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

• 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
• 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

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。 我们建议开发和验证胸部 CT 发现的恶性不确定性肺结节 (IPN)。 吸烟者肺癌基于临床、分子和成像的综合诊断模型 6- 25 mm 由于符合筛查资格而处于较高的肺癌风险中，并且其 该结节大小可能是在常规临床实践中通过筛查或偶然检测到的。 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 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) 他们最近在因疑似肺癌而接受支气管镜检查的吸烟者中扩大了这些范围。 “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 此外，加州大学洛杉矶分校的研究人员还鉴定了两种定性的鼻上皮。 以及影像特征，可告知筛查和偶然检测到的结节的定量诊断风险 在该提案的目标 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- 距国家肺部筛查试验 (NLST) 25 毫米的 CT 臂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的模型，以及 在目标 3 中，综合临床、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，其中包含筛选和明确检测到的 IPN 我们的工作假设是整合诊断模型。 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 鉴于肺癌筛查的日益广泛实施，不确定性最大。 IPN 数量急剧增加，我们预计具有高 NPV 的敏感生物标志物将使 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

Bronchial epithelial gene expression and interstitial lung abnormalities.

• DOI: 10.1186/s12931-023-02536-w
• 发表时间: 2023-10-10
• 期刊: Respiratory research
• 影响因子: 5.8

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

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
• 作者: Lin Y;Fu M;Ding R;Inoue K;Jeon CY;Hsu W;Aberle DR;Prosper AE
• 通讯作者: Prosper AE

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
• 作者: Billatos E;Vick JL;Lenburg ME;Spira AE
• 通讯作者: Spira AE

Biomarkers for Lung Cancer Screening and Detection.

• DOI: 10.1158/1055-9965.epi-20-0865
• 发表时间: 2020-12
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Ostrin EJ;Sidransky D;Spira A;Hanash SM
• 通讯作者: Hanash SM