Correlation of EGFR Mutations and Response to Gefitinib

EGFR 突变与吉非替尼反应的相关性

• 批准号: 6905170
• 负责人: Naiyer A Rizvi
• 金额: $ 12.83万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-23 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6905170
• 关键词: biopsy; clinical research; computed axial tomography; epidermal growth factor; gene expression; gene mutation; growth factor receptors; human subject; human therapy evaluation; kinase inhibitor; microarray technology; neoplasm /cancer chemotherapy; nonsmall cell lung cancer; patient oriented research; protein structure function

DESCRIPTION (provided by applicant): Gefitinib is an EGFR TKI with a response rate of 10% in unselected patients with advanced NSCLC in the U.S. However, patients with NSCLC who are never smokers or have features of bronchioloalveolar lung cancer have response rates of 25-50%. At present, this "targeted" therapy is given to patients with advanced NSCLC regardless of whether EGFR signaling is a critical driver of their tumor's growth. Recent data would suggest that mutations in the EGFR tyrosine kinase domain correlate with response in small retrospective studies conducted in patients with advanced NSCLC. This is a prospective study in patients with Stage I and II NSCLC who have features that correlate with response (never or minimal smokers and features of BAG) to "enrich" for response to gefitinib. Fifty patients who are candidates for surgery will be treated on this study; we will obtain fresh frozen tissue by core biopsy before treatment with gefitinib after which patients will be treated with at least 21 days of gefitinib pre-operatively. Patients will be assessed for response by repeat CT scan after gefitinib therapy and subsequently undergo surgical resection; additional fresh frozen tissue will be procured at surgery. Patients with a response to gefitinib therapy and/or patients with EGFR mutations identified from core biopsy will continue "maintenance" gefitinib for 2 years after surgery. The primary endpoints of this study are (1) Correlate the presence of mutations in the tyrosine kinase domain of EGFR gene and radiographic response prospectively in patients with Stage I/II NSCLC patients; (2) Determine kinase activity of specific mutations as assessed by phosphotyrosine activity and autophosphorylation of EGFR in transient transfection assays and sensitivity to gefitinib as compared to wild-type EGFR. Secondary Endpoints are (1) Identify gene(s) or gene clusters that exhibit changes in gene expression before and after treatment with gefitinib, and identify significant differences in gene expression between sensitive and resistant tumor, using microarray analysis; (2) Determine time to recurrence and survival in patients with Stage l/ll NSCLC patients treated with "maintenance" gefitinib. Further characterization of tumors harboring these mutations, may have significant therapeutic implications for patients with NSCLC and change the paradigm whereby we treat patients with NSCLC.

描述（申请人提供）：吉非替尼是一种 EGFR TKI，在美国未经选择的晚期 NSCLC 患者中的缓解率为 10%。然而，从不吸烟或具有细支气管肺泡肺癌特征的 NSCLC 患者的缓解率为 25-50%。目前，这种“靶向”疗法被用于晚期 NSCLC 患者，无论 EGFR 信号传导是否是肿瘤生长的关键驱动因素。最近的数据表明，EGFR 酪氨酸激酶结构域的突变与对晚期 NSCLC 患者进行的小型回顾性研究的反应相关。这是一项针对 I 期和 II 期 NSCLC 患者的前瞻性研究，这些患者具有与“丰富”吉非替尼反应反应相关的特征（从不或很少吸烟者和 BAG 特征）。这项研究将治疗 50 名适合手术的患者；在接受吉非替尼治疗之前，我们将通过核心活检获得新鲜的冷冻组织，之后患者将在术前接受至少 21 天的吉非替尼治疗。吉非替尼治疗后，将通过重复 CT 扫描评估患者的反应，然后进行手术切除；手术时将采购额外的新鲜冷冻组织。对吉非替尼治疗有反应的患者和/或通过核心活检鉴定出 EGFR 突变的患者将在手术后继续“维持”吉非替尼 2 年。本研究的主要终点是 (1) 将 EGFR 基因酪氨酸激酶结构域突变的存在与 I/II 期 NSCLC 患者的放射学反应前瞻性关联起来； (2) 确定特定突变的激酶活性，通过瞬时转染测定中 EGFR 的磷酸酪氨酸活性和自磷酸化进行评估，以及与野生型 EGFR 相比对吉非替尼的敏感性。次要终点是（1）使用微阵列分析识别在吉非替尼治疗前后表现出基因表达变化的基因或基因簇，并识别敏感和耐药肿瘤之间基因表达的显着差异； (2) 确定用“维持”吉非替尼治疗的 I/II 期 NSCLC 患者的复发时间和生存期。含有这些突变的肿瘤的进一步表征可能对 NSCLC 患者具有重要的治疗意义，并改变我们治疗 NSCLC 患者的范式。