Liquid biopsy of the lung to profile lung cancer

项目摘要/摘要 传统上，肺癌的诊断是通过经呼吸道的支气管镜检查进行肿瘤活检。 或者是胸壁的针吸。靶向和免疫疗法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。癌症诊断的收益率 使用现代支气管镜工具只接近50%的肺肿瘤活检频谱，并且 对分子和免疫图谱的额外要求进一步侵蚀了这一产量。这会导致延迟和 不理想的护理、增加的医疗成本和增加的患者发病率，因为患者经常需要 多个程序，以获得正确的治疗信息。我们的团队最近证明了 靶向支气管肺泡灌洗(BAL)--或在手术过程中对肺癌进行冲洗--是一种 肺肿瘤大环境(TMaE)中的基因组和细胞生物标记物的储存库。此外，我们还拥有 从肺TMAE中提取的BAL的分子分析表明，它概括了肺癌的生物学特性 微环境(TMIE)。虽然BAL在支气管镜检查期间是非常安全和常规的，但到目前为止，它是一种 用于癌症诊断的临床用途有限的稀少细胞液。除了细胞学上的低产量，还有 没有用于临床的分子或细胞分析来充分告知治疗肺癌的提供者。 正因为如此，严格关注BAL的收集方法、患者宿主因素和处理将如何 缺乏基于改变基因组和高维细胞的分析。我们的中心假设是：全球平衡 采样肿瘤微环境(TMIE)，以克服肿瘤异质性的限制，并具有更多 由于肿瘤特异量的增加，免疫基因组学分析比血液更敏感 生物标志物。为了实现我们的目标并证明我们的假设，深入分析影响BAL的条件 高维基因组和细胞分析是必需的。在这里，我们建议研究如何在基本条件 肺脏、BAL获取的差异以及BAL的储存和加工影响其在综合治疗中的应用 T细胞库的基因组图谱和分析。在确定了关键的分析前变量之后，我们 提出在观察性生物标记物和首例人类临床中实施的标准操作程序 以证明我们方法的临床实用性的试验。提案的成功将促进小说的引入 分子分析进入临床，加强现有的和发展中的血液和肿瘤分析。这一方法将 随着我们进入肺癌治疗的精确引导治疗时代，这一点尤其相关 在接下来的几年和几十年里，即使是在最高级的阶段，也开始降低死亡率。

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.