LACE-Bio-II: Identification, validation and implementation of prognostic and/or p

描述（由申请方提供）：来自四项关键辅助NSCLC试验（IALT、CALGB 9633、JBR. 10、ANITA）的研究者组成了肺辅助顺铂评价（LACE）-Bio-I联盟，对各组在收集的福尔马林固定肿瘤（FFPE）中鉴定的生物标志物进行交叉验证/汇总荟萃分析，以确认其在较大数据集中的稳健性/实用性。LACE-Bio-I主要侧重于免疫组织化学方法（IHC）和单基因分析。JBR.10还收集了一部分患者的新鲜冷冻肿瘤（FFT）和正常肺，并鉴定了一种mRNA表达特征，该特征具有强预后性，可预测顺铂/长春瑞滨ACT的获益。随着肺癌中癌症基因组测序工作的不断进行以及鉴定代表NSCLC中关键“致癌驱动因素”的新型遗传畸变的报道，我们还迫切需要一种更具适应性的策略来探索这些新标志物作为早期患者预后和预测标志物的价值。LACE-Bio-II有一个新的战略方向。我们将探索基于核酸的新标记，包括基因拷贝数变化（扩增和缺失），体细胞基因突变和可能涉及多基因mRNA签名的基于RNA的标记。使用LACE-Bio FFPE肿瘤样本，我们计划验证JBR.10 15基因预后和预测mRNA特征，评估已知潜在致癌突变的预后和预测价值，并探索基因拷贝变异的预后和预测价值。我们还将鉴定和评估通过下一代测序对速冻JBR. 10样本发现的新型基因组畸变的预后和预测价值。已开发出使用FFPE样本的核酸材料测定和定量基因组畸变的新型高性能和灵敏技术，并已引入临床实验室改进修正案（CLIA）批准的实验室。如果我们的策略成功，鉴定和验证的标记物可以迅速引入临床实践。 公共卫生相关性：LACE-Bio-II的目标是寻找和测试基于组织的“生物标志物”，可以识别除了手术治疗早期可切除的非小细胞肺癌（NSCLC）外还将受益于辅助化疗（ACT）的患者;和/或识别不太可能受益但仅会经历化疗毒性的患者，使患者能够对最佳治疗方案做出明智的选择。

DESCRIPTION (provided by applicant): Investigators from the four pivotal adjuvant NSCLC trials (IALT, CALGB 9633, JBR.10, ANITA) formed the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-I consortium to conduct cross-validation/pooled meta-analyses of biomarkers that each group had identified on collected formalin fixed tumor (FFPE) to confirm their robustness/utility in a larger dataset. LACE-Bio-I had a focus predominantly on immunohistochemical methods (IHC) and single gene analyses. JBR.10 also collected fresh frozen tumor (FFT) and normal lung in a subset of patients and has identified an mRNA expression signature that is strongly prognostic and may be predictive of benefit from cisplatin/vinorelbine ACT. With the ongoing cancer genome sequencing efforts in lung cancer and the reporting of identification of novel genetic aberrations that represent crucial "oncogenic drivers" in NSCLC, we also urgently need a more adaptive strategy to explore the value of these new markers as prognostic and predictive markers in early stage patients. LACE-Bio-II has a new strategic direction. We will explore novel markers that are nucleic acid based, including gene copy number changes (amplifications and deletions), somatic gene mutations, and RNA-based markers that may involve multi-gene mRNA signatures. Using LACE-Bio FFPE tumor samples, we plan to validate the JBR.10 15-gene prognostic and predictive mRNA signature, evaluate the prognostic and predictive values of known potential oncogenic mutations, and explore the prognostic and predictive values of gene copy variations. We will also identify and evaluate the prognostic and predictive value of novel genomic aberrations discovered by Next Generation Sequencing on snap-frozen JBR.10 samples. New high performance and sensitive technologies for assaying and quantifying genomic aberrations using nucleic acid materials derived from FFPE samples have been developed and been introduced into Clinical Laboratory Improvement Amendments (CLIA)-approved laboratories. Should our strategy be successful, identified and validated markers can be rapidly introduced into clinical practice. PUBLIC HEALTH RELEVANCE: The goal of LACE-Bio-II is to find and test tissue-based 'biomarkers' which can identify patients who will benefit from adjuvant chemotherapy (ACT) in addition to surgery for their early stage, resectable non-small cell lung cancer (NSCLC); and/or, identify patients who are unlikely to benefit, but who would only experience toxicity from chemotherapy, allowing patients to make informed choices about their best treatment options.