Circulating DNA as a Marker of Treatment Efficacy and Failure in Lung Cancer

循环 DNA 作为肺癌治疗效果和失败的标志

• 批准号: 9242001
• 负责人: Abhijit Patel
• 金额: $ 38.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242001
• 关键词: Aftercare; Appearance; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Tests; Cells; Clinical; Confusion; DNA; Data; Deposition; Detection; Diagnostic; Diagnostic radiologic examination; Disease; Disease Progression; Disease regression; Drops; Ensure; Exhibits; Fibrosis; Goals; Image; Immune; Immunotherapy; Infiltration; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Metabolic; Morphologic artifacts; Mutation; Non-Small-Cell Lung Carcinoma; Patients; Performance; Positron-Emission Tomography; Progressive Disease; Radiation; Radiation Pneumonitis; Radiation therapy; Recurrence; Recurrent disease; Residual Tumors; Sensitivity and Specificity; Somatic Mutation; Specificity; Spottings; Systemic Therapy; Techniques; Testing; Treatment Efficacy; Treatment Failure; Tumor Burden; Tumor Markers; Tumor-Derived; X-Ray Computed Tomography; base; cancer biomarkers; cancer therapy; cancer type; chemotherapy; circulating DNA; circulating biomarkers; clinical decision-making; cost; curative treatments; falls; imaging study; killings; mutant; neoplastic cell; new technology; next generation sequencing; novel; novel diagnostics; palliative; public health relevance; response; success; tool; treatment response; tumor; tumor DNA

 DESCRIPTION (provided by applicant): For patients with non-small cell lung cancer (NSCLC), treatment response and disease progression are typically assessed based on radiographic changes in tumor size or metabolic activity. However, imaging studies can sometimes yield equivocal results that lead to confusion in clinical decision-making. For example, after radiation therapy for lung cancer, in-field tumor recurrence can be difficult to distinguish from radiation-induced pneumonitis or fibrosis based on radiographic appearance alone. Imaging can also miss small metastatic deposits after completion of curative-intent stereotactic body radiotherapy (SBRT) or concurrent radiation and chemotherapy for localized NSCLC. For patients treated with new immunotherapies, confusion commonly arises when trying to assess therapeutic efficacy because radiographic shrinkage of disease can be delayed by several months. For many other types of cancer, information from quantitative changes in circulating tumor markers can be used to supplement radiographic findings. Unfortunately, no such blood markers have been found to be routinely useful for lung cancer. In this proposal, we aim to investigate whether a novel, highly cancer-specific class of biomarkers - circulating tumor DNA (ctDNA) - might be well suited for this purpose. In particular, we will focus on clinical scenarios in that are commonly prone to radiographic ambiguity. Our laboratory is especially well equipped to carry out this study because we have developed a robust, ultrasensitive next-generation sequencing-based assay that allows broad-spectrum measurement of mutant ctDNA. We propose to take advantage of this novel technology to investigate the following Specific Aims: Aim 1: Establish estimates of ctDNA assay sensitivity and specificity in patients with early-stage, locally advanced, and metastatic NSCLC prior to initiating therapy. Aim 2: For patients treated with stereotactic body radiotherapy for inoperable early-stage NSCLC or with concurrent radiation and chemotherapy for locally advanced NSCLC, determine whether detectable or rising levels of ctDNA after completion of treatment correlate with disease recurrence. Aim 3: For patients treated with immunotherapy for metastatic NSCLC, determine whether an early drop in ctDNA levels can predict subsequent radiographic response.

 描述（由申请人提供）：对于非小细胞肺癌（NSCLC）患者，通常根据肿瘤大小或代谢活性的放射学变化来评估治疗反应和疾病进展。然而，影像学研究有时会产生模棱两可的结果，导致临床决策混乱。例如，肺癌放射治疗后，仅根据放射学外观很难将现场肿瘤复发与放射诱发的肺炎或纤维化区分开来。在完成局部非小细胞肺癌的治疗性立体定向放射治疗 (SBRT) 或同步放疗和化疗后，成像也可能会漏掉小的转移性沉积物。对于接受新免疫疗法治疗的患者来说，在尝试评估治疗效果时通常会出现困惑，因为放射学上疾病的缩小可能会延迟几个月。 对于许多其他类型的癌症，循环肿瘤标志物定量变化的信息可用于补充放射学检查结果。不幸的是，尚未发现此类血液标记物通常可用于肺癌。在本提案中，我们旨在研究一种新型的、高度癌症特异性的生物标志物——循环肿瘤 DNA (ctDNA)——是否非常适合此目的。特别是，我们将重点关注通常容易出现放射学模糊的临床场景。 我们的实验室装备精良，能够开展这项研究，因为我们开发了一种强大、超灵敏的下一代测序检测方法，可以对突变体 ctDNA 进行广谱测量。我们建议利用这项新技术来研究以下具体目标： 目标 1：在开始治疗之前对早期、局部晚期和转移性 NSCLC 患者的 ctDNA 检测敏感性和特异性进行估计。目标 2：对于无法手术的早期 NSCLC 接受立体定向全身放疗或局部晚期 NSCLC 同步放疗和化疗的患者，确定治疗完成后可检测到的或上升的 ctDNA 水平是否与疾病复发相关。目标 3：对于接受免疫疗法治疗转移性 NSCLC 的患者，确定 ctDNA 水平的早期下降是否可以预测随后的放射学反应。