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

 描述（由申请方提供）：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评估治疗缓解和疾病进展。然而，成像研究有时会产生模棱两可的结果，导致临床决策的混乱。例如，在肺癌的放射治疗后，仅基于放射学表现，很难将病灶内肿瘤复发与放射诱导的肺炎或纤维化区分开。在完成治疗性立体定向体部放疗（SBRT）或局部NSCLC的同步放疗和化疗后，成像也可能错过小的转移性沉积。对于接受新免疫疗法治疗的患者，在试图评估治疗效果时通常会出现困惑，因为疾病的放射学收缩可能会延迟数月。 对于许多其他类型的癌症，来自循环肿瘤标志物定量变化的信息可用于补充放射学发现。不幸的是，没有发现这种血液标记物对肺癌常规有用。在这项提案中，我们的目标是研究一种新型的、高度癌症特异性的生物标志物-循环肿瘤DNA（ctDNA）-是否可能非常适合这一目的。特别是，我们将集中在临床情况下，通常倾向于射线照相模糊。 我们的实验室特别适合进行这项研究，因为我们已经开发了一种强大的，超灵敏的下一代基于测序的检测方法，可以对突变ctDNA进行广谱测量。我们建议利用这种新技术来研究以下特定目的：目的1：在开始治疗前，在早期、局部晚期和转移性NSCLC患者中建立ctDNA检测灵敏度和特异性的估计值。目标二：对于接受立体定向体部放疗治疗不可手术的早期NSCLC或同时接受放疗和化疗治疗局部晚期NSCLC的患者，确定治疗完成后可检测到的ctDNA水平或ctDNA水平升高是否与疾病复发相关。目标3：对于接受免疫治疗的转移性NSCLC患者，确定ctDNA水平的早期下降是否可以预测随后的放射学缓解。

 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.