EFIRM-Liquid Biopsy (eLB): Ultrasensitive ctDNA and miRNA Detection for Early Assessment of Lung Cancer

EFIRM-液体活检 (eLB)：用于肺癌早期评估的超灵敏 ctDNA 和 miRNA 检测

• 批准号: 10456340
• 负责人: DENISE R. ABERLE
• 金额: $ 64.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456340
• 关键词: Address; Area; Attenuated; Benign; Biological; Biological Assay; Biological Markers; Biological Testing; Blood; Blood Volume; Blood specimen; Caliber; Cancer Biology; Cancer Detection; Categories; Characteristics; Classification; Clinical; Clinical Data; Clinical Management; Collaborations; Complement; DNA Sequence Alteration; Data Element; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Detection Research Network; Early Diagnosis; Eligibility Determination; Engineering; Epidermal Growth Factor Receptor; Evaluation; FDA approved; Goals; Image; Individual; Industrialization; Industry; Knowledge; Lung; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Methods; MicroRNAs; Modeling; Molecular; Mutation; Nodule; Non-Small-Cell Lung Carcinoma; Pathologic; Pathologist; Patients; Penetration; Performance; Population; Prevalence; Procedures; Prospective cohort; Public Health; Publishing; ROC Curve; Research; Research Personnel; Risk; Scientist; Sensitivity and Specificity; Signal Transduction; Smoker; Specimen; Symptoms; System; Techniques; Technology; Testing; Thoracic Radiography; Time; Tissue Sample; Tumor Markers; Validation; X-Ray Computed Tomography; anticancer research; base; biomarker panel; blood-based biomarker; cancer diagnosis; cell type; circulating DNA; clinical material; clinical practice; clinical translation; comparative; computed tomography screening; detection platform; electric field; former smoker; high risk; industry partner; instrument; liquid biopsy; low dose computed tomography; lung basal segment; lung cancer cell; lung cancer screening; member; molecular marker; mortality; mutant; never smoker; non-smoker; novel; performance tests; peripheral blood; point of care; pre-clinical; preservation; prospective; quality assurance; screening; screening guidelines; seal; serial imaging; success; surveillance imaging; tool; tumor DNA

Project Summary/Abstract: Computed tomography (CT) is currently the most sensitive test for detecting preclinical lung cancer, which typically presents as an indeterminate pulmonary nodule (IPN). The success of CT for early detection was sealed by the National Lung Screening Trial, in which lung cancer mortality was reduced by 20% relative to chest radiography. However, in the NLST, the screen positivity rate was 24% and 96% of positive screens were false positive. Although these percentages have been partially attenuated by new screening guidelines, it is axiomatic that LDCT screening is highly sensitive for detecting lung cancer, but non-specific, and not without harms. Furthermore, more individuals, both smokers and non-smokers, are diagnosed outside of screening based on the finding of an indeterminate nodule. Methods are urgently needed to better differentiate between individuals with benign disease and those should undergo invasive diagnostic testing. Liquid biopsy has found its way into the cancer lexicon as a reference to tumor biomarkers within blood or other readily accessible biospecimens that reflect the presence and biology of cancer. This precompetitive collaboration brings together academic and industrial partners across the cancer spectrum to advance liquid biopsy technologies for early detection that are viable as clinical tools. Our partnership interleaves the expertise of lung cancer biologists, clinicians, and biostatisticians with industry engineers, converging on a novel liquid biopsy technology “EFIRM-Liquid biopsy (eLB)” that has already shown high sensitivity detecting circulating DNA mutations in patients with EGFR-mutant lung cancers. To address early lung cancer detection, our academic researchers will develop and validate independent assays for 10 DNA mutations commonly observed in lung cancer as well as introduce a 6-biomarker panel of miRNA to complement and strengthen the blood-based molecular signal of lung cancer. Our industry partners will convert these individual assays to a single array while preserving high sensitivity and specificity. With our clinician scientists, this integrated platform will be validated in patients with screen- or incidentally- detected lung nodules in the size ranges that are most diagnostically challenging. Our overall research proposition is that blood-based biomarkers using the eLB-Lung Cancer Detection Panel (eLB-LCDP) will inform the accurate and robust classification of nodules as benign or malignant. Beyond contributing molecular and technological expertise, standard operating procedures, and annotated clinical materials, we will compare eLB- LCDP with other lung cancer-associated liquid biopsy platforms to be developed in this and related NCI consortia to determine the highest performing biomarkers and platforms that should move to clinical translation, alone or in combination with models that include clinical and imaging variables acquired as part of patient management. Using this orthogonal, multiparametric interrogation approach, we hypothesize that the eLB-LCDP can achieve a classification performance area under the receiver operating characteristic curve (AUC) > 0.85 in near real- time clinical practice.

项目摘要/摘要： 计算机断层扫描（CT）是目前检测临床前肺癌最敏感的检查方法， 通常表现为不确定的肺结节 (IPN)。 CT 早期检测的成功已成定局 根据国家肺部筛查试验，肺癌死亡率相对于肺癌死亡率降低了 20% 射线照相。然而，在 NLST 中，筛查阳性率为 24%，其中 96% 的阳性筛查结果为假 积极的。尽管新的筛查指南已部分削弱了这些百分比，但这是不言而喻的 LDCT 筛查对于检测肺癌高度敏感，但非特异性，且并非没有危害。 此外，越来越多的人，无论是吸烟者还是非吸烟者，都是在筛查之外根据以下因素被诊断出来的： 发现不确定的结节。迫切需要更好地区分个体的方法 患有良性疾病的人应该接受侵入性诊断测试。液体活检已经找到了进入 癌症词典作为血液或其他容易获得的生物样本中肿瘤生物标志物的参考 反映癌症的存在和生物学。这种赛前合作汇集了学术界和 整个癌症谱系的工业合作伙伴将推进用于早期检测的液体活检技术 作为可行的临床工具。我们的合作伙伴关系融合了肺癌生物学家、临床医生和 生物统计学家与行业工程师共同研究新型液体活检技术“EFIRM-液体活检 (eLB)”，已显示出检测 EGFR 突变患者循环 DNA 突变的高灵敏度 肺癌。为了解决早期肺癌检测问题，我们的学术研究人员将开发并验证 对肺癌中常见的 10 种 DNA 突变进行独立测定，并引入 6 种生物标志物 一组 miRNA 来补充和增强肺癌的血液分子信号。我们的行业 合作伙伴将把这些单独的检测转换为单个阵列，同时保持高灵敏度和特异性。 与我们的临床科学家一起，这个集成平台将在患有筛查或偶然的患者中得到验证 检测到的肺结节的尺寸范围在诊断上最具挑战性。我们的整体研究 提议是使用 eLB-肺癌检测面板 (eLB-LCDP) 的基于血液的生物标志物将提供信息 准确而稳健地对结节进行良性或恶性分类。除了贡献分子和 技术专长、标准操作程序和注释临床材料，我们将比较 eLB- LCDP 以及本联盟和相关 NCI 联盟将开发的其他肺癌相关液体活检平台 确定应单独或单独进行临床转化的最高性能的生物标志物和平台 与包含作为患者管理一部分获得的临床和影像变量的模型相结合。 使用这种正交、多参数询问方法，我们假设 eLB-LCDP 可以实现 接收者操作特征曲线 (AUC) > 0.85 下的分类性能区域接近真实 时间临床实践。