Impact of metastatic status on the prognosis of EGFR mutation‑positive non‑small cell lung cancer patients treated with first‑generation EGFR‑tyrosine kinase inhibitors

Taniguchi,Yoshihiko; Tamiya,Akihiro; Nakahama,Kenji; Naoki,Yoko; Kanazu,Masaki; Omachi,Naoki; Okishio,Kyoichi; Kasai,Takahiko; Atagi,Shinji

doi:10.3892/ol.2017.7125

Impact of metastatic status on the prognosis of EGFR mutation‑positive non‑small cell lung cancer patients treated with first‑generation EGFR‑tyrosine kinase inhibitors

Authors:
- Yoshihiko Taniguchi
- Akihiro Tamiya
- Kenji Nakahama
- Yoko Naoki
- Masaki Kanazu
- Naoki Omachi
- Kyoichi Okishio
- Takahiko Kasai
- Shinji Atagi
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Affiliations: Department of Internal Medicine, National Hospital Organization Kinki‑chuo Chest Medical Center, Sakai, Osaka 591‑8555, Japan, Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, Osaka 560‑8552, Japan, Department of Clinical Research Center, National Hospital Organization Kinki‑chuo Chest Medical Center, Sakai, Osaka 591‑8555, Japan, Department of Pathology, National Hospital Organization Kinki‑chuo Chest Medical Center, Sakai, Osaka 591‑8555, Japan
Published online on: October 3, 2017 https://doi.org/10.3892/ol.2017.7125
Pages: 7589-7596

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Abstract

The aim of the present study was to analyze the impact of metastatic status on the prognosis of epithelial growth factor receptor (EGFR) mutation‑positive patients with non‑small cell lung cancer (NSCLC) treated with first‑generation EGFR‑tyrosine kinase inhibitors (TKIs). A total of 178 EGFR mutation‑positive patients with stage IIIB‑IV and relapsed NSCLC who were treated with gefitinib or erlotinib as the first‑line treatment were enrolled in the present study. Metastatic status, progression‑free survival (PFS), overall survival (OS) and treatment‑response rates were investigated. The association between the number of metastatic organ sites and patient prognosis was also investigated. The median age at the time of treatment was 72 (range, 39‑91) years. A total of 168 patients had adenocarcinoma; 156 were treated with gefitinib. Patients with brain metastases, bone metastases, liver metastases and pleural effusion exhibited a significantly reduced PFS and OS time in the univariate analysis, compared with patients without each of these symptoms. In the multivariate analysis, bone metastasis was associated with a poorer PFS (hazard ratio, 2.11; 95% confidence interval, 1.44‑3.09; P<0.001) and brain metastasis was associated with a poorer OS (hazard ratio, 2.41; 95% confidence interval, 1.46‑3.95; P<0.001). No association was observed between metastatic status and treatment response rates. Higher numbers of different sites of organ metastases were associated with significantly poorer PFS and OS. Bone, brain metastasis and higher numbers of metastatic organ sites are negative prognostic factors for EGFR mutation‑positive NSCLC patients treated with first‑generation EGFR‑TKIs.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J and Johnson DH: Eastern Cooperative Oncology Group: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 346:92–98. 2002. View Article : Google Scholar : PubMed/NCBI
3	Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, Nishiwaki Y, Saijo N, Ariyoshi Y and Fukuoka M: Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan. Ann Oncol. 18:317–323. 2007. View Article : Google Scholar : PubMed/NCBI
4	Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol. 21:2237–2246. 2003. View Article : Google Scholar : PubMed/NCBI
5	Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA. 290:2149–2158. 2003. View Article : Google Scholar : PubMed/NCBI
6	Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, et al: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet. 372:1809–1818. 2008. View Article : Google Scholar : PubMed/NCBI
7	Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, Nakagawa K, Shinkai T, Negoro S, Imamura F, Eguchi K, et al: Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 26:4244–4252. 2008. View Article : Google Scholar : PubMed/NCBI
8	Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 362:2380–2388. 2010. View Article : Google Scholar : PubMed/NCBI
9	Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, 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. 11:121–128. 2010. View Article : Google Scholar : PubMed/NCBI
10	Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, et al: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12:735–742. 2011. View Article : Google Scholar : PubMed/NCBI
11	Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13:239–246. 2012. View Article : Google Scholar : PubMed/NCBI
12	Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 361:947–957. 2009. View Article : Google Scholar : PubMed/NCBI
13	Lin JJ, Cardarella S, Lydon CA, Dahlberg SE, Jackman DM, Jänne PA and Johnson BE: Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol. 11:556–565. 2016. View Article : Google Scholar : PubMed/NCBI
14	Noronha V, Joshi A, Gokarn A, Sharma V, Patil V, Janu A, Purandare N, Chougule A, Jambhekar N and Prabhash K: The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC Patients. Chemother Res Pract. 2014:8561562014.PubMed/NCBI
15	Fujimoto D, Ueda H, Shimizu R, Kato R, Otoshi T, Kawamura T, Tamai K, Shibata Y, Matsumoto T, Nagata K, 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. 31:543–551. 2014. View Article : Google Scholar : PubMed/NCBI
16	Wu KL, Tsai MJ, Yang CJ, Chang WA, Hung JY, Yen CJ, Shen CH, Kuo TY, Lee JY, Chou SH, et al: Liver metastasis predicts poorer prognosis in stage IV lung adenocarcinoma patients receiving first-line gefitinib. Lung Cancer. 88:187–194. 2015. View Article : Google Scholar : PubMed/NCBI
17	Wu SG, Yu CJ, Tsai MF, Liao WY, Yang CH, Jan IS, Yang PC and Shih JY: Survival of lung adenocarcinoma patients with malignant pleural effusion. Eur Respir J. 41:1409–1418. 2013. View Article : Google Scholar : PubMed/NCBI
18	Park JH, Kim TM, Keam B, Jeon YK, Lee SH, Kim DW, Chung DH, Kim YT, Kim YW and Heo DS: Tumor burden is predictive of survival in patients with non-small-cell lung cancer and with activating epidermal growth factor receptor mutations who receive gefitinib. Clin Lung Cancer. 14:383–389. 2013. View Article : Google Scholar : PubMed/NCBI
19	Lee JY, Lim SH, Kim M, Jung HA, Chang WJ, Choi MK, Hong JY, Lee SJ, Sun JM, Ahn JS, et al: Is there any predictor for clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs? Cancer Chemother Pharmacol. 73:1063–1070. 2014. View Article : Google Scholar : PubMed/NCBI
20	Travis WD, Giroux DJ, Chansky K, Crowley J, Asamura H, Brambilla E, Jett J, Kennedy C, Rami-Porta R, Rusch VW, et al: The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 3:1213–1223. 2008. View Article : Google Scholar : PubMed/NCBI
21	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kimura H, Fujiwara Y, Sone T, Kunitoh H, Tamura T, Kasahara K and Nishio K: High sensitivity detection of epidermal growth factor receptor mutations in the pleural effusion of non-small cell lung cancer patients. Cancer Sci. 97:642–648. 2006. View Article : Google Scholar : PubMed/NCBI
23	Mast A and de Arruda M: Invader assay for single-nucleotide polymorphism genotyping and gene copy number evaluation. Methods Mol Biol. 335:173–186. 2006.PubMed/NCBI
24	D'Antonio C, Passaro A, Gori B, Del Signore E, Migliorino MR, Ricciardi S, Fulvi A and de Marinis F: Bone and brain metastasis in lung cancer: Recent advances in therapeutic strategies. Ther Adv Med Oncol. 6:101–114. 2014. View Article : Google Scholar : PubMed/NCBI
25	Weilbaecher KN, Guise TA and McCauley LK: Cancer to bone: A fatal attraction. Nat Rev Cancer. 11:411–425. 2011. View Article : Google Scholar : PubMed/NCBI
26	Yoneda T and Hiraga T: Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun. 328:679–687. 2005. View Article : Google Scholar : PubMed/NCBI
27	Rahmathulla G, Toms SA and Weil RJ: The molecular biology of brain metastasis. J Oncol. 2012:7235412012. View Article : Google Scholar : PubMed/NCBI
28	Shin DY, Na II, Kim CH, Park S, Baek H and Yang SH: EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 9:195–199. 2014. View Article : Google Scholar : PubMed/NCBI
29	Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C and Lee JS: 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. 65:351–354. 2009. View Article : Google Scholar : PubMed/NCBI
30	Porta R, Sanchez-Torres JM, Paz-Ares L, Massutí B, Reguart N, Mayo C, Lianes P, Queralt C, Guillem V, Salinas P, et al: Brain metastases from lung cancer responding to erlotinib: The importance of EGFR mutation. Eur Respir J. 37:624–631. 2011. View Article : Google Scholar : PubMed/NCBI
31	Jamal-Hanjani M and Spicer J: Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res. 18:938–944. 2012. View Article : Google Scholar : PubMed/NCBI
32	Park SJ, Kim HT, Lee DH, Kim KP, Kim SW, Suh C and Lee JS: 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. 77:556–560. 2012. View Article : Google Scholar : PubMed/NCBI
33	Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y and Yang JJ: 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. 24:993–999. 2013. View Article : Google Scholar : PubMed/NCBI
34	Togashi Y, Masago K, Masuda S, Mizuno T, Fukudo M, Ikemi Y, Sakamori Y, Nagai H, Kim YH, Katsura T and Mishima M: Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 70:399–405. 2012. View Article : Google Scholar : PubMed/NCBI
35	Lim SH, Lee JY, Sun JM, Ahn JS, Park K and Ahn MJ: Comparison of clinical outcomes following gefitinib and erlotinib treatment in non-small-cell lung cancer patients harboring an epidermal growth factor receptor mutation in either exon 19 or 21. J Thorac Oncol. 9:506–511. 2014. View Article : Google Scholar : PubMed/NCBI
36	Goldie JH and Coldman AJ: The genetic origin of drug resistance in neoplasms: Implications for systemic therapy. Cancer Res. 44:3643–3653. 1984.PubMed/NCBI
37	Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, et al: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 15:1236–1244. 2014. View Article : Google Scholar : PubMed/NCBI
38	Tamiya A, Tamiya M, Shiroyama T, Saijo N, Nakatani T, Minomo S, Tsuji T, Takeuchi N, Omachi N, Kurata K, et al: Phase II trial of carboplatin, S-1, and gefitinib as first-line triplet chemotherapy for advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations. Med Oncol. 32:402015. View Article : Google Scholar : PubMed/NCBI
39	Kanda S, Horinouchi H, Fujiwara Y, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Kubota K, Tamura T and Ohe Y: Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Lung Cancer. 89:287–293. 2015. View Article : Google Scholar : PubMed/NCBI
40	Sugawara S, Oizumi S, Minato K, Harada T, Inoue A, Fujita Y, Maemondo M, Yoshizawa H, Ito K, Gemma A, et al: Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902. Ann Oncol. 26:888–894. 2015. View Article : Google Scholar : PubMed/NCBI
41	Park K, Tan EH, O'Byrne K, et al: Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 17:577–589. 2016. View Article : Google Scholar : PubMed/NCBI
42	Dempke WC, Edvardsen K, Lu S, Reinmuth N, Reck M and Inoue A: Brain Metastases in NSCLC-are TKIs changing the treatment strategy? Anticancer Res. 35:5797–5806. 2015.PubMed/NCBI