Skip to main content
Top
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

Exon 19 deletion of epidermal growth factor receptor is associated with prolonged survival in brain metastases from non-small-cell lung cancer

Authors: Hongwei Li, Xiaqin Zhang, Jianzhong Cao, Pengcheng Su, Jianhong Lian, Xing Song, Weihua Yang, Songyan Han, Yanfeng Xi, Yaohua Wang

Published in: Tumor Biology | Issue 12/2015

Login to get access

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.
Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
12.
13.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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/​0284186051002969​9.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
26.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
Exon 19 deletion of epidermal growth factor receptor is associated with prolonged survival in brain metastases from non-small-cell lung cancer
Authors
Hongwei Li
Xiaqin Zhang
Jianzhong Cao
Pengcheng Su
Jianhong Lian
Xing Song
Weihua Yang
Songyan Han
Yanfeng Xi
Yaohua Wang
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3653-2

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine