Liquid biopsy of the lung to profile lung cancer

项目总结/摘要 传统上，肺癌诊断的肿瘤活检是通过气道使用支气管镜检查进行的， 或者通过胸壁进行针吸靶向和免疫治疗的进展现在通常需要 更多的组织用于分子和免疫分析，以最佳地管理肺癌。癌症诊断的产量 使用现代支气管镜工具，在肺肿瘤活检谱中仅接近50%， 对分子和免疫谱的额外要求进一步削弱了这种产率。这导致延迟和 次优护理、增加的医疗保健成本和增加的患者发病率，因为患者通常需要 多个程序，以获得正确的治疗信息。我们的团队最近证明， 靶向支气管肺泡灌洗（BAL）-或在手术过程中进行的肺癌清洗-是一种有效的方法， 肺肿瘤宏观环境（TMaE）中基因组和细胞生物标志物的储存库。您因前述 表明来自肺TMaE的BAL的分子分析概括了肺肿瘤中的癌症生物学 微环境（TMiE）。虽然BAL是非常安全的，并且是支气管镜检查期间的常规检查，但迄今为止，它是一种 对癌症诊断的临床效用有限的少细胞液体。除了低产量的细胞学， 没有分子或细胞分析用于临床，以充分告知治疗肺癌的提供者。 正因为如此，严格关注如何收集方法，病人宿主因素和处理BAL将 缺乏基于改变基因组和高维细胞的测定。我们的中心假设是：全球范围内的BAL 对肿瘤微环境（TMiE）进行采样，以克服肿瘤异质性的局限性， 由于肿瘤特异性抗体的量增加， 生物标志物。为了实现我们的目标和证明我们的假设，深入分析了影响BAL的条件， 需要更高维度的基因组和细胞测定。在这里，我们建议研究如何在基本条件 肺，BAL采集的变化以及BAL的储存和处理影响其用于综合治疗的效用。 T细胞库的基因组谱分析和分析。在确定了关键的分析前变量之后，我们 提出一个标准操作程序，用于在观察性生物标志物和首次人体临床试验中实施 试验来证明我们的方法的临床实用性。提案成功将促进小说的推出 分子检测进入临床，增强现存的和发展中的血液和肿瘤检测。这种方法将 尤其是当我们进入肺癌治疗的精确指导治疗时代时， 在未来的几年和几十年里，即使是最晚期的死亡率也开始下降。

PROJECT SUMMARY/ABSTRACT A tumor biopsy is traditionally performed for lung cancer diagnosis using either bronchoscopy through the airway or a needle aspiration through the chest wall. Advances in targeted and immune therapies now often require more tissue for molecular and immune profiling to optimally manage lung cancer. The yield for cancer diagnosis using modern bronchoscopic tools approaches only 50% across the spectrum of lung tumors biopsied, and the additional requirement for molecular and immune profiling erodes this yield further. This leads to delayed and suboptimal care, increased healthcare costs, and increased patient morbidity since patients can often require multiple procedures to obtain the correct information for treatment. Our group has recently demonstrated that targeted Bronchoalveolar Lavage (BAL) – or a washing of the lung cancer performed during a procedure – is a reservoir of genomic and cellular biomarkers in the lung tumor macroenvironment (TMaE). Further, we have demonstrated that molecular analyses of BAL from the lung TMaE recapitulate cancer biology in the lung tumor microenvironment (TMiE). While BAL is very safe and routinely performed during bronchoscopy, to date, it is a pauci-cellular fluid that is of limited clinical utility for cancer diagnosis. Beyond cytology that is low yield, there are no molecular or cellular assays that are used in the clinic to fully inform providers who treat lung cancer. Because of this, rigorous attention to how methods of collection, patient host factors and processing of BAL will alter genomic and high dimensional cell based assays is lacking. Our central hypothesis is: BAL globally samples the tumor microenvironment (TMiE) to overcome limitations of tumor heterogeneity and is more sensitive than blood for immunogenomic profiling due to increased quantities of tumor specific biomarkers. To realize our goal and prove our hypothesis, in depth analysis of the conditions affecting BAL for high dimensional genome and cell assays is required. Here, we propose studying how basic conditions in the lung, variations in acquisition of BAL, and storage and processing of BAL affect its utility for comprehensive genome profiling and analysis of the T cell repertoire. Following identification of key pre-analytic variables, we propose a standard operating procedure for implementation in observational biomarker and first-in-man clinical trials to demonstrate the clinical utility of our approach. Proposal success will facilitate the introduction of novel molecular assays into the clinic that augment extant and developing blood and tumor assays. This approach will be particularly relevant as we move into the era of precision guided therapies for lung cancer treatment, which have begun to reduce mortality in even the most advanced stages, over the coming years and decades.