1. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30. https://doi.org/10.3322/caac.21387

2. Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan Detroit Cancer surveillance system. J Clin Oncol 22(14):2865–2872. https://doi.org/10.1200/jco.2004.12.149

3. Mujoomdar A, Austin JHM, Malhotra R, Powell CA, Pearson GDN, Shiau MC, Raftopoulos H (2007) Clinical predictors of metastatic disease to the brain from non–small cell lung carcinoma: primary tumor size, cell type, and lymph node Metastases1. Radiology 242(3):882–888

4. Han G, Bi J, Tan W, Wei X, Wang X, Ying X, Guo X, Zhou X, Hu D, Zhen W (2016) A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? Oncotarget 7(35):56998–57010. https://doi.org/10.18632/oncotarget.10933

5. Langer CJ, Mehta MP (2005) Current management of brain metastases, with a focus on systemic options. J Clin Oncol 23(25):6207–6219. https://doi.org/10.1200/jco.2005.03.145

6. Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, Chang JY, Wefel JS, McGovern SL, Garland LL, Chen SS, Holt J, Liao Z, Brown P, Sulman E, Heymach JV, Kim ES, Stea B (2013) Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31(7):895–902. https://doi.org/10.1200/jco.2011.40.1174

7. Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, Lee JS (2012) Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 77(3):556–560. https://doi.org/10.1016/j.lungcan.2012.05.092

8. Yatabe Y, Takahashi T, Mitsudomi T (2008) Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res 68(7):2106–2111. https://doi.org/10.1158/0008-5472.can-07-5211

9. Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M (2010) Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140(2):268–279. https://doi.org/10.1016/j.cell.2009.12.046

10. Larsen AK, Ouaret D, El Ouadrani K, Petitprez A (2011) Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther 131(1):80–90. https://doi.org/10.1016/j.pharmthera.2011.03.012

11. Stanic K, Zwitter M, Hitij NT, Kern I, Sadikov A, Cufer T (2014) Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival. Radiol Oncol 48(2):173–183. https://doi.org/10.2478/raon-2014-0016

12. Hendriks LE, Smit EF, Vosse BA, Mellema WW, Heideman DA, Bootsma GP, Westenend M, Pitz C, de Vries GJ, Houben R, Grunberg K, Bendek M, Speel EJ, Dingemans AM (2014) EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer 84(1):86–91. https://doi.org/10.1016/j.lungcan.2014.01.006

13. Baek MY, Ahn HK, Park KR, Park HS, Kang SM, Park I, Kim YS, Hong J, Sym SJ, Park J, Lee JH, Shin DB, Cho EK (2018) Epidermal growth factor receptor mutation and pattern of brain metastasis in patients with non-small cell lung cancer. Korean J Intern Med 33(1):168–175. https://doi.org/10.3904/kjim.2015.158

14. Wells GA, Shea BJ, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P (2014) The Newcastle–Ottawa scale (NOS) for assessing the quality of non-randomized studies in Meta-analysis. Appl Eng Agric 18 (6):págs. 727–734

15. Lee YJ, Park IK, Park M-S, Choi HJ, Cho BC, Chung KY, Kim SK, Chang J, Moon JW, Kim H, Choi SH, Kim J-H (2009) Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol 135(12):1647–1654. https://doi.org/10.1007/s00432-009-0611-7

16. Doebele RC, Lu X, Sumey C, Maxson DA, Weickhardt AJ, Oton AB, Bunn PA Jr, Baron AE, Franklin WA, Aisner DL, Varella-Garcia M, Camidge DR (2012) Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer. Cancer 118(18):4502–4511. https://doi.org/10.1002/cncr.27409

17. Enomoto Y, Takada K, Hagiwara E, Kojima E (2013) Distinct features of distant metastasis and lymph node stage in lung adenocarcinoma patients with epidermal growth factor receptor gene mutations. Respir Investig 51(3):153–157. https://doi.org/10.1016/j.resinv.2013.02.004

18. Akamatsu H, Kaira K, Murakami H, Serizawa M, Koh Y, Ono A, Shukuya T, Tsuya A, Nakamura Y, Kenmotsu H, Naito T, Takahashi T, Endo M, Harada H, Nakajima T, Yamamoto N (2014) The impact of clinical outcomes according to EGFR mutation status in patients with locally advanced lung adenocarcinoma who recieved concurrent chemoradiotherapy. Am J Clin Oncol 37(2):144–147. https://doi.org/10.1097/COC.0b013e31826e04f9

19. Fujimoto D, Ueda H, Shimizu R, Kato R, Otoshi T, Kawamura T, Tamai K, Shibata Y, Matsumoto T, Nagata K, Otsuka K, Nakagawa A, Otsuka K, Katakami N, Tomii K (2014) Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis. Clin Exp Metastasis 31(5):543–551. https://doi.org/10.1007/s10585-014-9648-3

20. Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH (2014) EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol 9(2):195–199

21. Iuchi T, Shingyoji M, Itakura M, Yokoi S, Moriya Y, Tamura H, Yoshida Y, Ashinuma H, Kawasaki K, Hasegawa Y, Sakaida T, Iizasa T (2015) Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations. Int J Clin Oncol 20(4):674–679. https://doi.org/10.1007/s10147-014-0760-9

22. Li B, Sun SZ, Yang M, Shi JL, Xu W, Wang XF, Song MM, Chen HM (2015) The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma. J Neuro-Oncol 124(1):79–85. https://doi.org/10.1007/s11060-015-1776-3

23. Schuette W, Schirmacher P, Eberhardt WE, Fischer JR, von der Schulenburg JM, Mezger J, Schumann C, Serke M, Zaun S, Dietel M, Thomas M (2015) EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Cancer Epidemiol Biomark Prev 24(8):1254–1261. https://doi.org/10.1158/1055-9965.EPI-14-1149

24. Tanaka K, Hida T, Oya Y, Oguri T, Yoshida T, Shimizu J, Horio Y, Hata A, Kaji R, Fujita S, Sekido Y, Kodaira T, Kokubo M, Katakami N, Yatabe Y (2015) EGFR mutation impact on definitive concurrent Chemoradiation therapy for inoperable stage III adenocarcinoma. J Thorac Oncol 10(12):1720–1725. https://doi.org/10.1097/JTO.0000000000000675

25. Yagishita S, Horinouchi H, Katsui Taniyama T, Nakamichi S, Kitazono S, Mizugaki H, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Sumi M, Shiraishi K, Kohno T, Furuta K, Tsuta K, Tamura T (2015) Epidermal growth factor receptor mutation is associated with longer local control after definitive chemoradiotherapy in patients with stage III nonsquamous non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 91(1):140–148. https://doi.org/10.1016/j.ijrobp.2014.08.344

26. Chen YM, Lai CH, Rau KM, Huang CH, Chang HC, Chao TY, Tseng CC, Fang WF, Chen YC, Chung YH, Wang YH, Su MC, Huang KT, Liu SF, Chen HC, Chang YC, Chang YP, Wang CC, Lin MC (2016) Advanced non-small cell lung cancer patients at the extremes of age in the era of epidermal growth factor receptor tyrosine kinase inhibitors. Lung Cancer 98:99–105. https://doi.org/10.1016/j.lungcan.2016.05.020

27. Hsu F, Caluwe AD, Anderson D, Nichol A, Toriumi T, Ho C (2016) EGFR mutation status on brain metastases from non-small cell lung cancer. Lung Cancer 96:101–107

28. Li BT, Lou E, Hsu M, Yu HA, Naidoo J, Zauderer MG, Sima C, Johnson ML, Daras M, DeAngelis LM, Fleisher M, Kris MG, Azzoli CG (2016) Serum biomarkers associated with clinical outcomes fail to predict brain metastases in patients with stage IV non-small cell lung cancers. PLoS One 11(1):e0146063. https://doi.org/10.1371/journal.pone.0146063

29. Li H, Cao J, Zhang X, Song X, Wang W, Jia S, Li Z, Jia H, Cao X, Zhou W, Lian J, Han S, Yang W, Xi Y, Lian S, Jing H (2017) Correlation between status of epidermal growth factor receptor mutation and distant metastases of lung adenocarcinoma upon initial diagnosis based on 1063 patients in China. Clin Exp Metastasis 34(1):63–71. https://doi.org/10.1007/s10585-016-9822-x

30. Luo YH, Wu CH, Huang CY, Wu CW, Wu WS, Lee YC, Whang-Peng J, Chen YM (2017) Brain metastasis features and association with tumor epidermal growth factor receptor mutation in patients with adenocarcinoma of the lung. Asia Pac J Clin Oncol 13(5):e440–e448. https://doi.org/10.1111/ajco.12576

31. Renaud S, Seitlinger J, Falcoz PE, Schaeffer M, Voegeli AC, Legrain M, Beau-Faller M, Massard G (2016) Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery. Br J Cancer 115(3):346–353. https://doi.org/10.1038/bjc.2016.182

32. Mizuno T, Yatabe Y, Kuroda H, Sakakura N, Sakao Y (2016) Impact of the oncogenic status on the mode of recurrence in resected non-small cell lung cancer. Jpn J Clin Oncol 46(10):928–934. https://doi.org/10.1093/jjco/hyw094

33. Bhatt VR, D’Souza SP, Smith LM, Cushmanvokoun AM, Noronha V, Verma V, Joshi A, Chougule A, Jambhekar N, Kessinger A (2017) Epidermal growth factor receptor mutational status and brain metastases in non–small-cell lung Cancer. J Glob Oncol 3(3):208–217

34. Ge M, Zhuang Y, Zhou X, Huang R, Liang X, Zhan Q (2017) High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases. J Neuro-Oncol 135(2):413–418. https://doi.org/10.1007/s11060-017-2590-x

35. Russo A, Franchina T, Ricciardi GR, Fanizza C, Scimone A, Chiofalo G, Giordano A, Adamo V (2017) Influence of EGFR mutational status on metastatic behavior in non squamous non small cell lung cancer. Oncotarget 8(5):8717–8725

36. Wang BX, Ou W, Mao XY, Liu Z, Wu HQ, Wang SY (2017) Impacts of EGFR mutation and EGFR-TKIs on incidence of brain metastases in advanced non-squamous NSCLC. Clin Neurol Neurosurg 160:96–100. https://doi.org/10.1016/j.clineuro.2017.06.022

37. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. https://doi.org/10.1136/bmj.327.7414.557

38. Hubbs JL, Boyd JA, Hollis D, Chino JP, Saynak M, Kelsey CR (2010) Factors associated with the development of brain metastases: analysis of 975 patients with early stage nonsmall cell lung cancer. Cancer 116(21):5038–5046. https://doi.org/10.1002/cncr.25254

39. Sun DS, Hu LK, Cai Y, Li XM, Ye L, Hou HY, Wang CH, Jiang YH (2014) A systematic review of risk factors for brain metastases and value of prophylactic cranial irradiation in non-small cell lung cancer. Asian Pac J Cancer Prev : APJCP 15(3):1233–1239

40. Chen G, Wang Z, Liu XY, Liu FY (2011) High-level CXCR4 expression correlates with brain-specific metastasis of non-small cell lung cancer. World J Surg 35(1):56–61. https://doi.org/10.1007/s00268-010-0784-x

41. Arora S, Ranade AR, Tran NL, Nasser S, Sridhar S, Korn RL, Ross JT, Dhruv H, Foss KM, Sibenaller Z, Ryken T, Gotway MB, Kim S, Weiss GJ (2011) MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration. Int J Cancer 129(11):2621–2631. https://doi.org/10.1002/ijc.25939

42. Yoo JY, Yang SH, Lee JE, Cho DG, Kim HK, Kim SH, Kim IS, Hong JT, Sung JH, Son BC (2012) E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model. J Neuro-Oncol 109(2):219–227

43. Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284(1):31–53

44. Dearden S, Stevens J, Wu YL, Blowers D (2013) Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Annals Oncol 24(9):2371–2376

45. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, Johnson BE (2010) Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res 16(23):5873–5882. https://doi.org/10.1158/1078-0432.ccr-10-1588

46. Sekine A, Kato T, Hagiwara E, Shinohara T, Komagata T, Iwasawa T, Satoh H, Tamura K, Kasamatsu T, Hayashihara K, Saito T, Takahashi H, Ogura T (2012) Metastatic brain tumors from non-small cell lung cancer with EGFR mutations: distinguishing influence of exon 19 deletion on radiographic features. Lung Cancer 77(1):64–69. https://doi.org/10.1016/j.lungcan.2011.12.017

47. Breindel JL, Haskins JW, Cowell EP, Zhao M, Nguyen DX, Stern DF (2013) EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis. Cancer Res 73(16):5053–5065. https://doi.org/10.1158/0008-5472.can-12-3775

48. Benedettini E, Sholl LM, Peyton M, Reilly J, Ware C, Davis L, Vena N, Bailey D, Yeap BY, Fiorentino M, Ligon AH, Pan BS, Richon V, Minna JD, Gazdar AF, Draetta G, Bosari S, Chirieac LR, Lutterbach B, Loda M (2010) Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. Am J Pathol 177(1):415–423. https://doi.org/10.2353/ajpath.2010.090863

49. Nie F, Yang J, Wen S, An YL, Ding J, Ju SH, Zhao Z, Chen HJ, Peng XG, Wong ST, Zhao H, Teng GJ (2012) Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis. Cancer 118(21):5198–5209. https://doi.org/10.1002/cncr.27553

50. Singh M, Garg N, Venugopal C, Hallett R, Tokar T, McFarlane N, Mahendram S, Bakhshinyan D, Manoranjan B, Vora P, Qazi M, Arpin CC, Page B, Haftchenary S, Rosa DA, Lai PS, Gomez-Biagi RF, Ali AM, Lewis A, Geletu M, Murty NK, Hassell JA, Jurisica I, Gunning PT, Singh SK (2015) STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation. Oncotarget 6(29):27461–27477. https://doi.org/10.18632/oncotarget.4742

51. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, Travis WD, Bornmann W, Veach D, Clarkson B, Bromberg JF (2007) Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117(12):3846–3856. https://doi.org/10.1172/jci31871

52. Pottgen C, Eberhardt W, Grannass A, Korfee S, Stuben G, Teschler H, Stamatis G, Wagner H, Passlick B, Petersen V, Budach V, Wilhelm H, Wanke I, Hirche H, Wilke HJ, Stuschke M (2007) Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 25(31):4987–4992. https://doi.org/10.1200/jco.2007.12.5468

53. Gore EM, Bae K, Wong SJ, Sun A, Bonner JA, Schild SE, Gaspar LE, Bogart JA, Werner-Wasik M, Choy H (2011) Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol 29(3):272–278. https://doi.org/10.1200/jco.2010.29.1609