Molecular and Imaging Biomarkers for Early Lung Cancer Detection in the Setting of Indeterminate Pulmonary Nodules

摘要 有一个迫切的，未满足的临床需要，开发非侵入性的方法来区分良性与恶性肿瘤。 胸部CT发现恶性不确定性肺结节（IPN）。我们建议开发并验证 患有结节的吸烟者肺癌的综合临床、分子和基于成像的诊断模型6- 25 mm，由于符合筛选合格标准而处于肺癌高风险中，并且 结节可能在常规临床实践中被筛查检测到或偶然检测到。这个结节的大小 范围代表疾病的中等风险，在以下方面存在最大的临床不确定性： 诊断管理BU的研究人员已经开发并验证了一种基因表达生物标志物， 最近作为CLIA检测试剂盒（PerceptaTM）在商业上推出， 支气管上皮细胞对肺癌的高敏感性和高阴性预测值（NPV）检测 吸烟者因疑似肺癌接受支气管镜检查。他们最近将这些 在“损伤领域”内的癌症特异性分子改变，以开发和验证与癌症相关的类似生物标志物。 较少侵入性地收集鼻上皮。此外，加州大学洛杉矶分校的研究人员已经确定了两个定性 和定量成像特征，告知筛查和意外检测到的结节的诊断风险 老年吸烟者在本提案的目标1中，我们将完善定性和定量成像生物标志物， 确认它们的可重复性，并确定它们对结节患者诊断模型的贡献6- 距离国家肺筛查试验（NLST）的CT组25 mm。目的2将确定是否支气管 最初在高风险队列中验证的基因表达生物标志物在特定背景下同样有效 接受支气管镜检查作为早期肺癌检测的一部分的6-25 mm IPN患者， 军事人员（DECAMP）联盟，以及整合这种生物标志物与基于成像的标志物， 目标1.鉴于并非所有IPN患者都接受支气管镜检查，Aim 2还将验证最近开发的 鼻基因表达生物标志物，并构建整合临床、成像和 分子生物标志物在目标3中，整合临床、鼻基因表达和基于成像的生物标志物 然后将在多个队列中进行前瞻性验证，这些队列具有筛选和意外检测到的IPN， 接受CT监测或活检。我们的工作假设是， 分子生物标志物、临床变量和成像特征的正交特征集将提供 在6-25 mm尺寸范围内，良性和恶性IPN之间的最高区分度， 不确定性最大。鉴于肺癌筛查的日益广泛实施， 随着IPN数量的急剧增加，我们预计具有高NPV的敏感生物标志物将使 医生避免对肺部良性疾病患者进行不必要的手术， 相关的医疗风险和经济成本。

ABSTRACT There is an urgent, unmet clinical need to develop non-invasive approaches for distinguishing benign vs. malignant indeterminate pulmonary nodules (IPN) identified on CT chest. We propose to develop and validate integrated clinical, molecular and imaging-based diagnostic models of lung cancer in smokers with nodules 6- 25 mm who are at elevated risk of lung cancer as a result of meeting eligibility criteria for screening, and whose nodules may have been screen-detected or incidentally-detected in routine clinical practice. This nodule size range represents an intermediate risk for disease for which there is the greatest clinical uncertainty in terms of diagnostic management. The investigators at BU have developed and validated a gene expression biomarker, recently launched commercially as a CLIA assay (PerceptaTM) measured in cytologically-normal mainstem bronchus epithelium with high sensitivity and high negative predictive value (NPV) for detecting lung cancer among smokers undergoing bronchoscopy for suspect lung cancer. They have recently extended these cancer-specific molecular alterations within the “field of injury” to develop and validate a similar biomarker in less invasively collected nasal epithelium. Additionally, investigators at UCLA have identified both qualitative and quantitative imaging features that inform diagnostic risk in both screen- and incidentally-detected nodules in older smokers. In Aim 1 of this proposal, we will refine qualitative and quantitative imaging biomarkers, confirm their reproducibility, and determine their contribution to diagnostic models in individuals with nodules 6- 25 mm from the CT arm of the National Lung Screening Trial (NLST). Aim 2 will determine whether bronchial gene expression biomarkers originally validated in high risk cohorts perform equally well in the specific context of patients with IPNs 6-25 mm undergoing bronchoscopy as part of the Detection of Early Lung Cancer Among Military Personnel (DECAMP) consortium, as well as integrate this biomarker with imaging-based markers from Aim 1. Given that not all IPN patients undergo bronchoscopy, Aim 2 will also validate a recently developed nasal gene-expression biomarker in this same cohort and construct models that integrate clinical, imaging, and molecular biomarkers. In Aim 3, the integrated clinical, nasal gene-expression and imaging-based biomarker will then be validated prospectively in multiple cohorts with screen- and incidentally-detected IPNs who are undergoing CT surveillance or biopsy. Our working hypothesis is that diagnostic models that integrate orthogonal feature sets of molecular biomarkers, clinical variables, and imaging features will provide the highest discrimination between benign and malignant IPNs in the 6-25 mm size range in which diagnostic uncertainty is greatest. Given the increasingly widespread implementation of lung cancer screening and dramatically increased numbers of IPNs, we anticipate that sensitive biomarkers with a high NPV would enable physicians to avoid unnecessary procedures in patients with benign disease of the lung, avoiding their associated medical risks and economic costs.