CT Volume Measurement of Lung Cancer treated with Erlotinib: Genomic Correlation

描述（由申请人提供）：肺癌是美国和世界范围内癌症死亡的主要原因。肺癌治疗的最新突破之一是发现了非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）酪氨酸激酶结构域的体细胞激活突变，其与对EGFR抑制剂如吉非替尼和厄洛替尼的显著临床反应相关。厄洛替尼在EGFR突变患者中特别有效。然而，大多数对厄洛替尼治疗具有初始应答的患者最终由于对厄洛替尼的获得性耐药性而复发。该提案的目的是分析在Dana-Farber癌症研究所的临床试验中接受厄洛替尼治疗的晚期NSCLC患者的肿瘤大小和体积的时间变化，并确定肿瘤体积是否比肿瘤大小更早检测到获得性耐药引起的复发。如果这一点得到证实，肿瘤体积可以作为监测治疗反应的主要标志物，而不是传统的标志物，肿瘤大小。通过肿瘤体积分析早期检测对厄洛替尼的获得性耐药将允许肿瘤学家改变治疗方案以延长无进展生存期。我们还旨在确定肿瘤大小和体积的初始比例减小是否与患者的无进展生存期和总生存期相关。如果是这种情况，通过CT测量的肿瘤体积可以用作预后的生物标志物。我们还将确定肿瘤大小和体积变化是否与晚期NSCLC患者循环肿瘤细胞和游离血浆DNA的基因组变化相关。NSCLC中循环肿瘤细胞和游离血浆DNA的基因组分析是一种新兴的非侵入性技术，其允许在治疗期间频繁评估基因组变化。该研究将使用Dana-Farber癌症研究所在晚期NSCLC患者中进行的厄洛替尼II期前瞻性临床试验中收集的数据进行。数据包括每八周进行一次胸部CT检查和EGFR突变分析。将使用市售的、美国食品药品监督管理局（FDA）批准的体积分析软件测量肿瘤大小和体积。将计算肿瘤大小和体积的变化，并将其与临床结局和基因组分析结果相关联。该项目的长期目标是通过将基因组信息整合到肿瘤体积分析中来确定最有效地预测对厄洛替尼的获得性耐药性的成像参数，以优化厄洛替尼的治疗益处并有助于延长肺癌患者的生存期。

DESCRIPTION (provided by applicant): Lung cancer is a leading cause of cancer death in the United States and worldwide. One of the recent breakthroughs in lung cancer treatment was the discovery of the somatic activating mutations of the epidermal growth factor receptor (EGFR) tyrosine kinase domain in non-small cell lung cancer (NSCLC), which is associated with a dramatic clinical response to EGFR inhibitors such as gefitinib and erlotinib. Erlotinib is particularly effective in patients with EGFR mutations. However, most patients with initial responses to erlotinib treatment eventually relapse due to acquired resistance to erlotinib. The purpose of this proposal is to analyze chronological changes in tumor size and volume in advanced NSCLC patients treated with erlotinib in clinical trials at Dana-Farber Cancer Institute, and determine if the tumor volume detects relapse caused by acquired resistance earlier than the tumor size does. If this is proven, tumor volume can be used as the primary marker for monitoring response to therapy instead of the conventional marker, tumor size. Early detection of acquired resistance to erlotinib by tumor volume analysis will allow oncologists to change therapeutic regimen for prolongation of progression-free survival. We also aim to determine if the initial proportional decreases in tumor size and volume correlate with progression-free survival and overall survival of the patients. If this is the case, tumor volume measured by CT can be used as a biomarker for prognosis. We will also determine if the tumor size and volume changes correlate with genomic changes in circulating tumor cells and free plasma DNA in advanced NSCLC patients. Genomic analysis of circulating tumor cells and free plasma DNA in NSCLC is an emerging non-invasive technique which allows for frequent assessment of genomic changes during therapy. The study will be performed using data collected in phase II prospective clinical trials of erlotinib in advanced NSCLC patients at the Dana-Farber Cancer Institute. Data includes chest CT examinations performed every eight weeks and EGFR mutation analysis. Tumor size and volume will be measured using a commercially available, Food and Drug Administration (FDA) approved volume analysis software. Changes of tumor size and volume will be calculated, and will be correlated with clinical outcome and genomic analysis results. The long term goal of the project is to determine the imaging parameters that most efficiently predict acquired resistance to erlotinib by integrating the genomic information into the tumor volume analysis, in order to optimize the therapeutic benefit of erlotinib and contribute to the prolongation of survival in lung cancer patients.