mTOR信号通路与手术后肺腺癌
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摘要
背景：非小细胞肺癌(NSCLC)目前仍然是世界范围内最重要的死亡原因之一,而EGFR/PI3K/Akt/mTOR信号通路与NSCLS的发生、发展密切相关。表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)目前在晚期NSCLC中被广泛使用,EGFR突变是EGFR-TKI敏感性相关的最重要的预测因子。但EGFR-TKI在早中期肺癌外科手术后应用很少,相关疗效及敏感性预测因子仍无人报道。
目的：研究肺腺癌EGFR突变、p-mTOR、p-4EBP1、EIF4E蛋白表达量情况,及与临床特征、EGFR-TKI敏感性、预后关系；探索EGFR-TKI在早中期肺癌术后应用的疗效评价
方法：本研究随访了356名2001-2011年在协和胸外科行手术治疗的肺腺癌患者,随访到257名。一方面通过阅读病历和随访收集患者临床资料,另一方面用Western Blot方法检测99例有冰冻标本患者的肿瘤组织中p-mTR、p-4EBP1、 EIF4E蛋白表达量情况。结合病历、随访和基础检测数据,用SPSS13.0完成数据统计分析。
结果：本研究中肺腺癌患者EGFR突变率为59.0%,且非吸烟、病理高分化患者突变率更高。肺腺癌组织中p-mTOR、EIF4E蛋白表达量明显高于癌旁组织,且p-mTOR、p-4EBP1、EIF4E三者的蛋白表达量相互之间有相关性,而三者与EGFR突变无明显相关性。肺腺癌外科手术后病情进展,应用EGFR-TKI药物可能会有一定获益(在Ⅲ期患者中有统计学差异)。但术后病情未进展的情况下应用EGFR-TKI是否获益,本研究未能得出相关结论。外科手术后EGFR-TKI疗效评价指标少、需随访时间长、用药时机差异大,需要前瞻性、长时间随访的研究来进一步探索EGFR-TKI在外科的应用。
结论：肺腺癌患者EGFR突变率为59.0%,且在非吸烟组、支气管肺泡细胞癌组、高分化组突变率更高。p-mTOR.EIF4E在肺腺癌中表达比癌旁组织高,且p-mTOR. p-4EBP1、EIF4E相互之间有相关性,但与EGFR突变都无明显相关性。外科手术后EGFR-TKI疗效评价更困难,需要前瞻性、长时间随访的研究来进一步探索。
Background:Non-small cell lung cancer (NSCLC) remains a highly lethal disease worldwide. The EGFR/PI3K/Akt/mTOR signal pathway is closely related with the development and progress of NSCLC. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of anvanced NSCLC, and the EGFR mutation is recognized as the most important predictor of the response to EGFR-TKI. EGFR-TKI used for postoperative patients is rarely reported, and sequentially, the efficacy of the treatment and the predictors are unkown there.
Purpose:Investgate the basic situation of the expression of p-mTOR、p-4EBP1、 EIF4E and EGFR mutation, and evaluate the correlation with the clinical characteristics, the response of EGFR-TKI and the prognosis. The activity of EGFR-TKI used for postoperative patients were evaluated too.
Methods:356patients who were diagnosed as lung adenocarcinoma and operated on from2001through2011were studied, and257patients out of them were successfully followed up. Expression of p-mTOR、p-4EBP1、EIF4E was detected by Western Blot in99of them. Data evaluation was carried out with SPSS13.0statistical software.
Results:EGFR mutation was detected in161patients, and59.0%of them showed positive results. People who didn't smoke or diagnosed as well differentiated tumor, would have more chance of EGFR mutation. The expression of p-mTOR、EIF4E in tumor specimen was significantly higher than that of adjacent tissues. Correlation of the expression of p-mTOR、p-4EBP1、EIF4E was observed. However, between the expression of those three proteins and EGFR mutation, there wasn't such correlation. Postoperative recurrent lung adenocarcinoma patients may get longer median OS if treated with EGFR-TKI (significantly in phase Ⅲ). But this study didn't get a conclusion about whether patients who didn't have any progress after the operation should be treated with EGFR-TKI. Evaluation of the activity and efficacy of EGFR-TKI in patients after operation is more difficult than in anvanced NSCLC patients, because the point for evaluation is less (only PFS and OS), and longer time for following up is needed, and the time to start with the EGFR-TKI treatment is heterogeneous. Therefore, Prospective Studies and longer-time follow up studies should be executed to evaluate EGFR-TKI using in operative patients.
Conclusion:The positive rate of EGFR mutation in adenocarcinoma is59.0%, and people who didn't smoke, or dignosed as diabronchioloalveolar cell carcinoma, or with well differentiated tumor, would have more chance of EGFR mutation positive. The expression of p-mTOR、EIF4E in tumor specimen was significantly higher than that of adjacent tissues, and the expression of p-mTOR、p-4EBP1and EIF4E correlated with eachother, but not with the EGFR mutation. Prospective Studies and longer-time follow up studies should be executed to evaluate EGFR-TKI using in operative patients.
目的：研究肺腺癌EGFR突变、p-mTOR、p-4EBP1、EIF4E蛋白表达量情况,及与临床特征、EGFR-TKI敏感性、预后关系；探索EGFR-TKI在早中期肺癌术后应用的疗效评价
方法：本研究随访了356名2001-2011年在协和胸外科行手术治疗的肺腺癌患者,随访到257名。一方面通过阅读病历和随访收集患者临床资料,另一方面用Western Blot方法检测99例有冰冻标本患者的肿瘤组织中p-mTR、p-4EBP1、 EIF4E蛋白表达量情况。结合病历、随访和基础检测数据,用SPSS13.0完成数据统计分析。
结果：本研究中肺腺癌患者EGFR突变率为59.0%,且非吸烟、病理高分化患者突变率更高。肺腺癌组织中p-mTOR、EIF4E蛋白表达量明显高于癌旁组织,且p-mTOR、p-4EBP1、EIF4E三者的蛋白表达量相互之间有相关性,而三者与EGFR突变无明显相关性。肺腺癌外科手术后病情进展,应用EGFR-TKI药物可能会有一定获益(在Ⅲ期患者中有统计学差异)。但术后病情未进展的情况下应用EGFR-TKI是否获益,本研究未能得出相关结论。外科手术后EGFR-TKI疗效评价指标少、需随访时间长、用药时机差异大,需要前瞻性、长时间随访的研究来进一步探索EGFR-TKI在外科的应用。
结论：肺腺癌患者EGFR突变率为59.0%,且在非吸烟组、支气管肺泡细胞癌组、高分化组突变率更高。p-mTOR.EIF4E在肺腺癌中表达比癌旁组织高,且p-mTOR. p-4EBP1、EIF4E相互之间有相关性,但与EGFR突变都无明显相关性。外科手术后EGFR-TKI疗效评价更困难,需要前瞻性、长时间随访的研究来进一步探索。
Background:Non-small cell lung cancer (NSCLC) remains a highly lethal disease worldwide. The EGFR/PI3K/Akt/mTOR signal pathway is closely related with the development and progress of NSCLC. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of anvanced NSCLC, and the EGFR mutation is recognized as the most important predictor of the response to EGFR-TKI. EGFR-TKI used for postoperative patients is rarely reported, and sequentially, the efficacy of the treatment and the predictors are unkown there.
Purpose:Investgate the basic situation of the expression of p-mTOR、p-4EBP1、 EIF4E and EGFR mutation, and evaluate the correlation with the clinical characteristics, the response of EGFR-TKI and the prognosis. The activity of EGFR-TKI used for postoperative patients were evaluated too.
Methods:356patients who were diagnosed as lung adenocarcinoma and operated on from2001through2011were studied, and257patients out of them were successfully followed up. Expression of p-mTOR、p-4EBP1、EIF4E was detected by Western Blot in99of them. Data evaluation was carried out with SPSS13.0statistical software.
Results:EGFR mutation was detected in161patients, and59.0%of them showed positive results. People who didn't smoke or diagnosed as well differentiated tumor, would have more chance of EGFR mutation. The expression of p-mTOR、EIF4E in tumor specimen was significantly higher than that of adjacent tissues. Correlation of the expression of p-mTOR、p-4EBP1、EIF4E was observed. However, between the expression of those three proteins and EGFR mutation, there wasn't such correlation. Postoperative recurrent lung adenocarcinoma patients may get longer median OS if treated with EGFR-TKI (significantly in phase Ⅲ). But this study didn't get a conclusion about whether patients who didn't have any progress after the operation should be treated with EGFR-TKI. Evaluation of the activity and efficacy of EGFR-TKI in patients after operation is more difficult than in anvanced NSCLC patients, because the point for evaluation is less (only PFS and OS), and longer time for following up is needed, and the time to start with the EGFR-TKI treatment is heterogeneous. Therefore, Prospective Studies and longer-time follow up studies should be executed to evaluate EGFR-TKI using in operative patients.
Conclusion:The positive rate of EGFR mutation in adenocarcinoma is59.0%, and people who didn't smoke, or dignosed as diabronchioloalveolar cell carcinoma, or with well differentiated tumor, would have more chance of EGFR mutation positive. The expression of p-mTOR、EIF4E in tumor specimen was significantly higher than that of adjacent tissues, and the expression of p-mTOR、p-4EBP1and EIF4E correlated with eachother, but not with the EGFR mutation. Prospective Studies and longer-time follow up studies should be executed to evaluate EGFR-TKI using in operative patients.
引文
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[1]. Jemal, A., et al., Cancer statistics,2005. CA Cancer J Clin,2005.55(1):p.10-30.
[2].Kris, M.G., 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, 2003.290(16):p.2149-58.
[3]. Fukuoka, M., 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,2003. 21(12):p.2237-46.
[4]. Thatcher, N., et al., Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer:results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet,2005.366(9496):p.1527-37.
[5].Cufer, T., et al., Phase Ⅱ, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage Ⅲb or Ⅳ) non-small-cell lung cancer. Anticancer Drugs,2006.17(4):p.401-9.
[6]. Kim, E.S., et al., Gefitinib versus docetaxel in previously treated non-small-eell lung cancer (INTEREST):a randomised phase Ⅲ trial. Lancet,2008.372(9652):p.1809-18.
[7]. Maruyama, R., 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,2008.26(26):p.4244-52.
[8]. Lee, D.H., et al., Randomized Phase Ⅲ trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res,2010. 16(4):p.1307-14.
[9]. Douillard, J.Y., et al., Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer:data from the randomized phase Ⅲ INTEREST trial. J Clin Oncol, 2010.28(5):p.744-52.
[10]. Giaccone, G., et al., Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer:a phase Ⅲ trial-INTACT 1. J Clin Oncol,2004.22(5):p.777-84.
[11].Herbst, R.S., et al., Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer:a phase Ⅲ trial-INTACT 2. J Clin Oncol,2004.22(5):p.785-94.
[12]. Paez, J.G., et al., EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004.304(5676):p.1497-500.
[13].Lynch, T.J., 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):p.2129-39.
[14].Asahina, H., et al., A phase Ⅱ trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer,2006.95(8):p.998-1004.
[15]. Inoue, A., et al., Prospective phase Ⅱ study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol,2006.24(21):p.3340-6.
[16]. Yang, C.H., et al., Specific EGFR mutations predict treatment outcome of stage IⅢB/Ⅳ patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol,2008.26(16):p.2745-53.
[17]. Mok, T.S., et al., Gefitinib or earboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009.361(10):p.947-57.
[18]. Han, J.Y., 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):p.1122-8.
[19]. Paez, J.G., et al., EGFR mutations in lung cancer:correlation with clinical response to gefitinib therapy. Science,2004.304(5676):p.1497-500.
[20]. Mitsudomi, T., T. Kosaka and Y. Yatabe, Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol,2006.11(3):p.190-8.
[21].Massarelli, E., et al., KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res,2007.13(10):p.2890-6.
[22]. Dziadziuszko, R., et al., Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin Cancer Res,2006.12(10):p. 3078-84.
[23]. Miller, V.A., et al., Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 2008.26(9):p.1472-8.
[24].Tiseo, M., et al., Predictors of gefitinib outcomes in advanced non-small cell lung cancer (NSCLC):study of a comprehensive panel of molecular markers. Lung Cancer,2010.67(3):p. 355-60.
[25]. Morinaga, R., et al., Association of epidermal growth factor receptor (EGFR) gene mutations with EGFR amplification in advanced non-small cell lung cancer. Cancer Sci,2008.99(12):p.2455-60.
[26]. Gupta, R., et al., Evaluation of EGFR abnormalities in patients with pulmonary adenocarcinoma: the need to test neoplasms with more than one method. Mod Pathol,2009.22(1):p.128-33.
[27]. Lee, H.J., et al., Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas:Comparison of four commercially available antibodies by immunohistochemistry and fluorescence in situ hybridization study. Lung Cancer,2010.68(3):p. 375-82.
[28].E1-Zammar, O.A., S. Zhang and A.L. Katzenstein, Comparison of FISH, PCR, and immunohistochemistry in assessing EGFR status in lung adenocarcinoma and correlation with clinicopathologic features. Diagn Mol Pathol,2009.18(3):p.133-7.
[29]. Pao, W., et al., KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med,2005.2(1):p. e17.
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