晚期NSCLC靶向和化疗方案选择的几个问题

高月娥 · 发表于 2013-12-22 21:11:09

学习了很多东西，真的很好

bhmy1402 · 发表于 2013-12-24 10:53:15

感谢！学习了。

老马 · 发表于 2013-12-25 07:53:51

本帖最后由老马于 2013-12-25 07:56 编辑

肺腺癌-小细胞肺癌复合癌:分子病理学时代全新视角
Small-Cell Carcinoma in the Setting of Pulmonary Adenocarcinoma: New Insights in the Era of Molecular Pathology
中文摘要:
引言：有报告显示，对表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）获得性耐药的肺腺癌可进展转化为小细胞肺癌（SCLC）。但SCLC与腺癌间存在自发关联。本研究试图比较在这种情况下患者的临床特征及各肿瘤成份的EGFR突变状态。方法：本研究对2001~2013年间于法国Marie Lannelongue外科中心确诊、接受或未接受过以TKI为基础治疗、与肺腺癌同时发生或肺腺癌确诊后发生的连续9例SCLC患者进行了分析。采用DNA直接测序分子法对福尔马林固定组织进行EGFR突变检测，组织标本主要来自手术切除肿瘤。结果：其中6例患者为腺癌确诊后的异时SCLC（2例经TKI治疗后发生）；3例患者为同时性发生。其中4例为SCLC/腺癌复合癌。7例腺癌成份检出EGFR突变：5例为外显子19缺失，2例为外显子21突变（L833_V834delinsFL和L858R）。 4例SCLC成份内检出EGFR突变。2例为接受过TKI治疗的从不吸烟的女性腺癌患者：1例检出外显子21 E872 突变；1例SCLC/腺癌复合癌，两种成份标本内均有外显子19缺失。有2例患者为自发：1例为非突变腺癌确诊后发生的外显子19缺失的SCLC；另1例为SCLC/腺癌复合癌，且两种成份标本内均可检出外显子21突变（L833_V834delinsFL）。结论：同时或异时腺癌-SCLC复合癌似乎与EGFR突变有关，无论是否使用TKI治疗。本研究结果表明，应对此类复合患者进行EGFR突变检验。
http://www.jtochina.com.cn/ch/re ... ter_id=4&falg=1

老马 · 发表于 2013-12-25 08:05:56

肺鳞状细胞癌中成纤维细胞生长因子受体（FGFR1）的基因扩增研究
中文摘要:
引言：有报导称在肺鳞状细胞癌中发现成纤维细胞生长因子受体（FGFR1）基因扩增，这使FGFR1可能成为治疗肺鳞状细胞癌的分子治疗靶标。然而，有关FGFR1基因扩增与临床及人口统计学的相关性目前尚不清楚。方法：本研究经机构审查委员会批准，对2005至2011年美国马萨诸塞州总医院中的226例肺鳞状细胞癌患者进行回顾性分析。我们获得了所有患者的临床和人口统计学特征资料，同时了解其包括手术，放疗和化疗在内的所有治疗细节，以及总生存情况。我们将肿瘤组织经福尔马林固定和石蜡包埋后，应用荧光原位杂交技术对 FGFR1基因扩增进行检测。同时，我们对现有的临床基因分型结果进行了审查分析。结果：226例肺鳞状细胞癌患者中有37例（16%）FGFR1基因呈阳性扩增，判定基因阳性扩增的标准是基因拷贝数的控制率≥2.2。FGFR1的扩增与年龄、性别、肿瘤分期、鳞状细胞的组织学亚型、吸烟史，以及每年吸烟数量均无关。对于总体人群，FGFR1的扩增状态对于患者的总生存期并无显著影响；对于晚期患者，由于样本量小，我们的研究结果尚无定论。结论：肺鳞状细胞癌患者临床队列中有16%的患者存在FGFR1基因扩增。目前尚未发现特定的临床人口统计学特征与FGFR1阳性扩增之间的联系，表明应当对所有肺鳞状细胞癌患者进行FGFR1扩增水平的检测。
英文摘要:
Introduction: Amplification of fibroblast growth factor receptor 1 (FGFR1) has been reported in squamous cell lung carcinoma and may be a molecular target for therapy. Little is known, however, about the clinical and demographic correlates of FGFR1 amplification. Methods: The study is an Institutional Review Board approved retrospective analysis of 226 patients with squamous cell lung cancer seen at the Massachusetts General Hospital from 2005 to 2011. Clinical and demographic characteristics of all patients were obtained, as well as treatment details including surgery, radiation, and chemotherapy, and overall survival. fluorescence in situ hybridization was performed for FGFR1 on formalin-fixed paraffin-embedded tumor tissue. Clinical genotyping results were also reviewed where available. Results: Thirty-seven of 226 patients (16%) with squamous cell lung cancer were found positive for amplification using a definition of amplification of a gene to copy number control ratio of 2.2 or higher. FGFR1 amplification status was not associated with age, sex, stage, histologic subtype within squamous cell, smoking history, or pack-years of smoking. We found no significant difference in overall survival by FGFR1 amplification status as a whole; in the advanced stage subset, our findings are inconclusive because of the small sample size. Conclusion: FGFR1 amplification was found in 16% of a clinical cohort of squamous cell lung cancer patients. The lack of any specific clinicodemographic features that correlates with FGFR1 amplification suggests that all squamous cell patients should be tested for this genomic change.

老马 · 发表于 2013-12-25 08:06:55

关于酪氨酸激酶抑制剂原发性和获得性耐药的EGFR突变的日本肺癌人群中肝细胞生长因子表达的研究
Hepatocyte Growth Factor Expression in EGFR Mutant Lung Cancer with Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors in a Japanese Cohort
中文摘要:
引言: 本研究旨在检测EGFR突变肺癌患者中表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)治疗原发性和获得性耐药相关因子（如: 肝细胞生长因子（HGF）高表达、EGFR T790M继发突变及MET基因扩增）的发生率。方法: 对来自日本11个机构的93例EGFR突变的肺癌患者的97份样本（23份样本来自20例获得性耐药患者、45份样本来自44例原发性耐药[治疗无效]患者、29份样本来自29例治疗敏感患者）进行分析。对HGF表达、EGFR T790M继发突变和MET 基因扩增分别用免疫组织化学、cycleave实时聚合酶链反应（PCR）和荧光原位杂交的方法进行检测。结果: HGF高表达、EGFR T790M继发突变和MET基因扩增在获得性耐药的肺癌患者的发生率分别为61％、52％和9％。在原发性耐药（治疗无效）的肺癌患者，HGF高表达的发生率为29%，而EGFR T790M继发突变和MET基因扩增的发生率分别为0％和4％。与治疗敏感患者相比获得性耐药患者的HGF表达显著增高（P<0.001，Student's t检验）。50％的获得性耐药肿瘤患者同时存在有HGF表达和EGFR T790M继发突变及MET基因扩增。结论: 在EGFR-TKI原发性和获得性耐药的EGFR突变的日本肺癌患者中，HGF高表达较EGFR T790M继发突变或MET基因扩增发生率更高。本研究结果提示HGF表达可能与EGFR突变肺癌EGFR-TKI治疗耐药相关。
英文摘要:
Introduction: This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer. Methods: Ninety-seven specimens from 93 EGFR mutant lung cancer patients (23 tumors with acquired resistance from 20 patients, 45 tumors with intrinsic resistance from 44 patients [nonresponders], 29 sensitive tumors from 29 patients) from 11 institutes in Japan were analyzed. HGF expression, EGFR T790M secondary mutation, and MET amplification were determined by immunohistochemistry, cycleave real-time polymerase chain reaction, and fluorescence in situ hybridization, respectively. Results: High-level HGF expression, EGFR T790M secondary mutation, and MET amplification were detected in 61, 52, and 9% of tumors with acquired resistance, respectively. High-level HGF expression was detected in 29% of tumors with intrinsic resistance (nonresponders), whereas EGFR T790M secondary mutation and MET amplification were detected in 0 and 4%, respectively. HGF expression was significantly higher in tumors with acquired resistance than in sensitive tumors (p=0.001, Student’s t test). Fifty percent of tumors with acquired resistance showed simultaneous HGF expression with EGFR T790M secondary mutation and MET amplification. Conclusions: High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.

老马 · 发表于 2013-12-25 08:08:33

通过基于疾病、基因与药物联系图（C-Map）的系统方法鉴定上皮细胞间充质转化抑制剂
Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach
中文摘要:
背景：上皮细胞通过上皮细胞间充质转化（EMT）获得间充质细胞表型，被认为是肿瘤转移多步过程中的一个早期事件。因此，对EMT予以抑制，可能是避免转移的一个合理策略。方法：我们采用一个由转化生长因子β（TGF-β）诱导的EMT细胞培养模型获得的全基因表达谱，对可能的EMT抑制剂进行了鉴定。我们使用的公用数据库（www.broad.mit.edu/cmap）包括多个不同细胞系对各种药物反应的基因表达谱，由此推导出由疾病、基因与药物联系图（一种模式匹配工具）获得的EMT基因表达谱的负相关性。结果：对鉴定化合物的实验性验证表明，雷帕霉素作为一种新型的TGF-β信号转导通路抑制剂，与已知的TGF-β信号转导通路调节子17-AAG共同作用，完全阻断EMT及相关的迁移和浸润表型。鉴定的另一种化合物——LY294002显示出对间充质细胞标志物、细胞迁移和浸润具有选择性抑制作用，而不影响E-钙粘蛋白表达的缺失或Smad磷酸化。结论：数据表明与17-AAG和LY294002一样，雷帕霉素是一种新型的TGF-β信号调控子，可以用来抑制EMT。该研究证实了一种鉴定复杂生物学过程新型调控子的系统方法的潜力。

老马 · 发表于 2013-12-25 08:11:53

通过依赖和非依赖上皮标志物的方法分析非小细胞肺癌患者的循环肿瘤细胞
Analysis of Circulating Tumor Cells in Patients with Non-small Cell Lung Cancer Using Epithelial Marker-Dependent and -Independent Approaches
中文摘要:
引言：非小细胞肺癌（NSCLC）患者体内可检出上皮样循环肿瘤细胞（CTCs）。然而，由于诸多报道认为的癌症转移的先决条件----细胞发生上皮-间质转化导致对患者体内的CTC数量的低估。我们直接比较了通过依赖上皮标志物（CellSearch）和非依赖上皮标志物（上皮肿瘤细胞大小分离法[ISET]）的技术鉴定CTC的情况，同时还检测了CTC的分子特征。方法：收集40例未进行过化疗的IIIA-IV期NSCLC患者配对的外周血样本。采用上皮细胞粘附分子免疫磁珠捕获法（CellSearch，Veridex）和过滤法（ISET，RareCell Diagnostics）计算CTC的数量。对过滤法分离的CTC进行免疫组织化学分析，评价上皮标志物的表达情况（细胞角蛋白、上皮细胞粘附分子、表皮生长因子受体）及其增殖状态（Ki67）。结果：80%（32/40）的患者通过ISET法可检出CTCs，而仅23%（9/40）的患者通过CellSearch法可检出CTCs。ISET法分离的某一CTCs亚群不表达上皮性标志物。采用ISET法分析的患者中，43%可见循环肿瘤微栓（CTM，每个栓子 ≥ 3个CTCs），但采用CellSearch法分析的患者并未检出CTM。高达62%的单一CTCs的增殖标志物Ki67为阳性，但CTM中的细胞为非增殖状态。结论：两种技术平台均可检出NSCLC的CTCs。ISET法可检出更多的CTCs，包括上皮标志物为阴性的肿瘤细胞。ISET也可分离出CTM，并确定分子特征。结合我们先前CellSearch数据证实的CTC数量可作为NSCLC的独立预后标志物这一结论，我们认为将这种互补技术用于分析CTC可更完整地检测NSCLC患者的CTCs。
英文摘要:
Introduction: Epithelial circulating tumor cells (CTCs) are detectable in patients with non-small cell lung cancer (NSCLC). However, epithelial to mesenchymal transition, a widely reported prerequisite for metastasis, may lead to an underestimation of CTC number. We compared directly an epithelial marker-dependent (CellSearch) and a marker-independent (isolation by size of epithelial tumor cells [ISET]) technology platform for the ability to identify CTCs. Molecular characteristics of CTCs were also explored. Methods: Paired peripheral blood samples were collected from 40 chemon?ive, stages IIIA to IV NSCLC patients. CTCs were enumerated by Epithelial Cell Adhesion Molecule-based immunomagnetic capture (CellSearch, Veridex) and by filtration (ISET, RareCell Diagnostics). CTCs isolated by filtration were assessed by immunohistochemistry for epithelial marker expression (cytokeratins, Epithelial Cell Adhesion Molecule, epidermal growth factor receptor) and for proliferation status (Ki67). Results: CTCs were detected using ISET in 32 of 40 (80%) patients compared with 9 of 40 (23%) patients using CellSearch. A subpopulation of CTCs isolated by ISET did not express epithelial markers. Circulating tumor microemboli (CTM, clusters of ≥3 CTCs) were observed in 43% patients using ISET but were undetectable by CellSearch. Up to 62% of single CTCs were positive for the proliferation marker Ki67, whereas cells within CTM were nonproliferative. Conclusions: Both technology platforms detected NSCLC CTCs. ISET detected higher numbers of CTCs including epithelial marker negative tumor cells. ISET also isolated CTM and permitted molecular characterization. Combined with our previous CellSearch data confirming CTC number as an independent prognostic biomarker for NSCLC, we propose that this complementary dual technology approach to CTC analysis allows more complete exploration of CTCs in patients with NSCLC.