Han SW, Kim TY, Hwang PG, 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.PubMedCrossRef

18.

Han SW, Hwang PG, Chung DH, et al. Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa, ZD1839) in chemotherapy-resistant non-small cell lung cancer. Int J Cancer.2005;113:109–115.PubMedCrossRef

19.

Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6:244–285.PubMedCrossRef

20.

Sun Y, Ren Y, Fang Z, et al. Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol. 2010;28:4616–4620.PubMedCentralPubMedCrossRef

21.

Zhang Y, Sun Y, Pan Y, et al. Frequency of driver mutations in lung adenocarcinoma from female never-smokers varies with histologic subtypes and age at diagnosis. Clin Cancer Res. 2012;18:1947–1953.PubMedCentralPubMedCrossRef

22.

Li C, Sun Y, Fang Z, et al. Comprehensive analysis of epidermal growth factor receptor gene status in lung adenocarcinoma. J Thorac Oncol. 2011;6:1016–1021.PubMedCrossRef

23.

Oxnard GR, Lo PC, Nishino M, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol. 2013;8:179–184.PubMedCentralPubMedCrossRef

24.

Arcila ME, Nafa K, Chaft JE, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013;12:220–229.PubMedCentralPubMedCrossRef

25.

Sasaki H, Endo K, Takada M, et al. EGFR exon 20 insertion mutation in Japanese lung cancer. Lung Cancer. 2007;58:324–328.PubMedCrossRef

26.

Berger MB, Mendrola JM, Lemmon MA. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett. 2004;569:332–336.PubMedCrossRef

27.

Fujimoto N, Wislez M, Zhang J, et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. 2005;65:11478–11485.PubMedCrossRef

Title: Prevalence, Clinicopathologic Characteristics, and Molecular Associations of EGFR Exon 20 Insertion Mutations in East Asian Patients with Lung Adenocarcinoma
Authors: Yunjian Pan, MD
Yang Zhang, MD
Yuan Li, MD
Haichuan Hu, MD
Lei Wang, MD
Hang Li, MD
Rui Wang, MD
Ting Ye, MD
Xiaoyang Luo, MD
Yiliang Zhang, MD
Bin Li, MD
Deng Cai, MD
Lei Shen, MD
Yihua Sun, MD
Haiquan Chen, MD
Publication date: 01-12-2014
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-013-3452-1

ACC 2024 Congress

Springer Medicine

Prevalence, Clinicopathologic Characteristics, and Molecular Associations of EGFR Exon 20 Insertion Mutations in East Asian Patients with Lung Adenocarcinoma

Abstract

Purpose

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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