外周血CEA、CA125、CYFRA211与EGFR-TKIs初治EGFR突变的肺腺癌疗效的相关性研究

目的:通过对外周血肿瘤标志物水平的检测,旨在预测晚期EGFR突变型肺腺癌患者使用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的疗效及远期生存。方法:回顾性分析2010年3月至2016年3月收住我院肿瘤科一线接受EGFR-TKIs治疗的EGFR突变型Ⅲb期、Ⅳ期肺腺癌47例患者的临床资料,分析外周血肿瘤标志物水平与EGFR-TKIs疗效及生存的关系。结果:总体客观有效率为42.55％,疾病控制率为70.21％。癌胚抗原（CEA）增高组与正常组EGFR-TKIs疗效分别为:ORR 50％ vs 31.57％（P=0.21）,DCR 82.14％ vs 52.63％（P=0.03)。细胞角蛋白19片段（CYFRA211）以及糖类抗原（CA125）正常组与增高组EGFR-TKIs的疗效分别为:ORRCYFRA211 38.89% vs 44.83%（P=0.69）,DCRCYFRA211 72.22% vs 68.97%（P=0.81）,ORRCA125 45.45% vs 40.00%（P=0.71）,DCRCA125 72.72% vs 68.00%（P=0.72)。CEA水平增高组较正常组总生存期明显延长（中位OS 33.51个月vs 22.88个月,P=0．04)。多因素分析显示,性别、年龄、吸烟、转移情况、临床分期、美国东部肿瘤协作组评分、CYFRA211、CA125与总生存无关（P>0.05）,而与CEA水平有关（P=0.04)。结论:初治EGFR突变的肺腺癌患者外周血CEA水平可以预测一线接受EGFR-TKIs治疗的疗效,外周血CEA增高预示着总生存期延长。外周血CA125、CYFRA211水平不能预测EGFR-TKIs治疗的疗效。     

Comparing the effectiveness of different EGFR-TKIs in patients with EGFR mutant non–small-cell lung cancer: A retrospective cohort study in Taiwan

The study was to compare the effectiveness of different epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) and received EGFR-TKIs as first-line therapy. This retrospective cohort study was conducted using data from real-world settings. Patients with stage IIIB and IV NSCLC and first received gefitinib, erlotinib, or afatinib between 2011 and 2015 were included. The date of the first claim for EGFR-TKIs was set as the index date. Study endpoints were all-cause death and treatment failure that was defined when patients added on or switched to chemotherapy or terminal care. A total of 5,940 patients, including 3,982 (67.0%) receiving gefitinib, 1,207 (20.3%) receiving erlotinib, and 751 (12.7%) receiving afatinib, were eligible for this study. The 1-year overall survival (OS) rates for gefitinib, erlotinib, and afatinib groups were 74% (95% confidence interval [CI]: 72–75%), 75% (95% CI: 73–77%), and 80% (95% CI: 77–83%), respectively. Compared to gefitinib, afatinib was associated with a lower risk of all-cause death (adjusted hazard ratio [aHR] = 0.82, 95% CI: 0.72–0.93) but not erlotinib (aHR = 0.95, 95% CI: 0.86–1.05). Similar results were also found regarding the effectiveness of treatment. All the three EGFR-TKIs showed no differences for both outcomes among patients with an Eastern Cooperative Oncology Group Performance Score of 2. The real-world data exhibited afatinib was more likely to be used for younger patients in a better condition than other EGFR inhibitors, and observed prolonged OS and treatment effectiveness compared to gefitinib after performing a multivariate Cox regression analysis.     

Ⅰ~Ⅲ期非小细胞肺癌根治术后不同干预方案疗效观察

目的：回顾性比较分析表皮生长因子受体-酪氨酸激酶抑制剂( EGFR-TKIs)、化疗和随访观察等不同干预方案对Ⅰ~Ⅲ期非小细胞肺癌( NSCLC)患者肺癌根治术后1年无瘤生存的影响。了解表皮生长因子受体( EGFR)突变阳性NSCLC患者术后靶向药物治疗的临床价值。方法入组Ⅰ~Ⅲ期行肺癌根治术并且EGFR突变结果明确的NSCLC患者48例,根据突变情况及术后治疗情况分为4组( EGFR突变阳性化疗组、 EGFR突变阴性化疗组、 EGFR突变阳性靶向组、术后随访观察组),以了解不同突变情况及术后不同干预方案下患者1年无瘤生存率的差异。结果肿瘤分期不同是影响1年无瘤生存率的因素, EGFR突变阳性化疗组与突变阳性靶向组1年无瘤生存率为78.6%(11/14) VS 75%(6/8), P=0.620。突变阳性化疗组与突变阴性化疗组1年无瘤生存率为78.6%(11/14) VS 50%(10/20), P=0.153。Ⅲ期患者中, EGFR突变阳性化疗者与EGFR突变阴性化疗者1年无瘤生存率为100%(5/5) VS 18.2%(2/11), P=0.005。对Ⅰ期患者,治疗组与随访观察组1年无瘤生存率为77.8%(7/9) VS 100%(5/5), P=0.505。对Ⅰ期患者,术后随访观察与化疗及靶向治疗比较,1年无瘤生存率无统计学差异。结论对Ⅰ~Ⅲ期接受肺癌根治术后的NSCLC术后患者,分期是影响1年无瘤生存率的因素。对EGFR突变阳性患者,术后化疗与靶向治疗未见1年无瘤生存率差异。对Ⅲ期NSCLC术后患者, EGFR突变阳性患者化疗较突变阴性患者化疗可能有更好的1年无瘤生存率。     

养肺消疹汤治疗EGFR-TKIs药物相关不良皮肤反应的临床观察

目的观察养肺消疹汤治疗表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）药物相关不良皮肤反应的疗效。方法将50例服用EGFR-TKIs后出现皮疹的非小细胞肺癌患者随机分为2组各25例,治疗组采用养肺消疹汤口服联合外洗进行治疗,对照组采用吡美莫司软膏外用的方法进行治疗,观察各组皮疹分级、中医证候、生活质量改善情况。结果治疗组在各个检测时点皮疹分级均有显著改善,且优于对照组;治疗30 d后治疗组、对照组皮疹治疗有效率分别为72%与44%;治疗前后治疗组与对照组中医证候改善率分别为92%与36%;治疗14,30 d后2组生活质量评分治疗组有显著优势。结论养肺消疹汤口服联合外洗对EGFRTKIs药物相关不良皮肤反应具有良好疗效。     

EGFR-TKIs在NSCLC中的耐药机制及治疗策略研究进展

表皮生长因子受体（EGFR）抑制剂是目前临床治疗非小细胞肺癌（NSCLC）的一线小分子靶向药物,随着EGFR酪氨酸激酶抑制剂（EGFR-TKI）的广泛使用,其耐药现象也日趋明显,已成为其治疗NSCLC的巨大挑战。本文总结了EGFR-TKIs在NSCLC中的主要耐药机制,并对相关逆转策略的研究进展进行综述。     

NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer(NSCLC),but acquired resistance limits their clinical application.NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy.In this study,we investigated the role of NRF2 in resistance to EGFR-TKIs.We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein.NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells.Furthermore,we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2,and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs.Thus,we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.     

Subsequent Treatment Choices for Patients with Acquired Resistance to EGFR-TKIs in Non-small Cell Lung Cancer: Restore after a Drug Holiday or Switch to another EGFR-TKI?

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages overtraditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately wehave to face the situation that most patients still fail to respond in the long term despite initially good control.Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we soughtto compile the available clinical reports in the hope to better understanding the subsequent treatment choices,particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better optionafter failure of one kind of EGFR-TKI.     

表皮生长因子受体酪氨酸激酶抑制剂对骨组织的影响研究进展

表皮生长因子受体（EGFR）是原癌基因c-erbB-1的表达产物,具有酪氨酸激酶活性。EGFR与配体结合可以激活下游信号通路并导致肿瘤细胞的增殖及侵袭。在肿瘤细胞中,EGFR过度表达可以激活骨吸收过程,导致肿瘤骨转移。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）主要包括吉非替尼、厄洛替尼、阿法替尼、奥希替尼等,这些药物可以抑制骨吸收和肿瘤骨转移,但也会导致骨形成障碍。联合用药可以解决耐药等问题,并改善药物对骨组织的影响。本文对常见的EGFR-TKIs在骨形成、骨吸收和肿瘤骨转移等过程中对骨组织的影响及其机制进行综述,对不同EGFR-TKIs联合用药的优点及其对骨组织的影响进行归纳,并就EGFR-TKIs对骨组织负面影响的解决方案进行展望。     

分阶段中药内服联合外洗治疗晚期非小细胞肺癌EGFR-TKIs相关皮疹的临床研究

[目的]观察中医辨证论治联合中药外洗治疗晚期非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinaseinhibitor,EGFR-TKI)相关皮疹的临床疗效。[方法]入组出现EGFR-TKI相关皮疹的晚期非小细胞肺癌患者63例,随机分为中医治疗组32例和对照组31例,中医治疗组根据皮疹发展的不同阶段及表现,中医辨证分为风热型(初期)、湿热型(中期)、阴虚型(晚期),分别予消风散、萆薢渗湿汤、沙参麦冬汤内服1剂/日,同时予中药外洗2次/日;对照组予红霉素软膏外用2次/日,合并感染予米诺环素100mg 2次/日口服。治疗疗程均为6周。观察治疗前后皮疹分级与中医临床症状的变化。[结果]中医治疗组有效25例,稳定4例,无效3例,有效率78.13%;对照组有效7例,稳定11例,无效13例,有效率22.6%,中医治疗组较对照组EGFR-TKIs相关皮疹改善明显,差异有统计学意义(P0.05)。中医治疗组与对照组治疗前肺癌中医症状评分分别为35.38±3.69与34.38±4.21,差异无统计学意义(P0.05);中医治疗组治疗后中医症状评分为29.59±3.06,较治疗前降低,差异有统计学意义(P0.05);对照组治疗后中医症状评分为33.29±4.08,较治疗前差异无统计学意义(P0.05);治疗后中医治疗组中医症状评分优于对照组,差异有统计学意义(P0.05)。[结论]中医分阶段辨证治疗联合中药外洗能显著改善晚期非小细胞肺癌患者EGFR-TKIs治疗相关皮疹,改善患者的中医临床症状。     

EGFR TKIs 联合化疗的给药顺序对NSCLC 细胞促凋亡的影响

目的 探究表皮生长因子受体络氨酸激酶抑制剂（EGFR TKIs）与化疗药物单用、联用,以及顺序给药时,对获得性TKI 耐药的非小细胞肺癌（NSCLC）细胞系凋亡的影响。方法 选用存在TKI 耐药基因突变（T790M,cMET）的NSCLC 细胞系PC9ER、H1975 和HCC827GR,以及TKI 敏感基因突变（19 外显子突变）的细胞系PC9 和HCC827。采用MTS 法检测化疗药物顺铂和紫杉醇,以及TKI 厄洛替尼单用、联用,或者顺序给药干预各NSCLC 细胞系时的细胞活性状态,并利用集落形成试验加以验证。采用Westernblot 检测各处理组蛋白裂解液中细胞凋亡标志物cPARP 含量变化。结果 MTS 法和集落形成试验结果发现,EGFR TKIs 联合化疗能协同增加NSCLC 细胞系的细胞毒性。同时给予EGFR TKIs 和化疗或先化疗再用EGFR TKIs,可获得最佳干预效果。Western bolt 检测结果表明,联合用药后cPARP 蛋白表达升高。而且先化疗后EGFR TKIs 干预比两者顺序颠倒的促凋亡作用更强。结论 先化疗后EGFR TKIs 干预的最优给药顺序可使对获得性TKI 耐药的NSCLC 细胞系产生最强的促凋亡作用。