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

不确定肺结节中早期肺癌检测的分子和影像生物标志物

基本信息

批准号：
10231155
负责人：
DENISE R. ABERLE
金额：
$ 18.11万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-23 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231155
关键词：
Adoption Appearance Benign Biological Assay Biological Markers Biopsy Boston Bronchi Bronchoscopy Cancer Detection Cancerous Categories Clinical Cytology Detection Diagnostic Diagnostic radiologic examination Discrimination Eligibility Determination Epithelial Evaluation Gene Expression Image Individual Injury Libraries Lung Lung diseases Lung nodule Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Medical Medical center Methods Military Personnel Modeling Molecular Molecular Biology Multi-Institutional Clinical Trial Nasal Epithelium Nodule Nose Patients Physicians Population Heterogeneity Populations at Risk Practice Management Predictive Value Reader Reproducibility Research Personnel Risk Sampling Screening procedure Smoker Testing Uncertainty Universities Unnecessary Procedures Visual Work X-Ray Computed Tomography arm base biomarker panel bronchial epithelium cancer biomarkers cancer diagnosis chest computed tomography clinical biomarkers clinical practice cohort diagnostic accuracy disorder risk economic cost high risk imaging biomarker improved lung cancer screening meetings molecular imaging molecular marker predictive marker predictive modeling prospective quantitative imaging screening

项目摘要

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.

抽象的临床迫切需要开发非侵入性方法来区分良性与非良性疾病，但这一需求尚未得到满足。胸部 CT 发现恶性不确定性肺结节 (IPN)。我们建议开发和验证吸烟者肺癌基于临床、分子和成像的综合诊断模型 6- 25 mm 由于符合筛查资格标准而面临较高的肺癌风险，并且其结节可能是在常规临床实践中通过筛查或偶然发现的。这个结节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。波士顿大学的研究人员开发并验证了一种基因表达生物标志物，最近以 CLIA 检测 (PerceptaTM) 的形式商业化，在细胞学正常的主干中进行测量支气管上皮细胞检测肺癌具有高灵敏度和高阴性预测值 (NPV) 因疑似肺癌而接受支气管镜检查的吸烟者。他们最近扩展了这些 “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还发现了两种定性的和定量成像特征，可告知筛查和偶然检测到的结节的诊断风险在老年吸烟者中。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，确认其可重复性，并确定其对结节个体诊断模型的贡献 6- 距离国家肺部筛查试验 (NLST) 的 CT 臂 25 毫米。目标 2 将确定是否有支气管最初在高风险人群中验证的基因表达生物标志物在特定背景下表现同样出色 IPNs 6-25 mm 的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 (DECAMP) 联盟，并将该生物标记物与基于成像的标记物相结合目标 1. 鉴于并非所有 IPN 患者均接受支气管镜检查，目标 2 还将验证最近开发的在同一队列中研究鼻腔基因表达生物标志物，并构建整合临床、成像和诊断的模型分子生物标志物。在目标 3 中，综合临床、鼻腔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，其中包含筛选和偶然检测到的 IPN，这些 IPN 是接受 CT 监视或活检。我们的工作假设是，诊断模型整合了分子生物标志物、临床变量和成像特征的正交特征集将提供在 6-25 毫米尺寸范围内，良性和恶性 IPN 之间的区分度最高，其中诊断不确定性是最大的。鉴于肺癌筛查的日益广泛实施和 IPN 数量急剧增加，我们预计具有高 NPV 的敏感生物标志物将能够医生应避免对患有良性肺部疾病的患者进行不必要的手术，避免他们相关的医疗风险和经济成本。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patient Adherence to Lung CT Screening Reporting & Data System-Recommended Screening Intervals in the United States: A Systematic Review and Meta-Analysis.

DOI：
10.1016/j.jtho.2021.09.013
发表时间：
2022-01
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
0
作者：
Lin Y;Fu M;Ding R;Inoue K;Jeon CY;Hsu W;Aberle DR;Prosper AE
通讯作者：
Prosper AE

Bronchial gene expression alterations associated with radiological bronchiectasis.

DOI：
10.1183/13993003.00120-2022
发表时间：
2023-01
期刊：
The European respiratory journal
影响因子：
0
作者：
通讯作者：

The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection.

DOI：
10.1158/1078-0432.ccr-16-3187
发表时间：
2018-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Billatos E;Vick JL;Lenburg ME;Spira AE
通讯作者：
Spira AE

Biomarkers for Lung Cancer Screening and Detection.

用于肺癌筛查和检测的生物标志物。