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Radiology and Oncology

The Journal of Association of Radiology and Oncology

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Volume 48, Issue 2


Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival

Karmen Stanic / Matjaz Zwitter
  • Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia / Faculty of Medicine, University of Maribor, Slovenia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nina Turnsek Hitij / Izidor Kern / Aleksander Sadikov / Tanja Cufer
Published Online: 2014-04-25 | DOI: https://doi.org/10.2478/raon-2014-0016


Background. The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.

Patients and methods. We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.

Results. Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.

Conclusions. Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.

Keywords: brain metastases; lung adenocarcinoma; EGFR mutations


  • 1. Bajard A, Westeel V, Dubiez A, Jacoulet P, Pernet D, Dalphin JC, et al. Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma. Lung Cancer 2004; 45: 317-23.PubMedCrossrefGoogle Scholar

  • 2. Sørensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain metastases in adenocarcinoma of the lung: frequency, risk groups, and prognosis. J Clin Oncol 1988; 6: 1474-80.PubMedGoogle Scholar

  • 3. 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: 1-10.CrossrefGoogle Scholar

  • 4. Ali A, Goffin JR, Arnold A, Ellis PM. Survival of patients with non-small-cell lung cancer after a diagnosis of brain metastases. Curr Oncol 2013; 20: e300-6.CrossrefGoogle Scholar

  • 5. Berger LA, Riesenberg H, Bokemeyer C, Atanackovic D. CNS metastases in non-small-cell lung cancer: Current role of EGFR-TKI therapy and future perspectives. Lung Cancer 2013; 80: 242-8.PubMedCrossrefGoogle Scholar

  • 6. Linnert M, Iversen HK, Gehl J. Multiple brain metastases - current management and perspectives for treatment with electrochemotherapy. Radiol Oncol 2012; 46: 271-8.PubMedGoogle Scholar

  • 7. Rami-Porta R, Crowley JJ, Goldstraw P. The revised TNM staging system for lung cancer. Ann Thorac Cardiovasc Surg 2009; 15: 4-9.Google Scholar

  • 8. Wang S-Y, Ye X, Ou W, Lin Y-B, Zhang B-B, Yang H. Risk of cerebral metastases for postoperative locally advanced non-small-cell lung cancer. Lung Cancer 2009; 64: 238-43.PubMedCrossrefGoogle Scholar

  • 9. Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM. Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 2001; 19: 1344-9.PubMedGoogle Scholar

  • 10. Mamon HJ, Yeap BY, Jänne PA, Reblando J, Shrager S, Jaklitsch MT, et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 2005; 23: 1530-7.PubMedCrossrefGoogle Scholar

  • 11. Smrdel U, Zwitter M, Kovač V. Brain metastases in lung cancer. Impact of prognostic factors on patient survival. Radiol Oncol 2003; 37: 213-6.Google Scholar

  • 12. Gaspar LE, Chansky K, Albain KS, Vallieres E, Rusch V, Crowley JJ, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III nonsmall- cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol 2005; 23: 2955-61.CrossrefGoogle Scholar

  • 13. Ceresoli GL, Reni M, Chiesa G, Carretta A, Schipani S, Passoni P, et al. Brain metastases in locally advanced nonsmall cell lung carcinoma after multimodality treatment: risk factors analysis. Cancer 2002; 95: 605-12.PubMedCrossrefGoogle Scholar

  • 14. Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y, Kohno T, et al. Frequent EGFR mutations in brain metastases of lung adenocarcinoma. Int J Cancer 2006; 119: 1491-4.PubMedCrossrefGoogle Scholar

  • 15. Fujiwara S, Murakami H, Shukuya T, Ono A, Tsuye A, Nakamura Y, et al. Clinical significance of EGFR on progression of brain meta. J Thorac Oncol 2011; 6(Suppl 2): S1214.Google Scholar

  • 16. Sekine A, Kato T, Hagiwara E, Shinohara T, Komagata T, Iwasawa T, et al. 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: 64-9.CrossrefGoogle Scholar

  • 17. Zhou Wei CD. East meets West:ethnic differences in epidemiology and clinical behaviours of lung cancer between East Asian and Caucasians. Chin J Cancer 2011; 30: 287-92.Google Scholar

  • 18. de Mello RA, Pires FS, Marques DS, Oliveira J, Rodrigues A, Soares M, et al. EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. Tumor Biol 2012; 33: 2061-8.CrossrefGoogle Scholar

  • 19. Li Z, Lu J, Zhao Y, Guo H. The retrospective analysis of the frequency of EGFR mutations and the efficacy of gefitinib in NSCLC patients with brain metastasis. J Clin Oncol 2011; 29: e18065.Google Scholar

  • 20. Sekine A. Characteristics of metastatic brain tumor in patients with lung adenocarcinoma with mutation of epidermal growth factor receptor gene. Am J Respir Crit Care Med 2010; 181: A5147Google Scholar

  • 21. Lee YJ, Park IK, Park M-S, Choi HJ, Cho BC, Chung KY, et al. Activating mutations within the EGFR kinase domain: a molecular predictor of disease-free survival in resected pulmonary adenocarcinoma. J Cancer Res Clin Oncol 2009; 135: 1647-54.CrossrefPubMedGoogle Scholar

  • 22. Porta R, Sánchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011; 37: 624-31.CrossrefPubMedGoogle Scholar

  • 23. Na II, Park JH, Choe DH, Lee JK, Koh JS. Association of epidermal growth factor receptor mutations with metastatic presentations in non-small cell lung cancer. ISRN Oncol 2011; 2011: 756265.PubMedGoogle Scholar

  • 24. Saad AG, Yeap BY, Thunnissen FBJM, Pinkus GS, Pinkus JL, Loda M, et al. Immunohistochemical markers associated with brain metastases in patients with nonsmall cell lung carcinoma. Cancer 2008; 113: 2129-38.PubMedCrossrefGoogle Scholar

  • 25. Cancer in Slovenia 2010. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2013.Google Scholar

  • 26. 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: 1193-9.CrossrefPubMedGoogle Scholar

  • 27. Heon S, Yeap BY, Britt GJ, Costa DB, Rabin MS, Jackman DM, et al. 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 2010; 16: 5873-82.CrossrefPubMedGoogle Scholar

  • 28. 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.CrossrefPubMedGoogle Scholar

  • 29. Hsiao SH. Impact of epidermal growth factor receptor mutations on intracranial treatment response and survival after brain metastases in lung adenocarcinoma patients. Lung Cancer 2013; 81: 455-61.PubMedCrossrefGoogle Scholar

  • 30. Komatsu T, Kunieda E, Oizumi Y, Tamai Y, Akiba T. Clinical characteristics of brain metastases from lung cancer according to histological type: Pretreatment evaluation and survival following whole-brain radiotherapy. Mol Clin Oncol 2011; 1: 692-8.Google Scholar

  • 31. Gow C-H, Chien C-R, Chang Y-L, Chiu Y-H, Kuo S-H, Shih J-Y, 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: 162-8.CrossrefPubMedGoogle Scholar

  • 32. Ceresoli GL. Role of EGFR inhibitors in the treatment of central nervous system metastases from non-small cell lung cancer. Curr Cancer Drug Targets 2012; 12: 237-46.CrossrefPubMedGoogle Scholar

  • 33. Das AK, Sato M, Story MD, Peyton M, Graves R, Redpath S, et al. Non-smallcell lung cancers with kinase domain mutations in the epidermal growth factor receptor are sensitive to ionizing radiation. Cancer Res 2006; 66: 9601-8.CrossrefGoogle Scholar

  • 34. Liang K, Ang KK, Milas L, Hunter N, Fan Z. The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol 2003; 57: 246-54.CrossrefGoogle Scholar

  • 35. Tanaka T, Munshi A, Brooks C, Liu J, Hobbs ML, Meyn RE. Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity. Clin Cancer Res 2008; 14: 1266-73.CrossrefPubMedGoogle Scholar

  • 36. Lind J, Lagerwaard F, Smit E, Senan S. Phase I Study of Concurrent Whole Brain Radiotherapy and Erlotinib for Multiple Brain Metastases From Non- Small-Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2009; 74: 1391-6.PubMedCrossrefGoogle Scholar

  • 37. Welsh JW, Komaki R, Amini A, Munsell MF, Unger W, Allen PK, et al. 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 2013; 31: 895-902.CrossrefPubMedGoogle Scholar

  • 38. 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 2009; 65: 198-203.CrossrefGoogle Scholar

  • 39. Olmez I, Donahue BR, Butler JS, Huang Y, Rubin P XY. Clinical outcomes in extracranial tumor sites and unusual toxicities with concurrent whole brain radiation (WBRT) and Erlotinib treatment in patients with non-small cell lung cancer (NSCLC) with brain metastasis. Lung cancer 2010; 70: 174-9.CrossrefPubMedGoogle Scholar

  • 40. Zhuang H, Yuan Z, Wang J, Zhao L, Pang Q, Wang P. Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma. Drug Des Devel Ther 2013; 7: 179-86.Google Scholar

  • 41. Togashi Y, Masago K, Fukudo M, Tsuchido Y, Okuda C, Kim YH, et al. Efficacy of increased-dose erlotinib for central nervous system metastases in nonsmall cell lung cancer patients with epidermal growth factor receptor mutation. Cancer Chemother Pharmacol 2011; 68: 1089-92.CrossrefPubMedGoogle Scholar

  • 42. Grommes C, Oxnard GR, Kris MG, Miller VA, Pao W, Holodny AI, et al. “Pulsatile” high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011; 13: 1364-9.PubMedCrossrefGoogle Scholar

  • 43. Kim ST, Uhm JE, Lee J, Sun J, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012; 75: 82-8.PubMedCrossrefGoogle Scholar

  • 44. Shimato S, Mitsudomi T, Kosaka T, Yatabe Y, Wakabayashi T, Mizuno M, et al. EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib. Neuro Oncol 2006; 8: 137-44.PubMedCrossrefGoogle Scholar

  • 45. Tang W-H, Chen J-H, Ye R-H, Ho C-L. Near Total Regression of Diffuse Brain Metastases in Adenocarcinoma of the Lung with an EGFR Exon 19 Mutation: A Case Report and Review of the Literature. Case Rep Oncol 2011; 4: 445-51.Google Scholar

  • 46. Heon S, Yeap BY, Lindeman NI, Rabin MS, Jackman DJ, Johnson BE. Rates of central nervous system (CNS) metastases in patients with advanced nonsmall cell lung cancer (NSCLC) and somatic EGFR mutations initially treated with gefitinib or erlotinib versus chemotherapy. J Clin Oncol 2011; 29(Suppl15): A7607.Google Scholar

  • 47. Ceresoli GL, Cappuzzo F, Gregorc V, Bartolini S, Crinò L, Villa E. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 2004; 15: 1042-7.PubMedCrossrefGoogle Scholar

  • 48. Lee YJ, Choi HJ, Kim SK, Chang J, Moon JW, Park IK, et al. Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall-cell lung cancer. Cancer 2010; 116: 1336-43.PubMedCrossrefGoogle Scholar

  • 49. Stuschke BM, Eberhardt W, Po C, Stamatis G, Wilke H, Stu G, et al. Prophylactic cranial irradiation in locally advanced Non Small Cell Lung Cancer after multimodality treatment: Long term follow up and investigation of late neuropsychological effects. J Clin Oncol 1999; 17: 2700-9.Google Scholar

  • 50. Lester JF, MacBeth FR, Coles B. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 2005; 63: 690-4.CrossrefPubMedGoogle Scholar

  • 51. Topkan E, Yildrim BA, Selek U YM. Cranial Prophylactic Irradiation in Locally Advanced Non-Small Cell Lung Carcinoma: Current Status and Future Perspectives. Oncology 2009; 76: 220-8.CrossrefGoogle Scholar

  • 52. Dimitropoulos C, Hillas G, Nikolakopoulou S, Kostara I, Sagris K, Vlastos F, et al. Prophylactic cranial irradiation in non-small cell lung cancer patients: who might be the candidates? Cancer Manag Res 2011; 3: 287-94.PubMedGoogle Scholar

  • 53. Tufman A, Belka C, Kuenel H, Huber RM. Prophylactic cranial irradiation after reaching complete response, partial response, or stable disease in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (ProACT). J Clin Oncol 2012; 30: TPS7617 Google Scholar

About the article

Received: 2013-12-24

Accepted: 2014-03-03

Published Online: 2014-04-25

Published in Print: 2014-06-01

Citation Information: Radiology and Oncology, Volume 48, Issue 2, Pages 173–183, ISSN (Online) 1581-3207, ISSN (Print) 1318-2099, DOI: https://doi.org/10.2478/raon-2014-0016.

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© by Karmen Stanic. This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. BY-NC-ND 3.0

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