Clinical Utility of Biomarkers Driven Management of Indeterminate Pulmonary Nodules

项目摘要 本申请的目的是测试生物标志物知情方法评价的临床效用， 不确定性肺结节（IPN）的管理。这项研究旨在解决这一重大问题， 由于在美国和国外采用肺癌筛查， 偶然识别的IPN的发生。我们在外部队列中开发并验证了高灵敏度 hs-CYFRA 21-1生物标志物测定和定量成像特征，共同改善了目前的非 IPNs的侵入性评估。在这个建议中，我们假设一个预测模型，结合临床 变量、hs-CYFRA 21-1血清浓度和定量成像特征将显示临床效用， 减少昂贵和侵入性的程序，同时缩短诊断时间。为了验证这一假设，我们建议 以下具体目标：首先，我们将在其第一个实验中测试生物标志物知情策略的临床效用。 类随机临床试验的IPN管理。我们将招募440名患有中度风险IPN的个体（10- 70%的癌症风险），目标是减少侵入性手术的数量和时间， 诊断.在对照组中，参与者将遵循标准护理，在干预组中， 生物标志物结果，表示为肺癌的检测后概率，将提供给提供者和参与者 为结核管理提供信息。第二，为了进一步确定新的候选生物标志物， 风险分层，我们将应用一个工作流程来评估候选人，并验证最佳候选人进入 类似于目标1中提议的未来试验。在一组前瞻性收集的标本中，评价 以盲法（ProBE设计）回顾性研究，我们将测试以下诊断准确性的改善： 基于马约风险模型，在具有肺癌中等风险的IPN患者中的候选生物标志物。一 Abbott实验室的血液生物标志物特征将单独进行检测，并与经验证的 放射组学评分，以确定它们是否共同重新分类至少20%的中度风险（10-70%）， 根据马约风险模型分为低风险（<10%）或高风险（>70%）组。康贝特人将以 最佳和最具成本效益的马约模型+生物标志物组合或序列，以实现关键的 决策阈值在IPN的管理。在本项目结束时，我们将：a）演示 首次将生物标志物告知方法用于IPN管理的临床实用性，并获得了额外的 一项更大规模的后续随机多中心试验的结局数据，B）验证了增量诊断 用于管理IPN的新候选生物标志物的准确性，以及c）开辟了一条新的快速生物标记的途径。 测试最有效的候选人组合。

PROJECT SUMMARY The goal of this application is to test the clinical utility of a biomarker-informed approach to the evaluation and management of indeterminate pulmonary nodules (IPNs). The study is designed to address this major and growing unmet need given the adoption of lung cancer screening in the US and abroad and the common occurrence of incidentally identified IPNs. We have developed and validated in external cohorts a high sensitivity hs-CYFRA 21-1 biomarker assay and quantitative imaging features that together improve the current non- invasive assessment of IPNs. In this proposal we hypothesize that a prediction model that integrates clinical variables, hs-CYFRA 21-1 serum concentration, and quantitative imaging signature will show clinical utility by reducing costly and invasive procedures while shortening time to diagnosis. To test this hypothesis, we propose the following specific aims: First, we will test the clinical utility of a biomarker-informed strategy in a first of its kind randomized clinical trial of IPN management. We will enroll 440 individuals with intermediate risk IPNs (10- 70% risk for cancer) at four institutions with the goal of reducing the number of invasive procedures and time to diagnosis. In the control arm, participants will follow the standard of care and in the intervention arm the biomarker results, expressed as a post-test probability for lung cancer, will be given to providers and participants to inform nodule management. Second, to further our work in identifying new candidate biomarkers for better risk stratification, we will apply a workflow for evaluation of candidates and validate the best candidates for entry into a similar future trial to that proposed in Aim 1. In a set of prospectively collected specimens, evaluated retrospectively in a blinded fashion (ProBE design), we will test the improvement in diagnostic accuracy of candidate biomarkers in patients with IPNs of intermediate risk for lung cancer based on the Mayo risk model. A blood biomarker signature from Abbott laboratories will be tested alone and in combination with a validated radiomics score to determine if together they reclassify at least 20% of those at intermediate risk (10-70%) based on the Mayo risk model alone into either a lower risk (<10%) or higher risk (>70%) group. We will determine the optimal and most cost-effective Mayo model + biomarker combination or sequence needed to achieve the critical decision thresholds in the management of IPNs. At the end of this project, we will have: a) demonstrated for the first time the clinical utility of a biomarker informed approach to IPN management and acquired additional outcomes data for a larger follow-on randomized multicenter trial, b) validated the incremental diagnostic accuracy of new candidate biomarkers for the management of IPNs, and c) opened a new avenue for rapid testing of the most effective combination(s) of candidates.