驱动基因阳性晚期非小细胞肺癌靶向治疗

近年来,分子靶向治疗有效改善了驱动基因阳性晚期非小细胞肺癌(NSCLC)患者的预后,其中,针对存在人体表皮生长因子受体基因突变、棘皮动物微管相关样蛋白4-间变性淋巴瘤激酶融合基因、ROS1基因重排等的NSCLC患者,疗效尤为显著。对于驱动基因阳性晚期NSCLC患者,靶向治疗药物的选择尤为重要。     

肺鳞癌靶向治疗研究现状

随着肺癌驱动基因研究的逐步深入,肺癌靶向治疗已取得较大进展。与肺腺癌相比,肺鳞癌的靶向治疗进展明显滞后。对肺腺癌临床疗效确切的靶向药物,如：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）、棘皮类微管相关样蛋白-4（echinodern microtubule-associated-protein-like 4, EML4）-间变型淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因抑制剂等,均对肺鳞癌疗效欠佳,目前肺鳞癌缺少有效的靶向治疗药物。因此,迫切需要对肺鳞癌的驱动基因和靶向治疗进行更深入的研究。本文将对肺鳞癌靶向治疗的研究现状作一综述。     

非小细胞肺癌表皮生长因子受体基因突变的临床意义

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）已成为晚期非小细胞肺癌标准二线或三线治疗;其疗效受EGFR基因突变等诸多因素的影响。EGFR基因突变具有癌变作用,可能影响到非小细胞肺癌预后、化疗和靶向药物的疗效。     

免疫检查点抑制剂治疗少见突变非小细胞肺癌疗效的研究进展

驱动基因的发现及针对驱动基因的靶向治疗已显著提高了肺癌患者的生存质量和时间,但目前对于BRAF、HER2、MET、RET等少见驱动基因改变肺癌患者的靶向药物的选择仍然较少。近年来免疫检查点抑制剂在肺癌治疗中取得了一定的疗效,但因为少见驱动基因突变的肺癌患者本身样本量少,开展大规模临床随机对照试验尚存在一定的困难,目前此类患者接受免疫检查点抑制剂治疗的疗效情况仍不明确。本文将对目前已掌握的免疫检查点抑制剂治疗BRAF、HER2、MET、RET等少见驱动基因改变肺癌患者的临床研究结果进行综述,以期在一定程度上为临床工作提供一些依据和参考。     

T790M突变与EGFR-TKI耐药后治疗策略

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）治疗非小细胞肺癌已获得较好的疗效,患者生活质量明显改善。但EGFR-TKI耐药似乎成为了靶向治疗的瓶颈,耐药的产生可能存在多种机制,包括T790M突变、K-ras基因突变、C-Met基因扩增、BRAF基因突变、BIM多态性缺失、EML4-ALK融合基因突变及上皮间充质转化等,其中最常见的是T790M基因突变。目前研究表明,T790M基因还可能具有一定预测疗效和预后的作用。本文将简要介绍T790M基因的发现、起源、作用机制及预后,并主要针对EGFR-TKIs耐药后的治疗策略进行综述。     

2023年CSCO指南更新解读：驱动基因阳性非小细胞肺癌诊疗

靶向治疗为驱动基因阳性的非小细胞肺癌（non-small-cell lung cancer,NSCLC）患者带来显著生存获益。伴随新药研发、临床试验的开展及阳性结果的获得,驱动基因阳性的NSCLC也迎来了更多的治疗选择、更优的疗效及安全性。中国临床肿瘤学会（Chinese Society of Clinical Oncology,CSCO）基于过去1年的研究进展更新指南为《中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2023》。本版针对驱动基因阳性的NSCLC的更新包括：伏美替尼和莫博赛替尼在表皮生长因子受体（epidermal growth factor receptor,EGFR）突变晚期NSCLC治疗中的相关更新,布格替尼、洛拉替尼和恩沙替尼在间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）融合晚期NSCLC治疗中的相关更新以及其他靶向药物的更新。本文将对2023年CSCO NSCLC诊疗指南中驱动基因阳性的NSCLC的诊疗更新进行详细解读。     

驱动基因突变非小细胞肺癌免疫治疗的研究进展

随着肺癌靶点的发现和药物研发,靶向治疗改善了驱动基因突变非小细胞肺癌(NSCLC)的临床预后。同时,免疫检查点抑制剂在驱动基因阴性NSCLC中也取得了良好的疗效。虽然部分驱动基因突变患者从对应靶向治疗中明显获益,但对免疫治疗反应欠佳。在大部分免疫治疗临床研究和日常实践中,EGFR/ALK等驱动基因突变阳性的NSCLC患者也被排除在外,或者仅占少数。免疫治疗如何应用于驱动基因突变患者,以及如何在靶向治疗、化疗及免疫治疗中选择最佳治疗方案,制定最优治疗策略,对改善晚期驱动基因突变NSCLC患者预后至关重要。本文对不同基因突变肿瘤免疫微环境的特点及免疫治疗在不同基因突变的NSCLC患者中的应用进行简要综述。     

非小细胞肺癌对酪氨酸激酶抑制剂获得性耐药机制及治疗策略的研究进展

摘 要：表皮生长因子受体(epidermal growth factor receptor,EGFR)是非小细胞肺癌（non-small cell lung cancer,NSCLC）最常见的肿瘤驱动基因。以EGFR为靶点的酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）分子靶向治疗,可显著性改善携带这类基因突变的NSCLC患者的生存结局。然而,这些最初获得缓解的患者最终都会发生获得性耐药,成为进一步提高靶向药物TKI疗效的瓶颈。因此,了解TKI获得性耐药机制可指导NSCLC临床治疗。文章综述近年来NSCLC对TKI耐药机制的新进展及耐药后治疗的新策略。     

非小细胞肺癌靶向治疗的耐药特点及应对策略

分子靶向治疗在驱动基因阳性的晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者中已经获得显著的疗效,但靶向治疗后期发生的耐药问题也成为了非小细胞肺癌进一步治疗的难题。现有分子靶向治疗中已知多种肿瘤驱动基因靶点,常见的有EGFR、ALK、ROS1、HER-2、BRAF、MET等。本文将对上述基因突变靶点抑制剂的耐药特点及耐药后的进一步治疗进行综述。     

TKIs治疗EML4-ALK阳性非小细胞肺癌脑转移的研究进展

摘 要：间变性淋巴瘤激酶（anaplastic lymphoma kinase,ALK）基因重排是非小细胞肺癌（NSCLC）一种新的肿瘤驱动基因,促使肺癌发生和进展。近年来针对ALK融合基因的酪氨酸激酶抑制剂崭露头角,相关药物研究在非小细胞肺癌脑转移治疗中有较大进展,成为靶向治疗的热点。全文就治疗ALK阳性NSCLC脑转移的靶向药物的临床研究作一综述。     

Agents in the preclinical development stage for non-small cell lung cancer

Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed.     

Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy

In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions.     

肺癌靶向基因的研究及价值

肺癌的发生发展与众多肺癌相关基因的表达及突变有密切关系.近期国内外肺癌的相关基因研究显示,COPS3基因的表达在刺激肺癌细胞增殖的过程中可能发挥关键作用,棘皮动物微管样蛋白4-间变淋巴瘤激酶融合基因与表皮生长因子受体突变共存,GA733基因与肺癌的生存期密切相关.同时成纤维细胞生长因子受体1、高迁移率蛋白家族、类清道夫受体成员5和表皮生长因子受体为肺癌的基因靶向治疗提供了新思路.肺癌的治疗需要多基因联合治疗和基因治疗联合常规治疗.     

存在驱动基因突变肺鳞癌患者的临床病理特征及预后分析

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）、间变淋巴瘤激酶（anaplastic lymphoma kinase, ALK）以及KRAS基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的驱动基因。多项临床研究已证实,EGFR敏感突变及棘皮动物微管相关类蛋白4-间变淋巴瘤激酶（echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase,EML4-ALK）基因重排的晚期肺腺癌患者,一线治疗选择靶向药物优于化疗,其在总缓解率（overall response rate, ORR）、无进展生存期（progression-free survival, PFS）及生活质量方面均有明显优势。然而,在肺鳞癌患者中,目前尚无明确的基因检测位点及靶向药物来指导临床治疗。本研究旨在分析肺鳞癌患者EGFR、ALK以及KARS基因的突变状态,以及相关的临床病理特征,从而为今后的治疗提供相应指导。方法回顾性分析已行相关驱动基因检测的肺鳞癌患者90例,利用突变扩增阻滞系统（ampliifcation refractory mutation system, ARMS）的方法进行EGFR及KRAS基因检测,荧光原位杂交（fluorescencein situ hybridization, FISH）技术进行ALK基因融合检测。结果90例患者均进行了EGFR及KRAS基因检测,8例患者为EGFR基因突变（8.8%）;2例患者为KRAS基因突变（2.2%）;18例患者通过FISH方法进行了ALK基因融合检测,1例患者存在EML4-ALK基因融合（5.6%）。女性患者的EGFR基因突变率高于男性（P=0.022）。EGFR突变及野生型患者在病理分期（P=0.042）及分化程度（P=0.003）上均有差异。以胸膜为首发转移部位的EGFR突变患者比率高于EGFR野生型患者（P=0.013）。靶向治疗与化疗对EGFR突变患者的PFS无影响（P=0.607）。结论 ALK基因融合患者应用靶向治疗后可获得理想疗效。     

分子基因指标对非小细胞肺癌靶向治疗的预测作用

随着众多靶向治疗药物进入非小细胞肺癌(NSCLC)的治疗指南或各期临床试验,许多研究者对分子基因指标在预测NSCLC靶向治疗疗效中的作用进行了深入研究.表皮生长因子受体(EGFR)基因突变检测指导EGFR酪氨酸激酶抑制剂(EGFR-TKI)的选择就是一个良好的开端.根据分子基因指标选择个体化的治疗方案,将是今后一段时间的重要研究方向,也是提高NSCLC治疗水平、延长患者生存的关键措施.随着靶向治疗研究的深入,相信会有更多的分子基因指标指导个体化治疗的制定.     

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries.     

Targeted therapy for non-small-cell lung cancer: past,present and future

Therapy for advanced non-small-cell lung cancer has developed significantly with new awareness of histologic subtype as an important factor in guiding treatment and the development of targeted agents for molecular subgroups harboring critical mutations that spur on cancer growth. In this comprehensive review, we look back at developments in targeted therapy for advanced non-small-cell lung cancer, reviewing in detail efforts, both successful and in some cases less so, to target EGFR, VEGF and ALK. This review provides an overview of where the field stands at present and the areas we feel are most likely to provide challenges and potential successes in the next 5 years including immune checkpoint inhibition, epigenetic therapy and driver mutation targeting.     

肺癌分子分型与靶向治疗研究进展

随着肺癌发生、发展和预后相关分子机制研究的不断深入,肺癌靶向治疗取得了较大的进展,每一种分子分型的发现都会带来相应靶向药物的研究。2004年表皮生长因子受体(epidermal growth factor receptor,EGFR)基因在非小细胞肺癌中的发现,为我们带来了EGFR突变高度敏感有效的酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)。2007年棘皮类微管相关样蛋白-4-间变型淋巴瘤激酶(EML4-ALK)融合基因的出现为肺癌的分子发展带来了新的有效靶点。目前多个肺癌分子靶点及其靶向药物正在研究中。本文旨在回顾并总结肺癌分子分型及其靶向治疗的研究进展。     

Correlation of genes associated with drug response to prognosis of large cell lung carcinoma

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and inter...