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手术后转移性疾病的早期检测

• 批准号: 10426073
• 负责人: Steven M. Dubinett
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426073
• 关键词: Address; Adjuvant; Adjuvant Therapy; Aggressive behavior; Biological Assay; Biological Markers; Biological Specimen Banks; Blood; Cancer Etiology; Cells; Cessation of life; Characteristics; Cisplatin; Clinical; Clinical Trials; Collaborations; Detection; Development; Disease; Distant; Early Diagnosis; Early Intervention; Early treatment; Effectiveness; Elements; Excision; Frequencies; Gene Expression Profile; Heterogeneity; Immune; Indolent; Inferior; International; Intervention; Malignant Neoplasms; Malignant neoplasm of lung; Medical center; Methods; Molecular; Monitor; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Pathway interactions; Patient Care; Patient Selection; Patient-Focused Outcomes; Patients; Phenotype; Pilot Projects; Plasma; Plasma Cells; Postoperative Period; Recurrence; Research; Resected; Residual Neoplasm; Residual Tumors; Resources; Retrospective Studies; Sampling; Screening for cancer; Solid; Somatic Mutation; Source; Specimen; Survival Rate; Systems Analysis; Therapeutic; Tumor stage; Veterans; base; biomarker development; cancer recurrence; cancer surgery; cell free DNA; chemotherapy; clinical decision-making; cohort; driver mutation; effective therapy; exome sequencing; high risk; improved; improved outcome; innovation; lung cancer screening; novel; novel therapeutics; patient population; patient stratification; prospective; standard of care; surgery outcome; survival outcome; tumor; tumor DNA; tumor microenvironment

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.

美国退伍军人早期肺癌手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，治疗的支柱却受到术后复发的困扰，这种复发最常见 表现为转移性疾病。过去 15 年没有取得重大改进，并且， 手术后，总体 5 年生存率仍低于 50%。新的有效策略克服了 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 NSCLC 可带来良好的生存结果。在目标 1 中，我们将 识别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，通过执行以下子目标：A) 识别和表征不同的体细胞突变 使用全外显子组测序区分侵袭性肺癌和惰性肺癌，B) 开发肿瘤基因 与重要驱动突变相关的表达特征并确定基因表达是否 特征将具有生物学相关突变的肿瘤分组，从而作为区分的标记 侵袭性肺癌和惰性肺癌之间的区别 C) 描述其中发现的免疫细胞表型 区分侵袭性肺癌和惰性肺癌的肿瘤微环境。在目标 2 中，我们将开发一个 用于最小残留病 (MRD) 和癌症复发检测的新型高灵敏度方法 执行以下子目标：A) 从术前血浆循环肿瘤 DNA 中识别树干突变 (cfDNA) 样本，B) 使用术后血浆 cfDNA 样本检测 MRD/复发，C) 评估 MRD 预测评分在确定复发方面的统计显着性。在本次 VA 优点评审中 补充提案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 NSCLC 转移的理解、预测和检测。