Abstract
Brain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). Recent studies have shown that oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were effective for BM from NSCLC with EGFR mutation. However, the relationship between EGFR mutations and prognosis of NSCLC BM patients remains to be determined. In this study, we investigated the impact of EGFR mutation status on the survival of BM patients from NSCLC. One hundred six patients with BM from NSCLC were retrospectively reviewed. Thirty-three subjects (24.3 %) were confirmed to have an exon 19 deletion, while another 33 had an exon 21 point mutation (L858R) (24.3 %). Log-rank test and Cox proportional hazards model were used to analyze the impact of variables on survival. The median survival of NSCLC with BM was 8 months. Log-rank test analysis showed that Eastern Cooperative Oncology Group Performance Status (ECOG-PS) at BM (p < 0.0001), control of primary tumor (p = 0.005), pathology (p = 0.01), EGFR mutations (p = 0.045), and 19 exon deletion (p = 0.007) were associated with a longer survival. In a Cox proportional hazards model, EGFR exon 19 deletion (p = 0.034), control of primary tumor (p = 0.024), and ECOG PS at BM (p = 0.006) were found to be independent prognostic factors. Moreover, there were prognostic differences between groups according to Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification system (p < 0.0001). Exon 19 deletion is an independent prognostic factor in BM from NSCLC. It should be integrated into the prognostic scoring classification system for NSCLC.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22(14):2865–72. doi:10.1200/jco.2004.12.149.
Sorensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol. 1988;6(9):1474–80.
Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–51.
Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther. 2014;7:2075–84. doi:10.2147/OTT.S67586.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, 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(21):2129–39. doi:10.1056/NEJMoa040938.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500. doi:10.1126/science.1099314.
Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, et al. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013;24(4):993–9. doi:10.1093/annonc/mds529.
Hsiao SH, Lin HC, Chou YT, Lin SE, Kuo CC, Yu MC, et al. Impact of epidermal growth factor receptor mutations on intracranial treatment response and survival after brain metastases in lung adenocarcinoma patients. Lung Cancer. 2013;81(3):455–61. doi:10.1016/j.lungcan.2013.06.004.
Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol. 2010;12(11):1193–9. doi:10.1093/neuonc/noq076.
Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, et al. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008;14(1):162–8. doi:10.1158/1078-0432.CCR-07-1468.
Luo D, Ye X, Hu Z, Peng K, Song Y, Yin X, et al. EGFR mutation status and its impact on survival of Chinese non-small cell lung cancer patients with brain metastases. Tumour Biol. 2014;35(3):2437–44. doi:10.1007/s13277-013-1323-9.
Lee DW, Shin DY, Kim JW, Keam B, Kim TM, Kim HJ, et al. Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastasis: integrating with lung specific GPA score. Lung Cancer. 2014;86(3):363–8. doi:10.1016/j.lungcan.2014.10.001.
Lee HL, Chung TS, Ting LL, Tsai JT, Chen SW, Chiou JF, et al. EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases. Radiat Oncol. 2012;7:181. doi:10.1186/1748-717X-7-181.
Burel-Vandenbos F, Ambrosetti D, Coutts M, Pedeutour F. EGFR mutation status in brain metastases of non-small cell lung carcinoma. J Neurooncol. 2013;111(1):1–10. doi:10.1007/s11060-012-0990-5.
Sekine A, Satoh H, Iwasawa T, Tamura K, Hayashihara K, Saito T, et al. Prognostic factors for brain metastases from non-small cell lung cancer with EGFR mutation: influence of stable extracranial disease and erlotinib therapy. Med Oncol. 2014;31(10):228. doi:10.1007/s12032-014-0228-9.
Won YW, Han JY, Lee GK, Park SY, Lim KY, Yoon KA, et al. Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations. J Clin Pathol. 2011;64(11):947–52. doi:10.1136/jclinpath-2011-200169.
Zhang Y, Sheng J, Kang S, Fang W, Yan Y, Hu Z, et al. Patients with exon 19 deletion were associated with longer progression-free survival compared to those with L858R mutation after first-line EGFR-TKIs for advanced non-small cell lung cancer: a meta-analysis. PLoS One. 2014;9(9):e107161. doi:10.1371/journal.pone.0107161.
Zhu JQ, Zhong WZ, Zhang GC, Li R, Zhang XC, Guo AL, et al. Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals. Cancer Lett. 2008;265(2):307–17. doi:10.1016/j.canlet.2008.02.064.
Yang JC-H, Wu Y-L, Schuler M, Sebastian M, Popat S, Yamamoto N, et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141–51.
Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non–small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–92.
Bai H, Wang Z, Chen K, Zhao J, Lee JJ, Wang S, et al. Influence of chemotherapy on EGFR mutation status among patients with non–small-cell lung cancer. J Clin Oncol. 2012;30:3077–83.
Lagerwaard FJ, Levendag PC, Nowak PJ, Eijkenboom WM, Hanssens PE, Schmitz PI. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys. 1999;43(4):795–803.
Kepka L, Cieslak E, Bujko K, Fijuth J, Wierzchowski M. Results of the whole-brain radiotherapy for patients with brain metastases from lung cancer: the RTOG RPA intra-classes analysis. Acta Oncol. 2005;44(4):389–98. doi:10.1080/02841860510029699.
Viani GA, Castilho MS, Salvajoli JV, Pellizzon AC, Novaes PE, Guimaraes FS, et al. Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems. BMC Cancer. 2007;7:53. doi:10.1186/1471-2407-7-53.
Cortot AB, Italiano A, Burel-Vandenbos F, Martel-Planche G, Hainaut P. KRAS mutation status in primary nonsmall cell lung cancer and matched metastases. Cancer. 2010;116(11):2682–7. doi:10.1002/cncr.25014.
Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol. 2009;20(4):696–702. doi:10.1093/annonc/mdn679.
Hauswald H, Dittmar JO, Habermehl D, Rieken S, Sterzing F, Debus J, et al. Efficacy and toxicity of whole brain radiotherapy in patients with multiple cerebral metastases from malignant melanoma. Radiat Oncol. 2012;7:130. doi:10.1186/1748-717X-7-130.
Yamamoto M, Serizawa T, Sato Y, Kawabe T, Higuchi Y, Nagano O, et al. Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases. J Neurooncol. 2013;111(3):327–35. doi:10.1007/s11060-012-1019-9.
Sun M, Behrens C, Feng L, Ozburn N, Tang X, Yin G, et al. HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin Cancer Res. 2009;15(15):4829–37. doi:10.1158/1078-0432.CCR-08-2921.
Acknowledgments
This study was supported by WU JIEPING MEDICAL FOUNDATION and Research Project Supported by Scholarship Council of China.
Conflicts of interest
None.
Research involving human participants
The study was reviewed and approved by the ethical Institutional Review Board of Shanxi Tumor Hospital, Shanxi, China.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Hongwei Li and Xiaqin Zhang contributed equally to this work.
An erratum to this article is available at http://dx.doi.org/10.1007/s13277-015-3953-6.
Rights and permissions
About this article
Cite this article
Li, H., Zhang, X., Cao, J. et al. Exon 19 deletion of epidermal growth factor receptor is associated with prolonged survival in brain metastases from non-small-cell lung cancer. Tumor Biol. 36, 9251–9258 (2015). https://doi.org/10.1007/s13277-015-3653-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3653-2