Management of Brain Metastases in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer

Overview

Journal Front Oncol

Specialty Oncology

Date 2018 Jul 19

PMID 30018881

Citations 44

Authors

William J Kelly

Neil J Shah

Deepa S Subramaniam

Affiliations

Soon will be listed here.

Abstract

Lung cancer remains a leading cause of mortality with 1.69 million deaths worldwide. Activating mutations in epidermal growth factor receptor (EGFR), predominantly exon 19 deletions and exon 21 L858R mutations, are known oncogenic drivers identified in 20-40% of non-small-cell lung cancers (NSCLC). 70% of EGFR-mutant NSCLC patients develop brain metastases (BM), compared to 38% in EGFR wild-type patients. First-generation tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib have proven to be superior to chemotherapy in the front-line treatment of EGFR-mutant NSCLC, as has afatinib, a second-generation TKI. The most common acquired resistance mechanism is the development of a gatekeeper mutation in exon 20 T790M. Osimertinib has emerged as a third-generation EGFR TKI with proven activity in the front-line setting as well as in patients with a T790M acquired resistance mutation with remarkable CNS activity. As long-term survival outcomes in EGFR-mutant NSCLC continue to improve, the burden of BM becomes a greater challenge. Here, we review the literature related to the management of BM in EGFR-mutant NSCLC including the role of the three generations of EGFR TKIs, immunotherapy, and brain radiation.

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References

Weber B, Winterdahl M, Memon A, Sorensen B, Keiding S, Sorensen L . Erlotinib accumulation in brain metastases from non-small cell lung cancer: visualization by positron emission tomography in a patient harboring a mutation in the epidermal growth factor receptor. J Thorac Oncol. 2011; 6(7):1287-9. DOI: 10.1097/JTO.0b013e318219ab87. View

Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M . Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2014; 10(1):156-63. PMC: 4276567. DOI: 10.1097/JTO.0000000000000380. View

Sekine A, Kato T, Hagiwara E, Shinohara T, Komagata T, Iwasawa T . Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features. Lung Cancer. 2012; 77(1):64-9. DOI: 10.1016/j.lungcan.2011.12.017. View

Hata A, Katakami N, Yoshioka H, Takeshita J, Tanaka K, Nanjo S . Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations. Cancer. 2013; 119(24):4325-32. DOI: 10.1002/cncr.28364. View

Mansfield A, Aubry M, Moser J, Harrington S, Dronca R, Park S . Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 2016; 27(10):1953-8. PMC: 5035793. DOI: 10.1093/annonc/mdw289. View

Gerber N, Yamada Y, Rimner A, Shi W, Riely G, Beal K . Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014; 89(2):322-9. PMC: 5691362. DOI: 10.1016/j.ijrobp.2014.02.022. View

Jiang T, Min W, Li Y, Yue Z, Wu C, Zhou C . Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis. Cancer Med. 2016; 5(6):1055-65. PMC: 4924363. DOI: 10.1002/cam4.673. View

Shepherd F, Pereira J, Ciuleanu T, Tan E, Hirsh V, Thongprasert S . Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005; 353(2):123-32. DOI: 10.1056/NEJMoa050753. View

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

10.

Subramaniam D, Hwang J . BIBW 2992 in non-small cell lung cancer. Expert Opin Investig Drugs. 2011; 20(3):415-22. DOI: 10.1517/13543784.2011.557063. View

11.

Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S . Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib. J Thorac Oncol. 2009; 4(11):1415-9. DOI: 10.1097/JTO.0b013e3181b62572. View

12.

Huang S, Li J, Armstrong E, Harari P . Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res. 2002; 62(15):4300-6. View

13.

Porta R, Sanchez-Torres J, Paz-Ares L, Massuti B, Reguart N, Mayo C . Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J. 2010; 37(3):624-31. DOI: 10.1183/09031936.00195609. View

14.

Ma S, Xu Y, Deng Q, Yu X . Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer. 2008; 65(2):198-203. DOI: 10.1016/j.lungcan.2008.10.028. View

15.

Bianco C, Tortora G, Bianco R, Caputo R, Veneziani B, Caputo R . Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res. 2002; 8(10):3250-8. View

16.

Steuer C, Behera M, Berry L, Kim S, Rossi M, Sica G . Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: Results from the Lung Cancer Mutation Consortium. Cancer. 2015; 122(5):766-72. PMC: 5038591. DOI: 10.1002/cncr.29812. View

17.

Ballard P, Yates J, Yang Z, Kim D, Yang J, Cantarini M . Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016; 22(20):5130-5140. DOI: 10.1158/1078-0432.CCR-16-0399. View

18.

Park K, Tan E, OByrne K, Zhang L, Boyer M, Mok T . Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016; 17(5):577-89. DOI: 10.1016/S1470-2045(16)30033-X. View

19.

Takamori S, Toyokawa G, Okamoto I, Takada K, Kozuma Y, Matsubara T . Discrepancy in Programmed Cell Death-Ligand 1 Between Primary and Metastatic Non-small Cell Lung Cancer. Anticancer Res. 2017; 37(8):4223-4228. DOI: 10.21873/anticanres.11813. View

20.

Wu C, Li Y, Wang Z, Li Z, Zhang T, Wei Z . Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer. 2007; 57(3):359-64. DOI: 10.1016/j.lungcan.2007.03.011. View