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The Importance of Brain Metastasis in EGFR Mutation Positive NSCLC Patients  [PDF]
Vanita Noronha,Amit Joshi,Anant Gokarn,Vibhor Sharma,Vijay Patil,Amit Janu,Nilendu Purandare,Anuradha Chougule,Nirmala Jambhekar,Kumar Prabhash
Chemotherapy Research and Practice , 2014, DOI: 10.1155/2014/856156
Abstract: Introduction. Brain metastasis is a poor prognostic marker in lung cancer. However it is not known whether amongst patients with EGFR mutation those with brain metastases have a worse outcome. Methods. We compared the survival outcomes between EGFR mutation positive patients with and without brain metastases. In this retrospective analysis of prospective database of all metastatic lung cancer patients at our centre between July 2009 and December 2012, patients were treated with either combination chemotherapy or oral TKI. All patients with brain metastases received whole brain radiation. Kaplan Meier method was used for survival analysis and compared using log rank test. Results. 101 patients with EGFR mutated, metastatic lung cancer were studied. Fourteen had brain metastases and 87 did not. The common EGFR mutations were exon 19 deletion (61.3%) and exon 21 L858R mutation (28.7%). Overall response was 64% in extracranial metastasis group as compared to 50% in brain metastasis group. There was a significant worsening of median OS in the patients with brain metastases (11.6 months) compared with only extracranial metastases (18.7 months), . Conclusion. Amongst patients with EGFR mutant NSCLC, the presence of brain metastases leads to a worse outcome as compared to patients with extracranial metastases alone. 1. Introduction Metastatic lung cancer is one of the leading causes of cancer mortality worldwide. The presence of brain metastasis confers an even worse prognosis [1]. The median survival amongst patients with adenocarcinoma of the lung with brain metastasis in one of the early reports was around 73 days [1]. Whole brain radiotherapy (WBRT) improves median survival to 4–6 months [2, 3]. Non-small cell lung cancer (NSCLC) patients with brain metastases who have activating mutations of epidermal growth factor receptor (EGFR) tend to do significantly better as compared to those with wild type EGFR (median survival of 12.9 months as compared to 3.1 months) [4], when treated with oral tyrosine kinase inhibitors (TKIs) and cranial irradiation. EGFR mutation positivity is a good prognostic marker and patients with EGFR mutant lung cancer tend to have a longer survival. However, patients with EGFR mutated NSCLC have a predilection to develop brain metastases. The incidence of EGFR mutation positivity among patients with brain metastases is higher, ranging from 44 to 63%, as compared to the usually described 10% incidence of EGFR mutation in all patients diagnosed with NSCLC [5]. Although the development of brain metastases in general predicts for a poor
Advances in the Research of Autophagy in EGFR-TKI Treatment and Resistance ?in Lung Cancer  [PDF]
Qicheng ZHANG, Ke XU
- , 2016, DOI: : 10.3779/j.issn.1009-3419.2016.09.09
Abstract: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is a group of targeted-drugs which effectively inhibits the growth of tumor cells with sensitive mutations in EGFR. However, the innate and acquired resistance are major obstacles of the efficiency. Autophagy is a highly conserved self-digesting process in cells, which is considered to be associated with cancer development andchemoresistance. The activation of EGFR may regulate autophagy through multiple signal pathways. EGFR-TKIs can induce autophagy, however, the function of the inducted autophagy remains biphasic. On one hand, autophagy induced by EGFR-TKI acts as a cytoprotective response in cancer cells, and autophagy inhibitors can enhance the cytotoxic effects of EGFR-TKI. On the other hand, a high level of autophagy after treatment of EGFR-TKI can also result in autophagic cell death lacking features of apoptosis, and the combination of EGFR-TKI with autophagy inducer might be beneficial. Thus, autophagy regulation represents a promising approach for improving the efficiency of EGFR-TKI in the treatment of cancer patients. Here we summarized the signaling pathways involved in EGFR-TKI induced autophagy, and reviewed the roles of autophagy in the treatment and chemoresistance of EGFR-TKI treatment in lung cancer.
Analysis of Treatment Response and Chest CT Characteristics for Patients Treated by EGFR-TKI in Relapse Advanced Lung Adenocarcinoma  [cached]
Yuzhou WANG,Xiaohong NING,Jianfeng ZHOU,Shuchang CHEN
Chinese Journal of Lung Cancer , 2008,
Abstract: Background and objective For previously treated recurrent non-small cell lung cancer, many studies have proven that inhibitors of the tyrosine kinase of epidermal growth factor receptor (EGFR-TKI), such as gefitinib and erlotinib can increase survival, especially in non-smoker adenocarcinoma. The objective of this study is to investigate the relationship between the characteristics of chest Computed tomography (CT) and objective response of gefitinib and erlotinib for recurrent lung adenocarcinoma. Methods Thirty-seven patients with recurrent advanced lung adenocarcinoma were treated from Jan 1, 2004 to Mar 31, 2007 in our department. The patients consisted of 17 males and 20 females previously treated with 1-6 cycle of platinum-based chemotherapy. The age changed from 54 to 85 yrs (media 67.5 yrs). The gefitinib and erlotinib was given 250 mg and 150 mg respectively per day until disease progression. The characteristics of chest CT were evaluated before therapy and reviewed every 2 month as follow up. The objective response was analyzed according to RECIST system. Results In 37 patients, 21 patients benefited (including 7 partial response and 14 stable disease) from the treatment. Chest CT characteristic analysis showed that, the benefit rate was 79.9% (15/19) in patients with greater than 3 metastasis of lung or diffused disease, vs. 33.3% (6/18) in others,P<0.05; the benefit rate was 73.1% (19/26) and 67.4% (31/46) respectively in patients with pleural effusion and moderate contrast disease focus in enhancement CT scanning, vs. 22.2% (2/9) and 37.5% (9/24) in patients without pleural effusion and non-enhancement respectively, P<0.05. But Cox regression analyses show no relationship between CT presentation and progress free survival (PFS) or overall survival (OS), HR, 0.766, P>0.05. Conclution For advanced lung adenocarcinoma, CT presentation of multiple metastasis of lung or diffused disease, pleural effusion and enhancing contrast disease focus may be a predictor for response when treated by EGFR-TKI. But those CT character does not represent as independent factor for prognosis.
Activity of pemetrexed and high-dose gefitinib in an EGFR-mutated lung adenocarcinoma with brain and leptomeningeal metastasis after response to gefitinib  [cached]
Yuan Ying,Tan Chunwen,Li Modan,Shen Hong
World Journal of Surgical Oncology , 2012, DOI: 10.1186/1477-7819-10-235
Abstract: About 20% to 40% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases during the natural course of their disease. The prognosis for such patients is very poor with limited survival. In addition to the standard whole brain radiation therapy (WBRT), some studies have shown that chemotherapy drugs and/or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can improve the outcome of these patients. Here, we report a stage IIIA patient who developed multiple brain metastases one year after operation. Oral gefitinib with concurrent WBRT were given as first-line therapy. Complete response and a 50-month progression-free survival (PFS) were obtained. Double dosage of gefitinib (500 mg per day) together with pemetrexed were given as the second-line therapy after the patient developed new brain lesions and leptomeningeal metastasis during the maintenance therapy of gefitinib. The PFS for the second-line therapy was six months. In total, the patient obtained an overall survival of 59 months since the first diagnosis of brain metastases. Mutational analysis showed a 15-nucleotide deletion and a missense mutation in exon 19 of the EGFR gene, and a missense mutation at codon 12 of the K-ras gene. These underlying genetic changes might partially explain the long-term survival of this patient after brain metastases when treated with concurrent or sequential therapies of EGFR-TKI, radiotherapy and chemotherapy.
Relationship between ID1 and EGFR-TKI Resistance ?in Non-small Cell Lung Cancer  [PDF]
Yuchen BAO, Yinmin ZHAO, Bin CHEN, Jie LUO, Qinfang DENG, Hui SUN, Boxiong XIE, Songwen ZHOU
- , 2016, DOI: : 10.3779/j.issn.1009-3419.2016.12.10
Abstract: Background and objective Non-small cell lung cancer (NSCLC) presents the highest morbidity and mortality among malignant tumors worldwide. The overall effective rate of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is 30% to 40%, and PFS (progression-free sruvival) is 12 months. However, EGFR-TKI resistance is typical in clinical observations, and this phenomenon significantly affects tumor suppression. To overcome this resistance, a new prognostic factor associated with lung cancer drug resistance should be discovered. This study investigated the relationship between the inhibitor of differentiation 1 (ID1) and non-small cell lung cancer EGFR-TKI resistance in vivo and in vitro to determine any statistical significance and discuss the underlying mechanism. Methods Western blot and qRT-PCR were used to quantify the expression of ID1 in lung cancer. IHC was used to detect the expression of ID1 in pathological tissues (lung cancer tissues and adjacent tissues). MTT was used to detect cell proliferation, in which the cells were treated with gefitinib after being transfected by ID1 slow virus vector. Lung cancer cells were inoculated in nude mice until the tumor diameter grew to certain measurement. Gefitinib treatment was started, and the tumor volume was estimated. Results ID1 was highly expressed in NSCLC (P<0.05). Both ID1 expression and drug resistance of EGFR-TKI in NSCLC were positively correlated (P<0.05). The treatment group with gefitinib showed obviously less expression than the control group. Conclusion ID1 is highly expressed in NSCLC. ID1 expression was positively related to drug resistance of EGFR-TKI in NSCLC. Gefitinib can be used to effectively treat NSCLC, and the mechanism may be associated with an increased level of STAT3 phosphorylation.
Current Status and Progress in Molecular Imaging of Non-small Cell Lung ?Cancer for Molecular Targeted EGFR-TKI Treatment Sensitivity and ?Treatment Tolerance Prediction  [PDF]
Dong DAI, Wengui XU, Qi WANG, Xiaofeng LI, Yanjia ZHU
- , 2017, DOI: : 110.3779/j.issn.1009-3419.2017.12.10
Abstract: More than 80% of lung cancer is non-small cell lung cancer (NSCLC), and the epidermal growth factor receptor (EGFR)-mediated signaling pathway is closely related to the occurrence and development of NSCLC. Small molecule EGFR-tyrosine kinase inhibitors (EGFR-TKI) targeting EGFR have been used in the clinical treatment of NSCLC, and positron emission tomography/computed tomgraphy (PET/CT) imaging can noninvasively monitor the expression and mutation status of EGFR in patients with NSCLC. 18F-FDG PET/CT imaging has predictive value for the activation of EGFR mutation and EGFR-TKI treatment efficacy, and in vivo can be directly observed drugs and systemic tumor targeting EGFR combined with the specific circumstances, by PET/CT imaging before and after treatment, to achieve dynamic monitoring, guide the therapy before treatment and treatment of sensitive population screening process, to achieve NSCLC EGFR-TKI precise treatment is essential.
The place of TKI in the treatment of EGFR mutation-positive lung cancer  [cached]
Fumihiro Oshita,Shuji Murakami
Journal of Solid Tumors , 2012, DOI: 10.5430/jst.v2n5p1
Abstract: About half of all Asian patients with non-small cell lung cancer (NSCLC) have tumors that are positive for epidermal growth factor receptor (EGFR) mutation, for which tyrosine kinase inhibitors (TKI) such as gefitinib or erlotinib are effective. Gefitinib has been shown to be a useful second-line treatment for NSCLC after platinum-based chemotherapy [1], and some small-scale studies have also examined its activity as a first-line treatment for NSCLC, demonstrating a response rate of about 20% [2, 3], which is similar to that of other anticancer drugs for NSCLC. However, gefitinib has failed to exert any additional effect when combined with platinum-based chemotherapy as a first-line treatment for NSCLC [4, 5]. On the other hand, two biological studies have demonstrated that gefitinib is effective in specifically targeting the EGFR gene with deletion in exon 19 or point mutation in exon 21, and tumor regression induced by gefitinib in NSCLC patients has been shown to be correlated with the presence of these mutations in lung tumors [6, 7]. A Japanese study has demonstrated that patients with postoperative recurrence of EGFR mutation-positive NSCLC showed a good tumor response to gefitinib and achieved longer survival than patients whose tumors lacked EGFR mutation [8]. A study designed to compare carboplatin plus paclitaxel with gefitinib for chemo-na ve Asian patients with both EGFR mutation-positive and -negative NSCLC demonstrated that patients with EGFR mutation-positive tumors achieved significantly longer overall and progression-free survival with gefitinib than with carboplatin plus paclitaxel in subset analysis [9]. Thereafter, two large studies designed to compare platinum-based chemotherapy with gefitinib therapy for chemo-na ve NSCLC patients with EGFR mutation were performed in Japan. In both studies, the progression-free survival achieved with gefitinib was about twice as long as that achieved with standard platinum-based chemotherapy [10, 11]. These data indicated that gefitinib is an effective first-line chemotherapy for NSCLC harboring EGFR mutation.
Clinical Analysis of Icotinib on Beneficiary of ?Advanced Non-small Cell Lung Cancer with EGFR Common Mutation  [PDF]
Xiaowen JIANG, Wenxian WANG, Yiping ZHANG
- , 2016, DOI: : 10.3779/j.issn.1009-3419.2016.04.04
Abstract: Background and objective Targeted therapy has become an indispensable therapy method in advanced non-small cell lung cancer (NSCLC) treatment. Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) can significantly prolong the survival of patients harboring EGFR gene mutation. Icotinb is China's first EGFR-TKI with independent intellectual property rights. The aim of this study is to investigate the clinical characteristics about the beneficiary of advanced NSCLC patients with EGFR Common mutation who were treated with Icotinib. Retrospectively collect the data about beneficiary [progression-free survival (PFS)≥6 months] and analysis of the related risk factors for prognosis. Methods From September 1, 2011 to September 30, 2015, 231 cases of advanced NSCLC beneficiary with EGFR common mutation were enrolled for treatment with icotinib in Zhejiang Cancer Hospital. Results The one year benefit rate was 67.9% in the group treated with Icotinib as first line, and in the groupas second line or above was 53.6%, which is statisticallysignificant. The two years benefit rate was 18.7% and 9.3%, respectively. The median PFS of first line group and the second line or above was 16.7 and 12.4 months, respectively. The presence of brain metastasis (P=0.010), Prior chemotherapy (P=0.001), Eastern Cooperative Oncology Group (ECOG) score (P=0.001) were the main factors influencing the prognosis. The most common adverse were skin rashes (51 cases, 22.1%) and diarrhea (27 cases, 11.7%). Conclusion Icotinib offers long-term clinical benefit and good tolerance for advanced NSCLC harboring EGFR gene mutation. Its advantage groups in addition to the patients with brain metastases and better ECOG score, the curative effect of patients with the first-line treatment is superior to second or further line.
Clinical Observation of EGFR-TKI as A First-line Therapy on Advanced Non-small Cell Lung Cancer  [cached]
Jianjie LI,Lili QU,Xing Wei,Hongjun GAO
Chinese Journal of Lung Cancer , 2012, DOI: 10.3779/j.issn.1009-3419.2012.05.09
Abstract: Background and objective It has been proven that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) significantly benefits advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations in progression-free survival time with better tolerance. This study is undertaken to analyze efficacy and tolerance of advanced NSCLC patients harboring EGFR mutations taking EGFR-TKI as a first-line therapy. Methods Tumor samples from 54 patients with advanced NSCLC were examined for EGFR activating mutations (deletion mutation in exon 19 and the L858R point mutation in exon 21) by direct sequencing. The patients were first-line treated with oral administration of EGFR-TKI until disease progression. The efficacy and adverse events were observed, and survival was followed up. Results Among the patients, 61% (33 of 54) had EGFR exon 19 deletion, and 39% (21 of 54) had EGFR L858R point mutation. All patients received first-line TKI therapy. The total response rate was 96%, median progression free survival (PFS) was 8.3 months and median survival was 19.5 months. The patients with EGFR exon 19 deletion had significantly longer median PFS (9 versus 7 months, P=0.002) and longer median overall survival (OS)(25 versus 16 months, P=0.001) than patients with EGFR L858R point mutation. There is no significance in efficacy between gefitinib and erlotinib, and gefitinib is safer than erlotinib. The most common adverse events were rash and diarrhea. Two (4%) grade 4 skin toxity effects, two (4%) grade 3 aminotransferase level elevations, and one (1) grade 3 stomatitis were observed. Conclusion The first-line EGFR-TKI treatment in advanced NSCLC patients harboring EGFR mutations is efficient and safe, which is more efficient in patients with EGFR exon 19 deletion than those with EGFR L858R mutation.
Comparison of therapeutic effects between EGFR-TKI in first-line and second-line therapy in non-small cell lung cancer (NSCLC) patients
Liang-an CHEN
Medical Journal of Chinese People's Liberation Army , 2011,
Abstract: Platinum-based chemotherapy is still the standard first-line treatment for patients with advanced non-small cell lung cancer(NSCLC).Molecular targeted agents provide a new option for NSCLC patients.Clinical trial had shown that survival rate with epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment was not inferior compared with platinum-based chemotherapy in second line NSCLC therapy.However,for the patients with EGFR gene mutation,a better outcome has been achieved with the use of EGFR-TKI as first-line treatment.Currently,controversy still exists in the use of EGFR-TKI for treatment of NSCLC as first-line or second-line therapy.In present paper,the optimal time to use EGFR-TKI for treatment of NSCLC has been discussed based on the analysis of a series of clinical trials.
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