Early detection of metastatic disease in US Veterans following surgery for early stage lung cancer

美国退伍军人早期肺癌术后转移性疾病的早期发现 手术仍然是早期非小细胞肺癌(NSCLC)最有效的治疗方法。这 然而，治疗的支柱是术后复发的发展，最常见的是 表现为转移性疾病。在过去的15年里，没有出现重大的改善， 手术后，总的5年存活率保持在50%以下。新的有效战略，克服 与转移相关的主要障碍将提高肺癌治愈率，并对VA产生重大影响 病人护理。早期发现非小细胞肺癌可获得良好的生存结果。在目标1中，我们将 确定可预测导致肺癌转移的侵袭性疾病的分子和细胞特征 手术后通过执行以下次级目标：a)识别和表征不同的体细胞突变 利用全外显子组测序在侵袭性和惰性肺癌之间进行比较，B)形成肿瘤基因 与重要的驱动程序突变相关的表达特征，并决定基因表达 标志物将具有生物相关突变的肿瘤分组，从而作为区分 侵袭性和惰性肺癌和C)之间的免疫细胞表型 区分侵袭性和惰性肺癌的肿瘤微环境。在目标2中，我们将开发一种 一种新的高灵敏度的最小残留病(MRD)和肿瘤复发检测方法 进行以下子目标：a)从术前血浆循环肿瘤DNA中识别躯干突变 (CfDNA)样本，B)使用术后血浆cfDNA样本检测MRD/复发，以及C)评估 MRD预测评分在判断复发中的统计学意义。在退伍军人事务部的这份功绩评估中 补充建议我们将进行一项试点研究，开始开发必要的平台，以促进 我们对美国退伍军人非小细胞肺癌转移的理解、预测和检测。

Early detection of metastatic disease in US Veterans following surgery for early stage lung cancer Surgery remains the most effective treatment for early stage non-small-cell lung cancer (NSCLC). This therapeutic mainstay, however, is plagued by the development of post-surgical recurrence which most often presents as metastatic disease. No significant improvements have been developed in the past 15 years and, following surgery, the overall 5-year survival rate remains below 50%. New effective strategies that overcome the major obstacles related to metastases will improve lung cancer cure rates and make a major impact in VA patient care. Detection of NSCLC at an early stage results in favorable survival outcomes. In Aim 1 we will identify molecular and cellular profiles that predict aggressive disease resulting in lung cancer metastasis following surgery by conducting the following subaims: A) Identify and characterize somatic mutations that differ between aggressive versus indolent lung cancers using whole exome sequencing, B) Develop tumor gene expression signatures associated with important driver mutations and determine whether gene expression signatures group tumors with biologically related mutations and thereby serve as markers for distinguishing between aggressive and indolent lung cancers and C) Characterize the immune cell phenotypes found within the tumor microenvironment that distinguish aggressive and indolent lung cancers. In Aim 2 we will develop a novel highly sensitive approach for Minimum Residue Disease (MRD) and cancer recurrence detection by conducting the follow subaims: A) Identify truncal mutations from pre-surgery plasma circulating tumor DNA (cfDNA) samples, B) Detect MRD/recurrence using post-surgery plasma cfDNA samples and C) Assess the statistical significance of the MRD predictive score in the determination of recurrence. In this VA Merit Review Supplement proposal we will conduct a pilot study that begins to develop the requisite platforms that facilitate our understanding, prediction, and detection of NSCLC metastases in US Veterans.