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

摘要 有一个迫切的，尚未得到满足的临床需求，即开发非侵入性方法来区分良性和非侵入性疾病。 胸部CT发现恶性不明肺结节(IPN)。我们建议开发和验证 有结节的吸烟者肺癌的综合临床、分子和影像诊断模型 25毫米，因符合筛查资格标准而罹患肺癌的风险增加，且 在常规临床实践中，结节可能已被筛查或偶然发现。这个结节的大小 范围代表疾病的中等风险，其临床不确定性最大的方面是 诊断管理。波士顿大学的研究人员已经开发并验证了一种基因表达生物标记物， 最近商业化推出的CLIA分析(PerceptaTM)在细胞学正常的主要组织中进行测量 高灵敏度、高阴性预测值(NPV)的支气管上皮诊断肺癌 因可疑肺癌而接受支气管镜检查的吸烟者。他们最近延长了这些 “损伤领域”内的癌症特异性分子改变以开发和验证类似的生物标记物 较少侵袭性采集的鼻黏膜上皮。此外，加州大学洛杉矶分校的调查人员已经确定了这两种定性 以及定量成像特征，告知筛查和偶然发现的结节的诊断风险 在年长的吸烟者中。在本提案的目标1中，我们将提炼定性和定量成像生物标记物， 确认它们的重复性，并确定它们对结节患者诊断模型的贡献6- 距离国家肺部筛查试验(NLST)CT臂25 mm。目标2将确定支气管炎 最初在高危人群中验证的基因表达生物标记物在特定背景下也同样表现良好 6-25 mm IPNS患者接受支气管镜检查作为早期肺癌检测的一部分 军事人员(德坎普)联盟，以及将该生物标记物与来自 目的1.鉴于并非所有IPN患者都接受支气管镜检查，AIM 2也将验证最近开发的 鼻部基因表达的生物标记物，并构建整合了临床、影像和 分子生物标志物。在目标3中，基于临床、鼻部基因表达和影像的综合生物标志物 然后将在多个队列中进行前瞻性验证，其中筛查和顺便检测到的IPN是 接受CT监视或活组织检查。我们的工作假设是，整合了 分子生物标记物、临床变量和成像特征的正交特征集将提供 在6-25 mm大小范围内对良性和恶性IPN的最高区分度 不确定性是最大的。鉴于越来越广泛地实施肺癌筛查和 IPN数量的急剧增加，我们预计具有高净现值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，避免 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.