Abstract
The study aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with non-small-cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography (PET/CT) scan. Patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging scan at initial diagnosis in Nanfang Hospital between July 2010 and June 2014 were consecutively enrolled. The correlation of EGFR mutation status with TNM stage and distant metastasis organs including brain, bone, liver, pleural, adrenals and contralateral lobe of lung were analyzed. A total of 401 patients were enrolled. Tumor size in EGFR mutation group was significantly smaller than the wild-type group (P < 0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (45.7 vs 32.2 %, P = 0.007). The rates of bone (32.2 vs 22.8 %, P = 0.007) and brain (16.3 vs 9.4 %, P = 0.008) metastasis were significantly higher in EGFR mutation group than the wild-type group. In the subgroup of 199 metastatic NSCLC patients, patients with EGFR mutation were significantly associated with a smaller tumor size (P = 0.013) and earlier N stage (P = 0.033). Of note, compared with the EGFR wild-type group, patients had a higher likelihood of developing brain plus bone metastases at initial diagnosis of EGFR mutation group (20.9 vs 7.5 %, P = 0.018). Taken together, we identify that EGFR mutations might associate with more aggressive tumor progression than the wild types in NSCLC. In addition, patients with tumor having EGFR mutation had a smaller tumor size than without mutation.
Similar content being viewed by others
References
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. doi:10.3322/caac.21262.
Youlden DR, Cramb SM, Baade PD. The international epidemiology of lung cancer: geographical distribution and secular trends. J Thorac Oncol. 2008;3(8):819–31. doi:10.1097/JTO.0b013e31818020eb.
Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121–8. doi:10.1016/S1470-2045(09)70364-X.
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57. doi:10.1056/NEJMoa0810699.
Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012;30(10):1122–8. doi:10.1200/JCO.2011.36.8456.
Hendriks LE, Smit EF, Vosse BA, Mellema WW, Heideman DA, Bootsma GP, et al. EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases? Lung Cancer. 2014;84(1):86–91. doi:10.1016/j.lungcan.2014.01.006.
Shin DY, Na II, Kim CH, Park S, Baek H, Yang SH. EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014;9(2):195–9. doi:10.1097/JTO.0000000000000069.
Enomoto Y, Takada K, Hagiwara E, Kojima E. Distinct features of distant metastasis and lymph node stage in lung adenocarcinoma patients with epidermal growth factor receptor gene mutations. Respir Investig. 2013;51(3):153–7. doi:10.1016/j.resinv.2013.02.004.
Togashi Y, Masago K, Kubo T, Sakamori Y, Kim YH, Hatachi Y, et al. Association of diffuse, random pulmonary metastases, including miliary metastases, with epidermal growth factor receptor mutations in lung adenocarcinoma. Cancer. 2011;117(4):819–25. doi:10.1002/cncr.25618.
Rankin S. PET/CT for staging and monitoring non small cell lung cancer. Cancer Imaging. 2008;8:S27–31. doi:10.1102/1470-7330.2008.9006 (Spec No A).
Halac M, Ozhan M, Aksoy SY, Vatankulu B, Aliyev A, Asa S, et al. The role of FDG-PET/CT in detecting unsuspected and unknown distant metastasis in the initial staging of NSCLC. Turk J Med Sci. 2014;44(6):1029–40.
Hochhegger B, Alves GR, Irion KL, Fritscher CC, Fritscher LG, Concatto NH, et al. PET/CT imaging in lung cancer: indications and findings. Jornal brasileiro de pneumologia: publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia. 2015;41(3):264–74. doi:10.1590/S1806-37132015000004479.
Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 2004;64(24):8919–23. doi:10.1158/0008-5472.CAN-04-2818.
Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46. doi:10.1093/jnci/dji055.
Wu M, Zhao J, Song SW, Zhuo M, Wang X, Bai H, et al. EGFR mutations are associated with prognosis but not with the response to front-line chemotherapy in the Chinese patients with advanced non-small cell lung cancer. Lung Cancer. 2010;67(3):343–7. doi:10.1016/j.lungcan.2009.04.011.
Ueno Y, Sakurai H, Tsunoda S, Choo MK, Matsuo M, Koizumi K, et al. Heregulin-induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells. Int J Cancer. 2008;123(2):340–7. doi:10.1002/ijc.23465.
Lu Z, Jiang G, Blume-Jensen P, Hunter T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol. 2001;21(12):4016–31. doi:10.1128/MCB.21.12.4016-4031.2001.
Sasaki T, Nakamura T, Rebhun RB, Cheng H, Hale KS, Tsan RZ, et al. Modification of the primary tumor microenvironment by transforming growth factor alpha-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model. Am J Pathol. 2008;173(1):205–16. doi:10.2353/ajpath.2008.071147.
Ho-Pun-Cheung A, Assenat E, Bascoul-Mollevi C, Bibeau F, Boissiere-Michot F, Cellier D, et al. EGFR and HER3 mRNA expression levels predict distant metastases in locally advanced rectal cancer. Int J Cancer. 2011;128(12):2938–46. doi:10.1002/ijc.25639.
Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76. doi:10.1053/ctrv.2000.0210.
De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D, et al. The role of the EGFR signaling in tumor microenvironment. J Cell Physiol. 2008;214(3):559–67. doi:10.1002/jcp.21260.
Mimeault M, Batra SK. Frequent gene products and molecular pathways altered in prostate cancer- and metastasis-initiating cells and their progenies and novel promising multitargeted therapies. Mol Med. 2011;17(9–10):949–64. doi:10.2119/molmed.2011.00115.
Fujimoto D, Ueda H, Shimizu R, Kato R, Otoshi T, Kawamura T, et al. Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis. Clin Exp Metastasis. 2014;31(5):543–51. doi:10.1007/s10585-014-9648-3.
Lu X, Kang Y. Epidermal growth factor signalling and bone metastasis. Br J Cancer. 2010;102(3):457–61. doi:10.1038/sj.bjc.6605490.
Delea TE, McKiernan J, Brandman J, Edelsberg J, Sung J, Raut M, et al. Impact of skeletal complications on total medical care costs among patients with bone metastases of lung cancer. J Thorac Oncol. 2006;1(6):571–6.
D’Antonio C, Passaro A, Gori B, Del Signore E, Migliorino MR, Ricciardi S, et al. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. Ther Adv Med Oncol. 2014;6(3):101–14. doi:10.1177/1758834014521110.
Machado M, Cruz LS, Tannus G, Fonseca M. Efficacy of clodronate, pamidronate, and zoledronate in reducing morbidity and mortality in cancer patients with bone metastasis: a meta-analysis of randomized clinical trials. Clin Ther. 2009;31(5):962–79. doi:10.1016/j.clinthera.2009.05.009.
Sun DS, Hu LK, Cai Y, Li XM, Ye L, Hou HY, et al. 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. 2014;15(3):1233–9.
Zeng YD, Zhang L, Liao H, Liang Y, Xu F, Liu JL, et al. Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study. Asian Pac J Cancer Prev APJCP. 2012;13(3):909–14.
Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C, et al. 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. 2012;77(3):556–60. doi:10.1016/j.lungcan.2012.05.092.
Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009;65(3):351–4. doi:10.1016/j.lungcan.2008.12.011.
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(2):198–203. doi:10.1016/j.lungcan.2008.10.028.
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;. doi:10.1200/JCO.2011.40.1174.
Minchom A, Yu KC, Bhosle J, O’Brien M. The diagnosis and treatment of brain metastases in EGFR mutant lung cancer. CNS Oncol. 2014;3(3):209–17. doi:10.2217/cns.14.19.
Yano M, Sasaki H, Kobayashi Y, Yukiue H, Haneda H, Suzuki E, et al. Epidermal growth factor receptor gene mutation and computed tomographic findings in peripheral pulmonary adenocarcinoma. J Thorac Oncol. 2006;1(5):413–6.
Acknowledgments
This work was supported by National Natural Science Foundation of China (81300029); Science and technology projects in Guangdong Province (2012B031800262); Natural Science Foundation of Guangdong Province (S2013040013505); President Foundation of Nanfang Hospital, Southern Medical University (2013Z010); President Foundation of Nanfang Hospital, Southern Medical University (2012Z002).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
Ethical approval was given by the Ethics Committee of the Nanfang Hospital of Southern Medical University (No. NFEC-2015-11). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
Additional information
Jian Guan and Min Chen have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Guan, J., Chen, M., Xiao, N. et al. EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan. Med Oncol 33, 1 (2016). https://doi.org/10.1007/s12032-015-0714-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-015-0714-8