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检测 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，治疗的支柱是由手术后复发的发展所困扰， 表现为转移性疾病。在过去15年中没有取得重大进展， 手术后，总的5年生存率保持在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 病人护理早期检测NSCLC可获得有利的生存结局。在目标1中， 鉴定预测导致肺癌转移侵袭性疾病的分子和细胞谱 A）识别和表征与在外科手术后的患者中存在的不同的体细胞突变， 使用全外显子组测序在侵袭性肺癌与惰性肺癌之间进行比较，B）开发肿瘤基因 与重要驱动突变相关的表达特征，并决定基因表达是否 特征将具有生物学相关突变的肿瘤分组，从而作为区分 和C）表征在侵袭性肺癌和惰性肺癌中发现的免疫细胞表型， 区分侵袭性和惰性肺癌的肿瘤微环境。在目标2中，我们将开发一个 一种用于最小残留疾病（MRD）和癌症复发检测的新型高灵敏度方法， A）从手术前血浆循环肿瘤DNA鉴定截断突变 B）使用手术后血浆cfDNA样品检测MRD/复发，和C）评估MRD/复发的可能性。 MRD预测评分在确定复发方面的统计学显著性。在这篇VA优点评论中 我们将进行一项试点研究，开始开发必要的平台， 我们对美国退伍军人NSCLC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.