BIM基因多态性对晚期肺腺癌一线EGFR-TKIs疗效影响回顾性研究

背景与目的 通过对85例肺腺癌患者石蜡包埋标本及部分全血样本BIM缺失多态性的检测,分析BIM多态性与酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)药物疗效相关性,初探不同类型标本BIM检测的相关性.方法 收集2013年2月-2014年11月间经宣武医院胸外科诊断明确的IIIb期-IV期肺腺癌患者,表皮生长因子受体(epidermal growth factor receptor,EGFR)19或21外显子突变85例,给予一线TKIs治疗,采用石蜡组织标本和部分全血进行BIM基因多态性检测,分析两组患者治疗客观有效率(objective response rate,ORR)、无进展生存期(progression-free survival,PFS),并根据吸烟、性别、EGFR突变位点等因素进行单因素分析,同时对比石蜡标本与血液检测BIM的相关性.结果 在受检的85例FFPE样本中,BIM基因具有缺失多态性14例(16.47%),纯和无缺失多态性71例(83.53%).在13例对照样本中,石蜡样本和血液样本检出BIM基因缺失多态性2例,且为相同患者样本.BIM多态性的患者在用药物后的客观缓解率与无多态性组无统计学差异(P>0.05).BIM基因缺失多态性、纯和无缺失患者接受药物治疗的中位PFS分别为7.1个月、12.8个月,存在统计学差异(P=0.013).男性和女性中位PFS(10.7个月、12.1个月,P=0.835)、吸烟组和非吸烟组中位PFS(9.7个月、12.1个月,P=0.974)、EGFR 19和21外显子中位PFS(8.7个月、12.2个月,P=0.303)比较均无统计学差异(P>0.05).结论 检测患者BIM基因多态性对晚期肺腺癌EGFR-TKIs治疗患者的评估预后可能有一定参考意义,但需要进行大样本的研究.     

盐酸埃克替尼治疗EGFR突变晚期肺腺癌的预后因素分析

目的 探讨晚期肺腺癌表皮生长因子受体（EGFR）突变患者应用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）盐酸埃克替尼片治疗与预后的关系。方法 入组河北省胸科医院基因检测提示EGFR19、21基因突变且接受盐酸埃克替尼片治疗的晚期肺腺癌患者,分析其临床特征、EGFR基因突变亚型及不同位点与预后的关系。结果 全组共纳入101例晚期肺腺癌患者,EGFR基因19外显子缺失突变（EGFR Del19）58例,21外显子点突变（EGFR L858R）43例。全组患者客观缓解率达63.4%,中位无疾病进展时间（mPFS）和中位生存时间（mOS）分别为13个月和27个月。EGFR Del19对比EGFRL858R及EGFR19突变746~750位点对比其他突变位点的患者mPFS和mOS均增高。多因素分析显示,转移部位数和有无胸膜转移为OS的独立影响因素（P=0.027, P=0.041）,转移部位数≤3和无胸膜转移组患者的mOS分别为29个月和27个月。结论 盐酸埃克替尼片治疗晚期肺腺癌患者EGFR不同突变亚型和位点总生存差异不显著,转移部位数≤3和无胸膜转移的患者总生存期更长。     

BIM联合Scribble预测晚期非小细胞肺癌化疗效果

背景与目的：BIM基因和Scribble均是参与细胞凋亡的重要介质。BIM基因的BH3域缺失,可引起凋亡受阻。Scribble低表达对肿瘤细胞增殖、肿瘤转移和耐药有促进作用。通过检测BIM基因多态性和Scribble表达,探讨其与晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）化疗效果的关系。方法：收集2014年1月—2015年12月于复旦大学附属中山医院就诊的96例晚期NSCLC患者,所有患者均一线接受含铂方案化疗。采用聚合酶链反应（polymerase chain reaction,PCR）检测NSCLC患者组织标本中的BIM基因多态性,采用免疫组织化学法检测标本中的Scribble表达水平,然后评估BIM基因多态性和Scribble表达与化疗疗效的关系。结果：BIM基因野生型组化疗的中位无进展生存期（progression-free survival,PFS）优于BIM基因缺失组（5.0个月 vs 2.7个月,P=0.01）。Scribble高表达组化疗的中位PFS优于Scribble低表达组（7.0个月 vs 4.0个月,P<0.001）。BIM基因野生型且Scribble高表达组（BIM-WT-Scrib-H）化疗的中位PFS优于BIM基因野生型或Scribble高表达组（BIM-WT/Scrib-H）和BIM基因缺失型且Scribble低表达组（BIM-del-Scrib-L）（10.0个月 vs 4.5个月 vs 2.0个月,P<0.001）。多因素分析结果显示,BIM基因缺失型为化疗具有更短PFS的独立预测因素（HR=3.221,P<0.001）;Scribble低表达为化疗具有更短PFS的独立预测因素（HR=3.312,P<0.001）。结论：BIM基因缺失型和Scribble低表达是晚期NSCLC化疗效果不佳的独立预测因素,两者联合应用有更好的预测价值。     

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials

Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which have been approved for second-line or third-line indication in previously treated advanced Non-small-cell lung cancer (NSCLC) patients. The results of comparing the EGFR-TKI with standard platinum-based doublet chemotherapy as the first-line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta-analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR-TKI as front-line therapy had a significantly longer progression-free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR)=0.37; 95% confidence intervals (CI)=0.27-0.52; p<0.001]. The overall response rate (ORR) of EGFR-TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR-TKI [relative risk (RR)=5.68; 95% CI=3.17-10.18; p<0.001]. The overall survival (OS) was numerically longer in the patients received EGFR-TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR=0.94; 95% CI=0.77-1.15; p=0.57). Comparing with first-line chemotherapy, treatment of EGFR-TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.     

表皮生长因子受体少见突变型非小细胞肺癌临床病理特征及治疗分析

  目的  分析非小细胞肺癌患者表皮生长因子受体（epidermal growth factor receptor,EGFR）少见突变型的临床病理参数及EGFR-TKIs治疗的初步疗效。  方法  收集2012年1月至2016年4月新疆医科大学附属肿瘤医院经病理证实的29例非小细胞肺癌携带少见EGFR突变患者临床病理资料,分析少见突变型的临床病理特征及与EGFR-TKIs疗效之间的关系。  结果  在29例少见突变患者中,最常见的远处转移器官依次为同侧/对侧肺组织、骨、脑、肝、肾上腺,最常见的淋巴结转移依次为肺门淋巴结、锁骨上/下淋巴结、颈根部淋巴结及纵隔淋巴结。少见突变中单突变16例,L861Q 5例,G719X 5例,20ins 4例,S768I 2例。双突变型11例,S768I及20ins突变4例,L858R及S768I双突变1例,19Del及T790M双突变1例,L861Q及G719X双突变2例,19Del及S768I突变1例,20ins及G719X突变1例,T790M及G719X突变1例。三突变2例,L858R、L861Q及G719X突变1例,S768I、20ins及G719X突变1例。一线EGFR-TKIs治疗客观缓解率（objective response rate,ORR）43.75%,疾病控制率（disease control rate,DCR）50.00%,中位无疾病进展生存期（median progression-free survival,mPFS）5.50个月。二线EGFR-TKIs治疗ORR为28.57%,DCR为42.85%,mPFS为4.00个月。三线EGFR-TKIs治疗ORR为33.33%,DCR为50.00%,mPFS为2.67个月。  结论  EGFR少见突变对EGFRTKIs治疗的有效率及生存时间存在较大个体差异,EGFR少见突变患者的ORR及PFS均较经典突变患者低,部分高于野生型。对少见突变患者,EGFR-TKIs治疗一线疗效略优于二、三线,但无显著性差异。      

转移性结直肠癌一线化疗稳定与有效的患者无生存差异分析

  目的  旨在探讨转移性结直肠癌患者一线化疗后不同疗效分组的生存差异, 以期更好地指导化疗方案的选择。  方法  研究纳入了接受一线化疗的232例复发转移性结直肠癌患者, 按化疗最佳疗效先后分为疾病未进展与疾病进展组, 化疗有效与疾病稳定组, 分别比较两组患者的生存差异, 并分析影响总生存的独立预后因素。  结果  全组患者中位总生存时间(mOS)为21.10个月, 中位无进展生存时间(mPFS)为9.17个月。一线化疗疾病未进展组与进展组的mOS分别为23.57个月和10.67个月, mPFS分别为10.83个月和2.83个月, 差异均有统计学意义(P < 0.001)。疾病稳定组与化疗有效组的mOS分别为23.57个月和24.30个月, mPFS分别为10.57个月和10.87个月, 差异均无统计学意义(P=0.935, P=0.985)。原发病灶是否根治性切除、病理分级、复发转移病灶局部处理、化疗后疾病进展情况是影响总生存的独立预后因素。  结论  复发转移性结直肠癌患者接受一线化疗后, 疾病进展时有必要更换化疗方案, 而近期疗效获得稳定的患者则无需更换化疗方案。      

EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy

Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p<0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.     

晚期胃癌不同一线及后线治疗方案的疗效对比分析北大核心

目的:分析晚期胃癌(advanced gastric cancer, AGC)一线及后线治疗方案的疗效及生存情况,为指导AGC的系统治疗及全程管理提供依据。方法:收集我院肿瘤科2015年01月至2019年12月收治的AGC患者的临床特征、辅助检查资料、治疗相关资料、疗效评估、疾病转归等相关临床资料,建立数据库,分析不同一线及后线治疗方案的疗效,以及不同人群、进行不同线数化疗的患者总生存期(overall survival, OS)的差异。结果:一线治疗总体客观缓解率(objective response rate, ORR)为37.6%,疾病控制率(disease control rate, DCR)为83.9%;二线治疗ORR为9.5%,DCR为44.6%;三线及以上治疗ORR为0%,DCR为15.2%。总体人群一线治疗中位无进展生存(median progression-free survival, mPFS)时间为7.0个月,中位总生存(medianoverall survival,mOS)时间为15.6个月;二线治疗mPFS时间为3.0个月,mOS时间为7.2个月。一线化疗采取含铂方案与含紫杉方案对比,mPFS分别为7.0个月、4.5个月(P=0.041),mOS分别为16.0个月、9.0个月(P=0.061);二线含紫杉方案与含伊立替康方案对比,mPFS分别为2.6个月、4.0个月(P=0.531),mOS分别为7.0个月、6.5个月(P=0.822)。仅进行一线治疗、一线+二线治疗、一线+二线+三线及以上治疗的AGC患者mOS分别为14.0个月、14.0个月及20.0个月,进行三线及以上治疗的患者mOS优于进行一线+二线治疗的患者(P=0.001)。一线方案中采用两药或三药及以上、有无免疫治疗对患者的mPFS及mOS无影响,且二线治疗中有无联合免疫治疗对患者的mPFS及mOS也无影响。结论:含铂双药方案疗效较佳,应作为AGC患者一线治疗的优选方案;二线及后线化疗有效率较低,二线化疗方案紫杉类与伊立替康疗效无差异;在非选择AGC人群中,一线及二线治疗中联合免疫治疗未见改善生存,化疗仍然是基石。     

对比EGFR-TKIs治疗EGFR突变状态未明晚期NSCLC疗效研究

目的探讨对比表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)一线、维持及二线治疗EGFR突变状态未明晚期非小细胞肺癌(non-small-cell lung cancer,NSCLC)的疗效。方法回顾性分析接受EGFR-TKIs治疗的57例EGFR突变状态未明晚期NSCLC,按照接受EGFR-TKIs治疗的时机分为EGFR-TKIs治疗一线组(19例)、维持组(18例)和二线组(20例),按照RECIST标准进行疗效评价。结果一线组、维持组和二线组客观有效率(52.6%vs 38.9%vs 35.0%,P=0.098)、中位无进展生存期(4.0月vs 7.8月vs 2.2月,P=0.417)差异无统计学意义,但一线组患者总生存期较维持组和二线组差(8.7月vs 20.0月vs 19.1月,P=0.009)。结论 EGFR突变状态未明晚期NSCLC EGFR-TKIs一线、维持和二线治疗的客观有效率和中位无进展生存期相似,但EGFR-TKIs一线治疗总生存期较短,建议EGFR-TKIs用于维持或二线治疗EGFR突变状态未明晚期NSCLC。     

EGFR-TKI一线治疗EGFR基因突变的晚期非小细胞肺癌临床观察

背景与目的研究表明,一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的客观缓解率及无进展生存期明显优于铂二联的化疗,且耐受性更好。本研究旨在分析EGFR-TKI一线治疗晚期EGFR突变阳性的NSCLC患者的疗效与耐受性。方法 54例晚期NSCLC患者肿瘤标本采用直接测序法证实EGFR活化突变(外显子19缺失或外显子21点突变),一线给予EGFR-TKI口服治疗直至疾病进展,观察疗效及不良反应,并进行生存随访。结果 54例患者外显子19缺失33例(61%),外显子21点突变21例(39%)。均一线接受EGFR-TKI治疗,总体缓解率为90%,中位无进展生存期(progression free survival,PFS)为8.3个月,中位生存期为19.5个月;外显子19缺失患者的中位PFS(9.0个月)较21点突变(7.0个月)时间长(P=0.002)。外显子19缺失患者的中位总生存期(overall survival,OS)(25.0个月)较21点突变(16.0个月)时间长(P=0.001);吉非替尼与厄洛替尼疗效相当,但吉非替尼组安全性更好;最常见的不良事件为皮疹和腹泻,有2例患者(4%)出现了3度皮肤毒性反应,2例患者(4%)出现了3度的转氨酶升高,1例患者(1%)出现了3度口腔炎。结论存在EGFR基因突变的晚期NSCLC患者一线接受EGFR-TKI治疗安全有效,且外显子19缺失比L858R突变疗效更优。     

表皮生长因子受体突变晚期非小细胞肺癌靶向治疗效果影响因素分析

目的:探讨表皮生长因子受体（EGFR）突变晚期非小细胞肺癌（NSCLC）EGFR-酪氨酸激酶抑制剂（EGFR-TKI）治疗效果的影响因素。方法:收集2015年1月至2019年10月南京医科大学附属无锡第二医院接受EGFR-TKI治疗的104例EGFR突变晚期NSCLC患者的临床资料。分析EGFR突变类型与患者的临床病理...     

Prospective Observational Study of Treatment Resistance-related Gene Screening Using Plasma Circulating Tumor DNA in Third-generation EGFR-TKI Osimertinib Therapy (Elucidator)

BackgroundOsimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR activating and EGFR T790M resistance mutations. Osimertinib was found to be more effective than first-generation EGFR-TKIs in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) harboring EGFR-positive mutations in a prior phase III trial. Osimertinib is, therefore, one of the most important standard therapies for EGFR mutation-positive patients. However, there are few reports about osimertinib resistance mechanisms in first-line EGFR-TKI therapy. Understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies in patients with NSCLC with EGFR-positive mutations. To clarify the resistance mechanisms of first-line osimertinib, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing method.Patients and MethodsWe aim to collect ctDNA samples from patients with the following key inclusion criteria: histologically or cytologically proven NSCLC, activating EGFR mutation-positive, planned treatment with first-line osimertinib, and written informed consent. Patients with comorbidities, who are deemed unsuitable for participation by an attending physician, would be excluded. We plan to enroll 180 cases and estimate a final analysis of 120 cases following registration and 2-year observation. ctDNA samples are collected at osimertinib treatment initiation, 3 and 12 months later, and disease progression. The key primary endpoint is to clarify the incidence and ratio of osimertinib resistance. The key secondary endpoint is to examine how the quantity of osimertinib resistance-associated mutations detected in ctDNA at treatment initiation influences disease progression.     

化疗后再使用EGFR-TKI治疗晚期非小细胞肺癌的临床研究

  目的  表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)虽疗效显著,且安全性好,但最终都会发生耐药。EGFR-TKI耐药机制复杂,应对困难,本研究旨在探讨EGFR-TKI治疗晚期NSCLC获得性耐药的患者,化疗后再次应用EGFR-TKI的疗效。  方法  前瞻性对EGFR-TKI治疗晚期NSCLC长期获益后获得性耐药的27例患者,先化疗,后再次应用EGFR-TKI治疗,吉非替尼250 mg qd或厄洛替尼150 mg qd至疾病进展;依据RECIST标准评价疗效,比较再使用原EGFR-TKI与另一种EGFR-TKI的疗效。  结果  27例患者全为晚期肺腺癌,完全缓解(CR)为1例(3.7%)、部分缓解(PR)为8例(29.6%)、稳定(SD)为14例(51.9%)、进展(PD)为4例(14.8%),有效率(RR)为33.3%,疾病控制率(DCR)为85.2% (95% CI为62~94),mPFS为6个月。13例再用原EGFR-TKI (同药组) CR为1例(7.6%),PR为2例(15.4%)、SD为8例(61.5%),RR为23%,PD为2例(15.4%),DCR为86.4%,其mPFS为5个月;14例再用另一种EGFR-TKI (换药组) CR为0例,PR为6例(42.8%),SD为6例(42.8%),进展为2例(14.3%),RR为42.8%,其mPFS为9.5个月,DCR为85.7%,两组DCR比较无显著性差异(P>0.05),两组的mPFS比较有显著性差异(P < 0.05);mPFS换药组明显长于同药组。  结论  EGFR-TKI治疗晚期NSCLC长期获益后获得性耐药的患者,先化疗、后再次应用EGFR-TKI,大部分患者仍能取得一定疗效。      

EGFR-TKIs治疗术后复发肺腺鳞癌患者的临床研究

  目的  分析表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors，EGFR-TKIs）治疗术后肺腺鳞癌（adenosquamous carcinoma of the lung，ASC）患者的疗效。  方法  回顾性分析2006年1月至2014年12月上海交通大学附属胸科医院诊治的ASC 205例，采用描述性分析及Kaplan-Meier法进行生存分析。  结果  筛选出27例EGFR突变并接受TKIs治疗的ASC患者，其中15例患者存在19号外显子缺失突变，12例患者存在21号外显子点突变。临床疗效方面，9例患者部分缓解（partial response，PR），11例患者疾病稳定（stable disease，SD），疾病控制率（disease control rate，DCR）为74.1%。生存分析结果显示，术后中位生存时间为39.0个月（95% CI:25.6~52.4），中位无进展生存时间为15.0个月（95% CI:12.9~17.1），3、5年生存率分别为51.9%、15.3%。  结论  具有EGFR敏感突变的ASC患者能够从TKIs治疗中获益，推荐对ASC患者进行常规EGFR基因突变检测，实现个体化、多学科治疗以改善患者预后。      

Real-World Pattern of Treatment and Clinical Outcomes of EGFR-Mutant Non-Small Cell Lung Cancer in a Single Academic Centre in Quebec

The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62–13.44) months for first-line treatment, and 4.4 (95% CI: 1.47–7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9–30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5–27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting.     

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27−32.91; 95% CI 3.64−6.22) and 14.70 (range, 0.27−32.91; 95% CI 0.27−43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p<0.05) and mOS (24.03 vs. 6.07 months, p<0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.     

EGFR mutation status in plasma and tumor tissues in non-small cell lung cancer serves as a predictor of response to EGFR-TKI treatment

Objective: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) can effectively control non-small cell lung cancer (NSCLC). Therefore, EGFR mutations should be detected before lung cancer patients undergo EGFR-TKI therapy. This study assessed the feasibility and predictive value of EGFR mutations in peripheral blood samples.Methods: EGFR mutations in exons 19 and 21 were analyzed in tumor tissue and plasma DNA samples from 121 NSCLC patients using amplification refractory mutation system (ARMS) and the integrated technique of mutant enriched PCR (me-PCR) and denaturing high performance liquid chromatography (DHPLC), respectively.Results: EGFR mutations were detected in 36.4% of tumor tissues and 34.7% of the plasma at a concordance rate of 85.1% (103/121). The sensitivity and specificity of plasma EGFR mutations were 77.3% and 89.6%, respectively. The gender and tumor histology of patients served as independent predictors of EGFR mutations in both tumor tissues and plasma, while CEA level was an independent predictor of EGFR mutations in the plasma. Furthermore, EGFR-TKI treatment showed a significantly higher objective response rate (ORR), median progression-free survival (mPFS), and overall survival (mOS) in patients harboring EGFR mutation than those that did not exhibit EGFR mutation (ORR: 69.4% versus 13.0% in tissues, P < 0.001; 64.5 % vs. 28.6% in the plasma, P = 0.006. mPFS: 10.4 months versus 4.1 months in tissues, P<0.001; 10.5 months vs. 5.2 months in the plasma, P=0.001. mOS: 25.7 months versus 8.3 months in tissues, P=0.005; 25.7 months vs. 13.5 months in the plasma, P=0.038).Conclusions: EGFR mutations can be detected in the plasma using the integrated technique of me-PCR and DHPLC, which enables us to predict patient response to EGFR-TKI therapy. High serum CEA levels served as an independent predictor for plasma EGFR mutations.     

EGFR-TKI治疗EGFR敏感突变的晚期肺鳞癌的疗效分析

目的 探讨表皮生长因子酪氨酸激酶抑制剂（Epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）治疗EGFR敏感突变的晚期肺鳞癌患者的疗效。方法 收集20例四川大学华西医院经病理确诊、EGFR检测敏感突变、并接受EGFR-TKI治疗的Ⅳ期或术后复发转移肺鳞癌患者,分析其与EGFR-TKI的疗效关系。结果 20例EGFR敏感突变的晚期鳞癌患者接受EGFR-TKI治疗,随访资料完整。10例19-del（+）,8例L858R（+）,1例同时存在外显子21（L858R）点突变和外显子20（T790M）突变,1例外显子18（G719X）突变。其中部分缓解（PR）9例,疾病稳定（SD）7例,疾病进展（PD）4例。客观缓解率（ORR）45%,疾病控制率80%,中位无进展生存期（mPFS）为5.0月,中位生存期（mOS）为14.7月。结论 EGFR-TKI对部分EGFR敏感突变的鳞癌患者有一定疗效。在临床工作中,应重视这部分患者的EGFR基因检测,以便明确获益的患者。     

Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis

Purpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC).

Methods: EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients.

Results: The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002).

Conclusion: The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.     

The BIM deletion polymorphism is a prognostic biomarker of EGFR-TKIs response in NSCLC: A systematic review and meta-analysis

The prognostic value of Bcl-2-like protein 11 (BIM) deletion polymorphism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC) were reported. However, the results remained controversial. Thus, we did this systematic review and meta-analysis to address this issue. Databases including PubMed, Embase, and the Cochrane Register of Controlled Trials were searched to find relevant studies. The primary outcome was progression-free survival (PFS). Five retrospective cohort studies were included. All of the studies were conducted in Asian population (n = 951). The methodological quality of all included studies was high. Compared with BIM wild type, BIM deletion polymorphism was predictive of shorter PFS in NSCLC patients who were treated with EGFR-TKIs (adjusted HR = 2.38, 95% CI 1.66–2.41, P < 0.001). In conclusion, the BIM deletion polymorphism was associated with poor response in NSCLC patients who received EGFR-TKIs treatment.