液体活检在非小细胞肺癌靶向治疗中应用

目的液体活检技术在肿瘤的检测方法中是尤为重要的检测手段。其在指导非小细胞肺癌(non-small cell lung cancer,NSCLC)靶向药物的选择、耐药监测以及预后评估等方面具有重要作用,本研究分析近年来国内外液体活检在NSCLC靶向治疗中的应用,以期明确液体活检对NSCLC靶向治疗的指导作用,进而有助于指导靶向药物在NSCLC治疗中的应用。方法应用PubMed、中国知网及中国期刊全文数据库检索系统,以"液体活检、循环肿瘤DNA、循环肿瘤细胞、靶向治疗、非小细胞肺癌"为关键词,检索2009-2019年发表的相关文献。纳入标准:(1)液体活检的机制;(2)靶向治疗在NSCLC中的应用;(3)NSCLC的治疗。排除标准:(1)中文非核心期刊的文献和英文非SCI收录文献;(2)结果重复且相对陈旧的实验研究。根据纳入标准和排除标准,最终29篇文献纳入分析。结果液体活检技术可对NSCLC的诊断、治疗及预后评估进行实时动态监测,及时获取肿瘤基因突变信息,在指导靶向药物选择,对耐药监测以及预后评估等方面具有重要作用。结论液体活检对指导NSCLC患者的靶向治疗具有重要作用,有助于NSCLC患者靶向药物治疗的选择。     

脑脊液液体活检在肺癌脑转移精准治疗中的应用研究进展

液体活检作为精准医疗的新兴焦点，在肺癌脑转移患者靶向治疗中发挥着重要作用。循环肿瘤DNA(ctDNA)、循环肿瘤细胞（CTC）和微小RNA(miRNA)是液体活检的主要检测标志物，它们可以从脑脊液和其它体液中被分离出来。而在中枢神经系统中，脑脊液易获得且是最能反映肿瘤遗传特征的液体介质，通过分析脑脊液中的基因组数据可以获得患者肿瘤特征的详细信息。目前已经开展多项脑脊液液体活检对肺癌脑转移患者靶向治疗作用的研究，利用靶向治疗前脑脊液液体活检标志物基因组特征，以及对脑脊液进行连续采样分析脑脊液活检标志物在治疗过程中的变化，能够监测患者病情活动、预测对靶向治疗的反应和检测耐药性等，从而临床指导患者进行个性化治疗。因此，脑脊液液体活检技术在肺癌脑转移患者精准治疗中已经显示出重要的临床应用价值和巨大潜力，针对脑脊液液体活检的分析可能成为转移性脑肿瘤靶向治疗的新型治疗手段。     

循环肿瘤细胞在非小细胞肺癌个体化诊疗中应用的研究进展

非小细胞肺癌(non-small cell lung cancer,NSCLC)是发病率及病死率最高的恶性肿瘤,确诊时大多数NSCLC患者已到疾病晚期,导致患者5年生存率低.随着肿瘤个体化治疗的进展,早期诊断以及对患者病情实时监测尤为重要.循环肿瘤细胞(circulating tumor cell,CTC)作为肿瘤血源性转移的生物学标志物之一,是“液体活检”的重要指标,可用于肿瘤患者实时动态监测.检测CTC有助于早期发现NSCLC微转移、重新确定临床分期、实时监测抗肿瘤治疗疗效、评估预后、制定个体化的治疗策略,不仅如此,对其进一步分子鉴定有助于阐明肿瘤的生物学进程及转移机制.然而,由于检测标准不统一、检测阳性率低等多种因素,现阶段CTC仍较难应用到临床工作中.本文对CTC的发展历程及其在NSCLC诊断、治疗及预后等方面的研究新近进展作一综述.     

非小细胞肺癌生物标志物新热点

 生物标志物是近年肺癌研究的热点之一,可为非小细胞肺癌（NSCLC）患者的个体化治疗提供可靠的依据。随着分子生物学研究的深入,其在临床上已显示出广阔的应用前景。文章结合近年来的研究对NSCLC生物标志物的新热点进行阐述。     

ctDNA在非小细胞肺癌放射治疗中的应用进展

循环肿瘤DNA（ctDNA）以其无创检测、克服肿瘤异质性等优点,已成为无创液体活检最为常用的分析指标。肺癌是全世界发病率和死亡率最高的恶性肿瘤,其中约85%为非小细胞肺癌（NSCLC）。放射治疗在NSCLC各个分期中应用广泛,其直接杀死肿瘤细胞根治癌症的同时,间接增加ctDNA释放,提高液体活检准确性。因此ctDNA在NSCLC放射治疗中的应用前景广阔。本文将对ctDNA用于NSCLC放疗患者诊断、预后评估、复发监测以及疗效预测各领域的新进展进行综述。     

ctDNA在非小细胞肺癌放射治疗中的应用进展

循环肿瘤DNA（ctDNA）以其无创检测、克服肿瘤异质性等优点,已成为无创液体活检最为常用的分析指标。肺癌是全世界发病率和死亡率最高的恶性肿瘤,其中约85%为非小细胞肺癌（NSCLC）。放射治疗在NSCLC各个分期中应用广泛,其直接杀死肿瘤细胞根治癌症的同时,间接增加ctDNA释放,提高液体活检准确性。因此ctDNA在NSCLC放射治疗中的应用前景广阔。本文将对ctDNA用于NSCLC放疗患者诊断、预后评估、复发监测以及疗效预测各领域的新进展进行综述。     

循环肿瘤细胞检测在非小细胞肺癌中的应用

循环肿瘤细胞（CTC）是非小细胞肺癌（NSCLC）发生复发转移的重要原因。随着检测技术的不断发展,近期研究结果提示,CTC 水平不仅可以用来判断肿瘤临床分期、评估患者预后及治疗反应,还可以用于早期 NSCLC 的风险评估。另外,作为一种非侵入性的“液体活检”,CTC 检测能反映原发肿瘤的分子生物学及遗传学特征,有助于患者获得最佳的个体化治疗。     

生物标志物在非小细胞肺癌中的研究进展

<正>肺癌是世界范围内常见的癌症且是导致癌症患者死亡的主要原因之一[1],非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌的80%⁸5%,总体而言,晚期非小细胞肺癌的预后仍然较差,5年生存率不到15%[2]。因此,寻求NSCLC新的治疗手段以及个体化治疗至关重要。当今,NSCLC患者个体化治疗中,利用分子标志物判断预后和指导治疗成为研究热点。通过检测分子标志物指导个体化治疗,能够选择最有效的治疗策略,使疗效最大化,最大程度降低毒性。然而,影响肺癌发病机制的分子生物学机制十分复     

液体活检在肺癌精准医疗中的应用

肺癌是目前世界范围内最常见的恶性肿瘤之一,同时也是发病率最高、死亡率最高、增长速度最快且预后最差 的恶性肿瘤之一。许多国家都报道肺癌的发病率和死亡率均明显增高,男性肺癌发病率和死亡率均占所有恶性肿瘤的第一位,女性发病率占第二位,死亡率占第二位。近十余年来,液体活检由于其具有创伤性小、费用低、敏感性高等优点,逐渐成为了肺癌精准医疗中的研究热点。目前液体活检在肺癌精准医疗中的应用主要包括CTCs、ctDNA和外泌体等的检测。其中,CTCs不仅是肺癌早期诊断的有效手段、对肺癌的分期有一定帮助,还可作为疾病潜在的预后指标;ctDNA不仅可以作为肺癌诊断的可行工具、个性化治疗的参考指标,还可作为肿瘤潜在的生物标志物,帮助预测患者术后的复发;而外泌体被广泛认为是血液中潜在的肿瘤生物标志物,对肺癌的早期诊断、治疗及预后判断极其重要,甚至可以作为肺癌治疗的潜在靶点。本文基于不同的液体活检生物标记物,就CTCs、ctDNA、外泌体的生物学特性及临床应用进行了综述。     

cfDNA在非小细胞肺癌中的研究进展

肺癌发病率及死亡率居全球癌症之首,尽管近年来肺癌的分子靶向治疗和免疫治疗技术不断发展,但患者的总生存并未显著延长。尽早确定肺癌患者的临床分期和分子分型,提升早期临床诊断效率,以及监测患者耐药性和探究其耐药机制,对提高肺癌患者生存率具有重要意义。对于晚期患者而言,由于取材等问题,作为金标准的病理诊断并不一定可用,且在非小细胞肺癌的发展过程中,连续手术组织活检仍然是一大难题,而cfDNA（cell-free DNA,cfDNA）的液体活检技术,正迅速成为标准肿瘤活检的重要微创辅助手段。肿瘤细胞可以通过凋亡或坏死释放DNA片段进入血液循环,形成细胞游离DNA,非小细胞肺癌患者的血浆cfDNA水平较高,分析患者血浆中cfDNA对非小细胞肺癌患者的早期临床诊断、基因突变检测以及预后的预测、耐药性监测等方面均有着重要价值,并有望成为重要的液体生物标志物和指导非小细胞肺癌精准治疗模式中的新方法。本文就cfDNA在非小细胞肺癌研究中的最新进展情况作一综述。     

The BATTLE trial: personalizing therapy for lung cancer

The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non-small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. SIGNIFICANCE: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with "real-time" biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment.     

非小细胞肺癌大分割放疗敏感性与PI3K/AKT/mTOR信号通路研究进展

常规分割放疗在中晚期非小细胞肺癌治疗中疗效有限,大分割放疗地位越来越重要,但仍有相当部分肿瘤细胞具有放射线抗拒,其分子机制未明。PI3K/AKT/mTOR信号通路与非小细胞肺癌常规分割放疗抗拒有关,但与大分割放疗抗拒关系尚未明确。调控PI3K/AKT/mTOR信号通路的基因表达及蛋白磷酸化水平有望增加NSCLC肿瘤细胞对大分割放疗的敏感性,并可能达到逆转放疗抗拒的效果;在PI3K/AKT/mTOR信号通路的诸多基因中,有望从临床样本中筛选获得预测NSCLC大分割放疗疗效的分子标记。      

How close are we to customizing chemotherapy in early non-small cell lung cancer?

Although surgery is the only potentially curative treatment for early-stage non-small cell lung cancer (NSCLC), 5-year survival rates range from 77% for stage IA tumors to 23% in stage IIIA disease. Adjuvant chemotherapy has recently been established as a standard of care for resected stage II-III NSCLC, on the basis of large-scale clinical trials employing third-generation platinum-based regimens. As the overall absolute 5-year survival benefit from this approach does not exceed 5% and potential long-term complications are an issue of concern, the aim of customized adjuvant systemic treatment is to optimize the toxicity/benefit ratio, so that low-risk individuals are spared from unnecessary intervention, while avoiding undertreatment of high-risk patients, including those with stage I disease. Therefore, the application of reliable prognostic and predictive biomarkers would enable to identify appropriate patients for the most effective treatment.This is an overview of the data available on the most promising clinicopathological and molecular biomarkers that could affect adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine practice. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information warranting further validation. On the other hand, real-time quantitative polymerase-chain reaction strategy involving relatively small number of genes offers a practical alternative, with high cross-platform performance. Although data extrapolation from the metastatic setting should be cautious, the concept of personalized, pharmacogenomics-guided chemotherapy for early NSCLC seems feasible, and is currently being evaluated in randomized phase 2 and 3 trials. The mRNA and/or protein expression levels of excision repair cross-complementation group 1, ribonucleotide reductase M1 and breast cancer susceptibility gene 1 are among the most potential biomarkers for early disease, with stage-independent prognostic and predictive values, the clinical utility of which is being validated prospectively. Inter-assay discordance in determining the biomarker status and association with clinical outcomes is noteworthing.     

Recent advances in squamous non-small cell lung cancer: evidence beyond predictive biomarkers

Squamous non-small cell lung cancer (NSCLC) has always been characterized by a limited number of therapeutic options and by the lack of actionable biomarkers compared to its non-squamous counterpart. Recent clinical trials have led to the approval of new anti-neoplastic drugs available to both non-squamous and squamous NSCLC, consisting in a vascular-disrupting agent and two immune check-point inhibitors; additionally, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) is currently under evaluation by the Food and Drug Administration (FDA). While predictive molecular biomarkers have not been identified with consistency and are still highly demanded, these agents proved themselves noteworthy and can be considered a powerful addition to the available treatments for squamous NSCLC.     

超声引导下肺肿块粗针活检在NSCLC患者EGFR基因突变检测中的价值

目的 探究超声引导下肺肿块粗针活检在非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)基因突变检测中的价值.方法 回顾性分析96例NSCLC患者临床资料.96例NSCLC患者均采用超声引导下肺肿块粗针活检,分析穿刺成功率及EGFR基因突变检测结果.结果 96例患者均采用16G粗针活检,并顺利完成穿刺活检,取材满...     

Circulating microRNA‐590‐5p functions as a liquid biopsy marker in non‐small cell lung cancer

Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR‐590‐5p as a potential prognostic marker in the progression of non‐small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real‐time PCR. Our data showed an ~7.5‐fold downregulation of miR‐590‐5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR‐590‐5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial‐to‐mesenchymal transition negatively correlated with miR‐590‐5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual‐luciferase reporter assays identified STAT3 as a direct target of miR‐590‐5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c‐Myc, Vimentin, and β‐catenin) involved in tumorigenesis. Taken together, our study suggests that miR‐590‐5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.     

晚期非小细胞肺癌疗效监测的研究进展

晚期非小细胞肺癌（NSCLC）具有高度异质性,其临床治疗强调个体化和综合性。随着肺癌分子机制的深入研究和不断阐明,以及分子靶向、单克隆抗体、免疫制剂和抗血管生成等多种新型药物的临床应用,晚期NSCLC患者疗效评价已不再局限于基于瘤体大小变化的实体瘤疗效评价标准,基于蛋白质和核酸水平的分子影像学、分子病理学和液体活检将是晚期NSCLC患者疗效监测新的发展方向。     

Tissue sampling in lung cancer: a review in light of the MERIT experience

Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy.A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies).Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC.However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice.     

Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents.     

纳武利尤单抗在非小细胞肺癌治疗中的研究进展

肺癌是全球癌症死亡的主要原因之一。其中非小细胞肺癌(non-small cell lung cancer,NSCLC)占所有肺癌病例的85%以上,尽管化疗及靶向治疗改善了患者临床疗效,但预后仍欠佳。免疫治疗的发展改变了NSCLC患者的治疗策略。纳武利尤单抗是一种针对程序性死亡受体-1(programmed cell death-1,PD-1)的完全人源化的IgG4单克隆抗体,是首个被批准用于晚期NSCLC治疗的免疫检查点抑制剂。纳武利尤单抗已经成为晚期NSCLC治疗的主要药物,但临床上尚缺乏预测疗效的生物标志物。本文针对纳武利尤单抗的作用机制、药代动力学、单药治疗、联合治疗、不良反应和潜在生物标志物的最新进展进行综述。