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
  • View Affiliations

  • Published online on: October 3, 2017     https://doi.org/10.3892/ol.2017.7125
  • Pages: 7589-7596
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.

Introduction

Globally, numerous patients succumb to lung cancer (1). The use of cytotoxic chemotherapy remains a major means of treating patients with unresectable non-small cell lung cancer (NSCLC). Nevertheless, the effectiveness of cytotoxic chemotherapy may be limited in certain patients, with a response rate of 20–35% and a median survival time of 10–12 months (2,3). For treating such patients, gefitinib and erlotinib, the first generation orally administered epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) were developed. At first, the effect of EGFR-TKIs was limited due to treating unselected patients with NSCLC (47). However, previous studies have revealed that the presence of EGFR mutation may be associated with increased responsiveness to EGFR-TKIs in patients with NSCLC (811). In previous studies, the response rate was 62.1–83.0%, with a median progression-free survival (PFS) and overall survival (OS) of 9.2–13.1 months and 19.3–30.5 months, respectively (812). The toxicities of EGFR-TKIs are decreased compared with those of cytotoxic drugs and patients can achieve a good quality of life while using them (8,12). In patients treated with first generation EGFR-TKIs, brain, bone and liver metastasis and pleural effusion (PE) predicted a poorer prognosis compared with patients without these metastasis (1317). However, few reports concern the association between the site of metastasis and prognosis (18,19). Understanding which metastatic organ sites influence the prognosis of patients treated with EGFR-TKIs and the prognostic significance of the number of metastatic organ sites is crucial in explaining the condition to patients and aiding them in tolerating the treatment.

Therefore, the present study was a retrospective cohort study conducted to analyze the association between the site and number of metastases, and the prognosis of EGFR-TKI-treated EGFR mutation-positive patients with NSCLC.

Materials and methods

Patients

Pathology reports from the National Hospital Organization Kinki-chuo Chest Medical Center (Osaka, Japan) were retrospectively reviewed between January 2009 and December 2014 and 533 patients were identified as having EGFR mutation-positive NSCLC. Patients with stage IA-IIIA disease, based on the 7th TNM staging system (20), and SCLC were excluded. All participants provided written informed consent for their data to be included. The study protocol was approved by the Institutional Review Board (approval no. 561; October 20, 2016) of the National Hospital Organization Kinki-chuo Chest Medical Center. Research was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments.

Data collection

Clinical data, including age, sex, type of EGFR mutation, TNM stage, smoking status, treatment history, PFS, OS and metastatic status were collected at the point of first-line treatment. Clinical responses were defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (21). PFS was measured from the date of the commencement of primary systemic therapy to the date of disease progression or mortality from any cause. OS was measured from the date of diagnosis to the date of death, loss to follow-up or last follow-up, whichever occurred first. Patients were followed-up for disease status until February 2016.

EGFR mutation identification

Lung cancer was pathologically confirmed using tissue specimens obtained from bronchoscopy, computed tomography-guided biopsy, PE cytology, or surgical procedures. Mutational analysis of the EGFR gene was performed using Scorpion technology in combination with the Amplified Refractory Mutation System or polymerase chain reaction-Invader technique, as previously described (22,23).

Statistical analysis

Statistical analysis was conducted using the JMP statistical software program, version 11 (SAS Institute Inc., Cary, NC, USA) to compare clinical outcomes according to the metastatic status of the patients. Survival curves were estimated using the Kaplan-Meier method and the differences between the groups were compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards models. Fisher's exact test was used to compare the non-parametric variables. P<0.05 was considered to indicate a statistically significant difference.

Results

Patient characteristics

Of the 533 EGFR mutation-positive patients with NSCLC initially recruited to the study, 355 were excluded based on the following criteria: Stage I–IIIA disease (n=228), treated with chemotherapy (n=50), treated with EGFR-TKIs and chemotherapy (n=31), received best supportive care only (n=25), treated with chemoradiotherapy (n=8), treated with second generation EGFR-TKIs (n=6), unknown TNM stage (n=3), small cell carcinoma (n=3) and treated with radiotherapy (n=1). A total of 178 patients remained, who were treated with first generation EGFR-TKIs as the first-line treatment (Fig. 1). Of these patients, 127 were female and 51 were male. The median age at the time of first-line treatment was 72 (range, 39–91) years. A total of 168 patients had adenocarcinoma, 134 patients had stage IV disease, 71 patients had a history of smoking and 156 patients were treated with gefitinib (Table I).

Table I.

Patient baseline characteristics.

Table I.

Patient baseline characteristics.

Metastasis

CharacteristicAll patientsBrainBoneLiverPleural effusion
Total, n17865781756
Sex, n
  Male511527516
  Female12750511240
Age in years, median (range)72 (39–91)71 (50–89)71 (42–89)71 (50–89)73 (39–91)
Histopathological subtype, n
  Adenocarcinoma16862741654
  Squamous cell carcinoma10000
  Not otherwise specified93412
Tumor node metastasis stage, n
  Stage IIIB10000
  Stage IV13455691748
  Postoperative recurrence3910806
  Post-radiotherapy recurrence40102
Smoking status, n
  Smoker711935421
  Non-smoker10245411233
EGFR mutation type, n
  Exon 19 deletion803432820
  p.L858R782333629
  Other2081337
EGFR-tyrosine kinase inhibitor therapy
  Gefitinib15652661548
  Erlotinib22131228

[i] EGFR, epithelial growth factor receptor.

Survival analysis

The Kaplan-Meier method was used to assess patient survival (Fig. 2). Patients with brain metastases (8.0 vs. 13.2 months, P=0.008; Fig. 2A), bone metastases (8.8 vs. 15.4 months, P<0.001; Fig. 2B), liver metastases (6.7 vs. 12.5 months, P<0.001; Fig. 2C) and PE (10.8 vs. 12.2 months, P=0.033; Fig. 2D) at the time of first-line treatment were associated with significantly poorer PFS compared with patients without each of these metastases. Patients with brain metastases (20.2 vs. 38.0 months, P<0.001l Fig. 2E), bone metastases (24.0 vs. 32.1 months, P=0.020; Fig. 2F), liver metastases (13.4 vs. 32.1 months, P<0.001; Fig. 2G), and PE (21.9 vs. 34.9 months, P=0.004; Fig. 2H) at the time of first-line treatment also exhibited significantly poorer OS times compared with patients without each of these metastases.

Response rate analysis

There were no significant differences in the rates of response between patients with brain metastases (58.5 vs. 60.2%, P=0.875), bone metastases (62.8 vs. 57.0%, P=0.446), liver metastases (64.7 vs. 59.0%, P=0.797) and PE (60.7 vs. 59.0%, P=0.871) at the time of first-line treatment and patients without each of these metastases (Table II).

Table II.

Response rates to erlotinib treatment.

Table II.

Response rates to erlotinib treatment.

Metastasis

CharacteristicAll patientsBrainBoneLiverPE
Total17865781756
CR/PR, n10638491134
RR, %   59.6   58.5   62.8   64.7   60.7
P-value0.8750.4460.7970.871

[i] PE, pleural effusion; CR, complete response; PR, partial response; RR, response rate.

Multivariate analysis of prognostic factors

In the multivariate analysis, bone metastasis was significantly associated with a poorer PFS time [hazard ratio (HR), 2.11; 95% confidence interval (CI), 1.44–3.09; P<0.001] and brain metastasis exhibited a trend towards a poorer PFS time, although it was not significant (HR, 2.11; 95% CI, 0.99–2.15; P=0.051; Table III). In addition, brain metastasis was significantly associated with a shorter OS time (HR, 2.41; 95% CI, 1.46–3.95; P<0.001; Table IV).

Table III.

Cox proportional hazards model analysis of factors associated with progression-free survival.

Table III.

Cox proportional hazards model analysis of factors associated with progression-free survival.

Univariate analysisMultivariate analysis


FactorHR95% CIP-valueHR95% CIP-value
Brain metastasis1.631.13–2.330.010a1.480.99–2.150.051
Bone metastasis2.221.55–3.20≤0.001a2.111.44–3.09≤0.001a
Liver metastasis2.731.51–4.620.002a1.420.74–2.560.280
Pleural effusion1.491.02–2.170.039a1.480.99–2.160.053

a P<0.05. CI, confidence interval; HR, hazard ratio; CI, confidence interval.

Table IV.

Cox proportional hazards model of factors associated with overall survival.

Table IV.

Cox proportional hazards model of factors associated with overall survival.

Univariate analysisMultivariate analysis


FactorHR95% CIP-valueHR95% CIP-value
Brain metastasis2.601.64–4.10≤0.001a2.411.46–3.95≤0.001a
Bone metastasis1.691.08–2.640.022a1.590.97–2.580.066
Liver metastasis3.811.96–6.90≤0.001a1.840.88–3.680.104
Pleural effusion1.941.21–3.050.006a1.620.99–2.600.052

a P<0.05. CI, confidence interval; HR, hazard ratio; CI confidence interval.

Effect of metastatic site number on prognosis

The number of metastatic organ sites per patient in the brain, bone, liver, and pleura, (0 in 43 patients, 1 in 81 patients, and ≥2 in 54 patients) was significantly associated with a reduced PFS (19.3 vs. 12.5 vs. 6.6 months, P<0.001) and OS (46.1 vs. 29.9 vs. 15.1 months, P<0.001; Fig. 2I and J) time. No significant differences in PFS (6.2 vs. 7.5 vs. 5.9 months, P=0.545) or OS (14.9 vs. 19.6 vs. 13.4 months, P=0.497) time were observed between patients with 2 (n=33), 3 (n=15) or 4 (n=6) metastatic organ sites.

Effect of EGFR exon 19 deletion and p.L858R mutations on prognosis

Patients with major EGFR mutations (including exon 19 deletion and p.L858R; n=158) were also evaluated. In a multivariate analysis, bone metastasis was identified to be significantly associated with a poorer PFS time. In addition, brain and liver metastases were significantly associated with a poorer OS time (Tables V and VI).

Table V.

Cox proportional hazards model analysis of factors associated with progression-free survival in patients with epithelial growth factor receptor exon 19 deletion and p.L858R mutations.

Table V.

Cox proportional hazards model analysis of factors associated with progression-free survival in patients with epithelial growth factor receptor exon 19 deletion and p.L858R mutations.

Univariate analysisMultivariate analysis


FactorHR95% CIP-valueHR95% CIP-value
Brain metastasis1.691.12–2.520.012a1.450.93–2.220.102
Bone metastasis1.971.33–2.91≤0.001a1.781.16–2.650.008a
Liver metastasis3.251.66–5.850.001a1.950.94–3.840.101
Pleural effusion1.440.95–2.160.083

a P<0.05. HR, hazard ratio; CI, confidence interval.

Table VI.

Cox proportional hazards model analysis of factors associated with overall survival in patients with epithelial growth factor receptor exon 19 deletion and p.L858R mutations.

Table VI.

Cox proportional hazards model analysis of factors associated with overall survival in patients with epithelial growth factor receptor exon 19 deletion and p.L858R mutations.

Univariate analysisMultivariate analysis


FactorHR95% CIP-valueHR95% CIP-value
Brain metastasis2.551.51–4.26≤0.001a2.061.16–3.58   0.014a
Bone metastasis1.430.86–2.360.165
Liver metastasis5.002.29–10.05≤0.001a3.051.34–6.51   0.009a
Pleural effusion1.891.12–3.160.018a1.660.97–2.810.066

a P<0.05. HR, hazard ratio; CI, confidence interval.

Discussion

In the univariate analysis of patients treated with first generation EGFR-TKIs, brain metastasis, bone metastasis, liver metastasis and PE were all associated with poorer PFS and OS times. Furthermore, in the multivariate analysis, bone metastasis was associated with a poorer PFS time and brain metastasis was associated with a poorer OS time. The number of metastatic organ sites was associated with a poorer PFS and OS time.

Between 30 and 40% of patients with lung cancer develop bone metastases during the course of their disease (24). To the best of our knowledge, this is the first study to assess the association between bone metastasis and a poorer PFS time in EGFR mutation-positive NSCLC patients. In a previous report, Fujimoto et al (15) revealed that bone metastasis was a significant independent negative predictive factor for OS time in EGFR mutation-positive patients. By contrast, in the present study, bone metastasis was not associated with OS time. One possible explanation for the association between bone metastasis and a poorer prognosis is the tumor-bone interaction that is reported to increase the malignant behavior of cancer cells. In the development of bone metastases, there is an exchange of factors from the bone matrix that are released during bone resorption, the most notable of which is transforming growth factor-β, which has been demonstrated to enhance tumor growth and the epithelial-mesenchymal transition (25,26).

Brain metastases are a frequent complication of NSCLC, with 25–40% of patients developing brain metastases during the course of their disease, often within the first 2 years following the diagnosis of the primary tumor (24,27). The risk of brain metastasis was increased in EGFR-mutated tumors at the time of diagnosis, as well as during the postoperative course of the disease. Compared with patients with wild-type tumors, patients with EGFR-mutated tumors exhibited more widespread brain lesions (28). The clinical activity of EGFR-TKIs against intracranial disease has previously been described (2933). Furthermore, erlotinib may exhibit a superior control of intracranial disease due to the higher central nervous system penetration and drug concentrations achieved relative to gefitinib (34). However, in the present study, 80% of patients were treated with gefitinib. In patients treated with EGFR-TKIs, brain metastasis has been reported as a risk factor for poorer PFS and OS (13,35). Similarly, in the present study, brain metastasis was the only negative prognostic factor identified by multivariate analysis for OS time.

Wu et al (17) reported that lung adenocarcinoma patients with Stage IV disease and malignant PE at the time of diagnosis have poorer OS times than patients who develop malignant PE following disease progression. However, the difference was only statistically significant in patients with distant metastases. For patients without distant metastases, there was no significant difference. In the present study, PE was not associated with a poorer PFS or OS by univariate analysis. In addition, Wu et al (16) reported that EGFR mutation-positive stage IV lung adenocarcinoma patients with liver metastases treated with gefitinib as first-line treatment exhibited significantly poorer PFS and OS times compared with patients who did not have liver metastases. In the present study, liver metastasis was not associated with a poorer PFS or OS by multivariate analysis. However, the number of patients with liver metastases was relatively small (n=17). This may explain why the results of the present study differ from the Wu et al study. Additionally, in patients with major EGFR mutations (exon 19 deletion and p.L858R), liver metastasis was significantly associated with a poorer OS time in the multivariate analysis (HR, 3.05; 95% CI, 1.34–6.51; P<0.001; Table VI).

Higher numbers of metastatic organ sites were associated with a poorer PFS and OS time, as previously reported (18,19). It has been suggested that the prognostic significance of the number of metastatic organ sites may be due to resistance in patients with a larger tumor burden (36). As aforementioned, patients with bone or brain metastases and patients with ≥2 metastatic organ sites do not respond effectively to treatment with first-generation EGFR-TKIs. Therefore, more effective treatments are required. For EGFR mutation-positive NSCLC patients, novel treatment approaches have been proposed. Seto et al (37) reported that bevacizumab in addition to erlotinib significantly improved PFS. Tamiya et al (38) reported that triplet chemotherapy with gefitinib, carboplatin and tegafur/gimeracil/oteracil as a first-line treatment was efficacious and well tolerated. Furthermore, Kanda et al (39) reported that the addition of cisplatin and docetaxel to gefitinib treatment may have prevented the development of acquired resistance to EGFR-TKIs in EGFR mutation-positive patients with advanced NSCLC. Sugawara et al (40) reported that concurrent chemotherapy with gefitinib and carboplatin or pemetrexed was efficacious as a first-line treatment for EGFR mutation-positive NSCLC patients. Furthermore, Park et al (41) reported that afatinib significantly improved the outcome in treatment-naive patients with EGFR mutation-positive NSCLC compared with gefitinib, with a manageable tolerability profile. Such therapies may be beneficial for patients with the poor prognostic factors identified in the present study; however, no research has been conducted in a clinical setting and further systemic and clinical research is therefore warranted. Furthermore, for patients with brain metastasis, combining EGFR-TKIs and radiotherapy has potential synergistic effects; radiation permeabilizes the blood-brain barrier and TKIs exhibit radio-sensitizing effects (42).

The present study has certain limitations. First, the retrospective design means that undefined biases may have existed, which could have influenced the patients' clinical outcomes. Second, the data collection and analysis was performed at a single tertiary academic center, thus imposing a possible selection bias.

To conclude, bone metastasis was associated with reduced PFS time and brain metastasis was associated with reduced OS time in NSCLC patients with EGFR mutations treated with first-generation EGFR-TKIs. The number of metastatic organ sites was also associated with a poorer PFS and OS.

Acknowledgements

The authors declare the following potential conflicts of interest: S. Atagi has received personal fees from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Hisamitsu Pharmaceutical Co, Bristol-Myers Squibb, Eli Lilly, Boehringer Ingelheim; and has received grants from Chugai Pharmaceutical, AstraZeneca, Pfizer, Merck Serono Co., Ltd., Taiho Pharmaceutical, Yakult Pharmaceutical Industry, Eli Lilly, Ono Pharmaceutical and Boehringer Ingelheim. A. Tamiya has received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly and Boehringer Ingelheim.

Glossary

Abbreviations

Abbreviations:

EGFR

epidermal growth factor receptor

CI

confidence interval

HR

hazard ratio

NSCLC

non-small cell lung cancer

OS

overall survival

PE

pleural effusion

PFS

progression-free survival

TKI

tyrosine kinase inhibitor

References

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

Related Articles

Journal Cover

December-2017
Volume 14 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Taniguchi Y, Tamiya A, Nakahama K, Naoki Y, Kanazu M, Omachi N, Okishio K, Kasai T and Atagi S: 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. Oncol Lett 14: 7589-7596, 2017.
APA
Taniguchi, Y., Tamiya, A., Nakahama, K., Naoki, Y., Kanazu, M., Omachi, N. ... Atagi, S. (2017). 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. Oncology Letters, 14, 7589-7596. https://doi.org/10.3892/ol.2017.7125
MLA
Taniguchi, Y., Tamiya, A., Nakahama, K., Naoki, Y., Kanazu, M., Omachi, N., Okishio, K., Kasai, T., Atagi, S."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". Oncology Letters 14.6 (2017): 7589-7596.
Chicago
Taniguchi, Y., Tamiya, A., Nakahama, K., Naoki, Y., Kanazu, M., Omachi, N., Okishio, K., Kasai, T., Atagi, S."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". Oncology Letters 14, no. 6 (2017): 7589-7596. https://doi.org/10.3892/ol.2017.7125