Research progress in the use of combinations of platinum-based chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors

In the past decade,the advent of the epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)has dramatically influenced the therapeutic strategies for treating lung cancer,but with tumor progression and drug resistance,patients will ultimately develop reduced sensitivity to EGFR-TKIs.How can we delay the emergence of drug resistance? What is the next strategy after drug resistance? How to reasonably combine platinum-based chemotherapy and EGFR-TKIs? These questions are currently the focus of lung cancer research.Clinical studies have reported that platinum-based chemotherapy can increase the sensitivity to EGFR-TKIs.However,results of pre-clinical and clinical studies have been inconsistent.The mechanisms of platinum chemotherapy and EGFR-TKIs are still unknown due to the lack of systematic research.Therefore,systematic studies are required to show the mechanisms of EGFR-TKIs and chemotherapy agents and define the markers sensitive to their combinations when given concurrently or sequentially.

New era of epidermal growth factor receptor-tyrosine kinase inhibitors for lung cancer

Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor(EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors(TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase Ⅰclinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.

基于关联分析和聚类分析的EGFR-TKI相关皮疹中药用药规律分析

目的 分析表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)相关皮疹中药用药规律,以指导临床用药。方法 计算机检索中国知网(CNKI)、万方数据知识服务平台、维普网、PubMed数据库,纳入内服或外用中药治疗EGFR-TKI相关皮疹的临床试验研究,分别对内服、外用中药的频数、药物性味、归经、功效进行统计,并对高频中药进行关联分析和聚类分析。结果 共纳入文献36篇,包含方剂44首,用法分为内服法、外用法。内服中药方剂24首,纳入中药83味,使用频次较高的中药为甘草、金银花、白鲜皮;外用中药方剂20首,纳入中药51味,使用频次较高的中药为紫草、白鲜皮、苦参。内服、外用中药中频次较高的性味均为寒、温、平,苦味、甘味、辛味,归经均以归肝经、肺经、胃经为主,功效以清热药、补虚药为主。对高频药物进行关联分析和聚类分析,得出高频内服中药组合13对,高频外用中药组合7对,二者均可形成4个类聚方。结论 中药治疗EGFR-TKI相关皮疹内服以清热补虚,兼具祛邪与养阴之功,外用则主要以清热燥湿止痒为主,高频中药的关联分析和聚类分析为临床提供治疗思路与方法。

Efficacy and Safety of Primary Radiotherapy in Combination with EGFR-TKIs for Non-Small Cell Lung Cancer Harboring EGFR Mutation

Objective: To evaluate the efficacy and safety of EGFR-TKI with the radiotherapy in EGFR mutant metastatic NSCLC. Methods: Retrospective analysis of 72 patients with stage IV lung cancer with EGFR-sensitive mutation. Patients in the A group were treated with the first-generation EGFR-TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) combined with radiotherapy for primary tumors (34 cases). The B group was treated with the first-generation EGFR-TKI alone until the disease progressed (38 cases). PFS, OS, pulmonary infection and hematological toxicity during treatment were commented in both groups. Results: The objective remission rate was 47.1% (16/34) in the A group and 21.1% (8/38) in the B group. There was a significant difference between the two groups. There was no significant difference in hematological toxicity between the A group and the B group. There were 10 patients (29.4%) with degree II pulmonary infection in the A group and 3 patients (7.9%) in the B group. The difference between the two groups was statistically significant, suggesting that the incidence of pneumonia in the A group was higher than that in the B group. The median PFS (Progression-Free Survival)) and OS (Overall Survival) of the A group were significantly longer than those of the B group (16.5 months vs 9 months) and the median OS (36 months vs 19 months). The PFS and OS in the A group were significantly longer than those in the B group. Conclusion: EGFR-TKI combined with primary radiotherapy can significantly prolong the drug resistance time of EGFR mutant metastatic NSCLC.

Successful treatment after toxic epidermal necrolysis induced by AZD-9291 in a patient with non-small cell lung cancer:A case report

BACKGROUND Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute lifethreatening skin reactions.AZD9291 has been developed as a third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)with activity against T790M mutation.CASE SUMMARY Herein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion.To the best of our knowledge,this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer(NSCLC).Cabozantinib combined with erlotinib had clinically meaningful effectiveness,with additional toxicity that was generally manageable.CONCLUSION Treatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients.We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs,and more safe and effective drugs can be developed.

Clinical Benefit of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors Plus Radiotherapy for Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small Cell Lung Cancer: A Retrospective Analysis on Real World Data

Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC),compared with TKIs alone.Methods: A total of 103 patients with stage Ⅳ EGFR-mutated NSCLC treated from February 2015 to May 2017 at Sichuan Cancer Hospital were analyzed retrospectively. Fifty patients were treated with EGFR-TKIs( gefitinib or erlotinib) plus radiotherapy( the TKI +RT group) and 53 patients received EGFR-TKIs alone( the TKI group). Tumor response,survival and toxicities were compared between the two groups. Results: Median follow-up time was 11. 7 months( 2. 8-36. 3 months). The overall response rate( ORR) and disease control rate( DCR) in the TKI + RT group vs the TKI group were 62% vs 37. 7%( P = 0. 014) and 88% vs 75. 5%( P =0. 101),respectively. The median progression-free survival( PFS) and median overall survival( OS) in the TKI + RT group were superior to those of the TKI group( 18. 87 months vs 12. 80 months,P = 0. 035 and 23. 10 months vs 18. 30 months,P = 0. 011). OS rates in the TKI + RT group and the TKI group were 56. 0% vs 35. 8% at year 1( P = 0. 04) and 16. 0% vs 3. 8% at year 2( P =0. 036). Multivariate Cox model found that TKI + RT related to significantly better OS( hazard ratio = 0. 209;95% CI,0. 066 to0. 661;P = 0. 008) than TKI alone. Adverse events did not differ significantly between the two groups( P > 0. 050). Conclusion:Compared with EGFR-TKIs alone,EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumor response and survival for EGFR mutation-positive metastatic NSCLC patients.

Plasma relative abundance of epidermal growth factor receptor mutations predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma

Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study,adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumortissues were detected by ADx-amplification refractory mutationsystem (ADx-ARMS). EGFR mutations of plasmafree tumor DNA were detected by ADx-ARMS and ADxsuperamplification refractory mutation system (ADx-SuperARMS)at the same time. Patients with EGFR-mutantin tumor tissues and receiving EGFR-TKIs were finallyenrolled. Plasma mutation-positive patients with bothmethods were high abundance group. Patients with positivemutations by ADx-SuperARMS but negative of ADx-ARMS were medium abundance group.

非小细胞肺癌患者EGFR-TKI靶向治疗前后肿瘤体积变化规律及其临床价值

目的:探讨非小细胞肺癌(NSCLC)患者表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)靶向治疗前后肿瘤体积的变化规律,阐明其临床价值。方法:回顾性分析EGFR-TKI靶向治疗的39例NSCLC患者资料,使用TPS自带体积测量软件及Image J图像处理软件分别测量靶向治疗前、治疗后每个月的肿瘤体积,采用配对样本比较的Wilcoxon符号秩检验配对分析EGFR-TKI靶向治疗前、治疗后肿瘤绝对体积和相对体积变化情况。结果:EGFR-TKI靶向治疗前和治疗后第1个月患者肿瘤绝对体积(mm^3)分别为14 822.11(7 524.73,54 999.41)和7 954.42(3 499.73,29 396.83),差异有统计学意义(Z=-3.257,P=0.001);治疗者第1个月和第2个月的肿瘤绝对体积分别为8 358.47(4 394.36,24 430.05)和7 028.76(3 634.98,21 056.71),差异也有统计学意义(Z=-2.213,P=0.027)。若将治疗前肿瘤体积设为1,则治疗后第1个月肿瘤相对体积为0.612 6(0.313 8,0.853 7),差异有统计学意义(Z=-3.855,P<0.001);第1个月和第2个月肿瘤相对体积分别为0.608 4(0.364 3,1.044 3)和0.423 0(0.248 8,0.877 7),差异也有统计学意义(Z=-2.173,P=0.030)。其余相邻月份间肿瘤绝对体积和相对体积比较差异无统计学意义(P>0.05)。肿瘤相对体积在治疗后3个月开始出现平台期,在治疗后第7~9个月达到最小值。结论:NSCLC患者靶向治疗后第1和2个月原发灶肿瘤体积下降较为明显,在治疗后第3~9个月介入放疗可能较适合。

EGFR-TKI获得性耐药晚期肺腺癌的临床特点分析

目的探讨携带表皮生长因子受体(EGFR)敏感基因突变的晚期肺腺癌患者经过一线EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗出现获得性耐药的临床特点。方法收集2011年1月至2015年12月携带EGFR敏感基因突变的193例患者,其中一线给予吉非替尼或埃克替尼治疗120例,分析EGFR-TKI治疗过程中疗效及EGFR突变类型与出现获得性耐药时临床进展特点的关系。结果一线行EGFR-TKI治疗的120例患者中无1例获完全缓解,获部分缓解(PR)80例(66.7%),中位无进展生存时间(PFS)为12.1个月;获稳定(SD)36例(30.0%),中位PFS为6.1个月,两者PFS的差异有统计学意义(P<0.05)。获PR和SD的116例患者中,EGFR 19号外显子缺失64例(55.2%),中位PFS为11.0个月;21号外显子L858R点突变52例(44.8%),中位PFS为8.6个月,两者PFS的差异有统计学意义(P<0.05)。出现获得性耐药时50例(43.1%)仅有原发病灶进展,66例(56.9%)出现了新的转移病灶。出现获得性耐药时肺部病灶进展最多(37.9%),其次是颅内转移(26.7%)。疗效评价为PR和SD及EGFR外显子19缺失和L858R突变的患者出现获得性耐药与转移部位无关,与新发或原发病灶亦无关(P>0.05)。结论携带EGFR敏感基因突变患者经EGFR-TKI治疗后出现获得性耐药的患者,肺部病灶进展最多,其次是颅内转移。转移部位与治疗疗效及EGFR突变基因型无明显关系。

FDG-PET/CT response evaluation during EGFR-TKI treatment in patients with NSCLC

Over recent years,[18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography(FDG-PET/CT)has proven its role as a staging modality in patients with non-small cell lung cancer(NSCLC).The purpose of this review was to present the evidence to use FDG-PET/CT for response evaluation in patients with NSCLC,treated with epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKI).All published articles from 1November 2003 to 1 November 2013 reporting on 18FFDG-PET response evaluation during EGFR-TKI treatment in patients with NSCLC were collected.In total 7studies,including data of 210 patients were eligible for analyses.Our report shows that FDG-PET/CT responseduring EGFR-TKI therapy has potential in targeted treatment for NSCLC.FDG-PET/CT response is associated with clinical and radiologic response and with survival.Furthermore FDG-PET/CT response monitoring can be performed as early as 1-2 wk after initiation of EGFR-TKI treatment.Patients with substantial decrease of metabolic activity during EGFR-TKI treatment will probably benefit from continued treatment.If metabolic response does not occur within the first weeks of EGFR-TKI treatment,patients may be spared(further)unnecessary toxicity of ineffective treatment.Refining FDG-PET response criteria may help the clinician to decide on continuation or discontinuation of targeted treatment.

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant difference was found between the two groups in PFS but not in response rate or D CR. Conclusion： Retreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.

Overcoming EGFR-TKI resistance by targeting the tumor microenvironment

Targeted therapy has ushered in a new era of precision medicine for non-small cell lung cancer(NSCLC).Currently,epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)stand as the recommended first-line therapy for advanced NSCLC harboring sensitive EGFR mutations.Nevertheless,most patients inevitably confront the challenge of drug resistance.This phenomenon arises not solely from intrinsic alterations within cancer cells but also from the intricate dynamics of the tumor microenvironment and the complex interactions that occur between cancer cells and their immediate surroundings.This review consolidates the current knowledge regarding EGFR-TKI resistance mechanisms,with a specific emphasis on unraveling the role played by the tumor microenvironment.In addition,the review delineates strategic approaches to surmount TKI resistance,thereby enriching the understanding of the interplay between therapeutic agents and the intricate milieu surrounding cancer cells.

盐酸埃克替尼的药理学及临床研究进展

非小细胞肺癌（ NSCLC）约占肺癌的80％～85％。晚期NSCLC主要以内科治疗为主，既往主要应用化疗，但疗效差。近年来，表皮生长因子受体酪氨酸激酶抑制剂（ EGFR-TKI）的应用为NSCLC的治疗提出了新的突破。盐酸埃克替尼作为一种国产的EGFR-TKI，其临床前期研究及其临床研究均显示其较好的安全性、耐受性和疗效，为晚期NSCLC治疗的新选择。

非小细胞肺癌脑转移药物治疗的研究进展

非小细胞肺癌（ NSCLC）是最常见的恶性肿瘤之一，也是导致癌症死亡的主要原因，其疗效欠佳、预后差，尤其是伴有脑转移患者。 NSCLC伴脑转移患者生活质量差，预后不良，自然中位生存期仅为1～2个月，全脑放射治疗虽然在一定程度上改善了患者的生活质量，延长了患者的生存期，但疗效仍不理想。近年来围绕培美曲塞、替莫唑胺以及表皮生长因子受体酪氨酸激酶抑制剂（ EGFR-TKIs）开展了一些研究，并取得了一定的成果。本文就针对培美曲塞、替莫唑胺及EGFR-TKIs等抗肿瘤药物在NSCLC伴脑转移中的研究进展进行综述。

晚期非小细胞肺癌外周血循环肿瘤DNAEGFR突变与TKI疗效的相关性

目的:探讨晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)外周血循环肿瘤DNA(circulating tumor DNA,ctDNA)表皮生长因子受体(epidermal growth factor receptor,EGFR)突变与EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗疗效的相关性。方法:利用突变扩增阻滞系统(amplification refractory mutation system,ARMS)法检测50例NSCLC患者外周血ctDNA EGFR突变,其中27例进行组织与ctDNA配对检测。给予TKI治疗一月后进行疗效评价。对ctDNA EGFR突变与患者的临床因素、疗效相关性进行分析,并比较ctDNA与肿瘤组织EGFR突变的一致性。结果:患者性别、年龄、PS评分、病理类型、吸烟史与ctDNA EGFR突变无明显相关性(P>0.05)。ctDNA EGFR突变组客观缓解率(76.5%)、疾病控制率(100%)均高于野生型组(30.3%,60.6%)(P<0.05)。生存分析结果显示:ctDNA EGFR突变组无进展生存期(12个月)较野生型组长(4个月)(P<0.05)。27例配对检测结果显示:ctDNA与肿瘤组织EGFR突变一致率为66.7%(18/27,Kappa=0.400,P<0.05)。无进展生存期:ctDNA(23个月)/肿瘤组织(12个月)EGFR突变组均长于野生型组(2个月/1个月)(P<0.05)。结论:晚期NSCLC外周血ctDNA EGFR突变患者TKI治疗有效率高,ctDNA与肿瘤组织EGFR突变一致性好,作为肿瘤组织的替代检测标本是可行的。

Bevacizumab Combined with Icotinib Overcomes Osimertinib Resistance in a Patient of Non-Small Cell Lung Cancer

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease progressed after 6 months remission.CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis,and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction(ARMS-PCR)confirmed EGFR T790M mutation.Treatment with osimertinib was initiated.After 2 months remission,the disease progressed.Re-biopsy was performed for the tumor in the inferior lobe of left lung,and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del.Icotinib was re-challenged,but disease progressed continuously.Bevacizumab was added,and partial response was achieved after 2-cycle of combination therapy.The non-small cell lung cancer(NSCLC)in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment.This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Sequential occurrence of T790M mutation and small cell lung cancer transformation in EGFR-positive lung adenocarcinoma:A case report

BACKGROUND The emergence of secondary drug resistance when treating epidermal growth factor receptor(EGFR)mutated non-small cell lung cancer(NSCLC)using EGFRtyrosine kinase inhibitors(EGFR-TKIs),seriously affects the therapeutic efficacy and survival of patients.Here,we report a case of advanced NSCLC focusing on the application of multiple biopsy modalities to reveal the development of multiple resistance mechanisms during targeted therapies.CASE SUMMARY A 54-year-old male patient presented with EGFR 19Del-mutated advanced lung adenocarcinoma,and exhibited the development of a T790M mutation during initial TKI treatment.Following 3 mo of Osimertinib treatment,a mixed response was observed.Tissue biopsy of the progressive lesion showed transformation to small cell lung cancer(SCLC)harboring RB1 and TP53 mutations,with loss of the original T790M mutation.A standard chemotherapy regimen with Anlotinib for SCLC was administered.Repeat biopsy revealed adenocarcinoma combined with SCLC after tumor progression.The patient’s overall survival was 24 mo.CONCLUSION Multiple biopsy modalities can reveal the development of multiple resistance mechanisms which help with treatment decision-making.Comprehensive treatment regimens according to the drug resistance mechanism significantly improved the prognosis of such patients.

Long-term survival of more than 3 years among patients with advanced non-small cell lung cancer treated with chemotherapy

AIM: To evaluate the prognostic factors of long-term survival of more than 3 years in patients with advanced non-small cell lung cancer(NSCLC). METHODS: We retrospectively analyzed the records of 474 patients with advanced ⅢB/Ⅳ NSCLC who received chemotherapy as initial treatment between September 2002 and March 2007.RESULTS: The median survival time(MST) was 12.5 mo and the 3 year and 5 year survival rates were 14.6% and 5.3%, respectively. Long-term survival of more than 3 and 5 years was observed in 65 and 16 patients, respectively. The MST for the 65 patients was61.5 mo(range, 60.1-81.0 mo). In the 474 patients, a good performance status(PS), female sex, non-smoking status and adenocarcinoma histology were significantly associated with a favorable outcome. Furthermore, female sex, a good PS, non-smoking status and adenocarcinoma histology were significantly correlated with longterm survival of more than 3 years and most of these patients(89.2%, 58/65) received epidermal growth factor receptor-tyrosine kinase inhibitors as any line treatment. Survival analysis of long-term survivors showed that a PS of 0 was an independent prognostic factor for predicting favorable outcomes. CONCLUSION: Our results suggest that a good PS and adenocarcinoma histology play an important role in long-term survival of more than 3 years. A PS of 0 was an independent prognostic factor for predicting favorable outcomes in patients with advanced NSCLC who survived for more than 3 years.

Low BMI patients with advanced EGFR mutation-positive NSCLC can get a better outcome from metformin plus EGFR-TKI as first-line therapy:A secondary analysis of a phase 2 randomized clinical trial

Background:The synergistic association between metformin and epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)has been confirmed in in vitro studies.It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment.Body mass index(BMI)was proved to be independently associated with prolonged progression-free survival(PFS)and overall survival(OS).This study aimed to in-vestigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation(EGFR m)-positive non-small cell lung cancer(NSCLC)among nondiabetic Asian population.Methods:We performed a post hoc analysis of a prospective,double-blind phase II randomized clinical trial(COAST,NCT01864681),which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFR m NSCLC.We stratified patients into those with a high BMI(≥24 kg/m^(2))and those with a low BMI(<24 kg/m^(2))to allow an analysis of the difference in PFS and OS between the two groups.The PFS and OS were analyzed using Kaplan-Meier curves,and the differences between groups were compared using log-rank test.Results:In the univariate analysis,patients who had a high BMI(n=56)in the gefitinib+metformin group(n=28)did not have a better PFS(8.84 months vs.11.67 months;P=0.351)or OS(15.58 months vs.24.36 months;P=0.095)than those in the gefitinib+placebo group(n=28).Similar results were also observed in the low-BMI groups.Strikingly,in the metformin plus gefitinib group,patients who had low BMI(n=69)showed significantly better OS than those with high BMI(24.89 months[95%CI,20.68 months-not reached]vs.15.58 months[95%CI,13.78-31.53 months];P=0.007),but this difference was not observed in PFS(10.78 months vs.8.84 months;P=0.285).Conclusions:Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.

Study of the Correlation of EGFR and K-RAS Gene Mutations with Its Protein Expression in Non-small Cell Lung Cancer

OBJECTIVE To investigate gene mutations of epidermal growth factor receptor （EGFR） and K-RAS （Kirsten rat sarcoma viral oncogene） in Chinese patients with non-small cell lung cancer （NSCLC）, and study the correlation with its protein expression and its clinical significance on gefitinib.METHODS Detect the EGFR and K-RAS gene mutations status by gene sequencing and use the method of immunohistochemistry to detect EGFR and K-RAS protein expression.RESULTS The frequency of EGFR mutations was 33%, mainly located in exon 19 and exon 21. The frequency of K-RAS mutations was 5.5%, mainly located in codon 12. There was no case which both had EGFR and K-RAS mutations, suggesting a mutually exclusive relationship between the two. EGFR mutations are more common in adenocarcinomas （particularly those with bronchioloalveolar features）, nonsmokers and females. 16% were detected EGFR positive expression and had no correlation with EGFR mutation （P 〉 0.05）, but had significant correlation with mutation in exon 19 （P 〈 0.05）. The frequency of K-RAS positive expression was 52.5% and had no correlation with K-RAS mutation （P 〉 0.05）. Twelve （8 cases were protein-negative） out of 15 gefitinib-treated NSCLC patients with disease control carry EGFR mutations.CONCLUSION EGFR protein expression has some correlation with exon 19 mutations. Combined detection of EGFR and K-RAS gene mutations can help clinicians to choose patients who may benefit from EGFR tyrosine kinase inhibitor （EGFR-TKI） and to predict the response and prognosis of gefitinib.