Project 04 - Develop a portfolio of agents for switching that match biology of residual tumor burden

摘要--项目4 新辅助化疗(NAC)后有大量残留病的妇女预后较差 早期复发的风险很大。相反，达到病理性完全应答或pCR的女性。 (彻底根除肿瘤)术前有非常好的效果。I-SPY2临床试验是一项 创新的多中心、多代理临床平台试验，使用自适应随机研究设计 加速开发新的药物和成对的生物标记物对局部晚期妇女的反应 乳腺癌。到目前为止，已经有10个新代理人开始评估，其中3个已经毕业，获得了很高的评价(&gt；85%) 第三阶段试验的成功概率；已有1000多名患者参加，每年还会增加250人。尽管 这些进步，可能女性仍然无法达到聚合酶链式反应。在核磁共振成像评估的进步的推动下，这 计划项目旨在通过修改I-SPY 2以包括非侵入性鉴定来提高PCR率 对NAC反应不足的患者，然后将他们的治疗重新定向到另一种生物靶向 根据肿瘤中存在的反应生物标记物选择治疗方法。在这个项目中，我们 将使用来自i-spy 2的大量存档标本和数据集来识别新的生物标记物并开发 循证选择替代疗法的框架。我们的假设是肿瘤 陈述时的特征将有助于成功识别药物策略 将“无反应者”转变为有聚合酶链式反应的患者。为了实现我们确定成功药物的目标 可用于改变患者治疗方向的方案，我们将遵循由三个部分组成的研究计划 具体目标：1)利用I-SPY2合格生物标记物评估(QBE)框架识别 基于肿瘤免疫微环境分析的药物反应，并为每个人分配概率分数 药物-生物标志物对；2)将I-SPY2预测药物敏感性组合扩展到单一药物或组合 基于应答者/非应答者的基因表达谱，尚不在I-SPY 2药物组合中的疗法 来自乳腺和其他癌细胞系的响应者和药物基因表达数据库；以及3)创建 整合所有来源的药物反应预测矩阵，建立定量和定性的 合理、循证地选择要重新分配的代理人的策略。我们将与 项目1临床团队以一种保持临床背景的方式改进我们的模型。我们期待着一个独特的 通过与Project 3的协作产生重要的协同效应，其目标是描述 治疗压力下耐药分子通路的动态变化。该项目还将利用 调查人员的广泛经验和共享核心内的生物信息学专业知识。临床部 整个计划项目的目标是这项研究的一个重要激励因素，这将导致 开发重要的新信息资源，这些资源将在I-SPY 2+试验及以后的试验中发挥作用。

SUMMARY – PROJECT 4 Women with substantial residual disease after neoadjuvant chemotherapy (NAC) have poor prognosis with substantial risk of early recurrence. Conversely, women who achieve pathologic complete response or `pCR' (complete eradication of tumor) prior to surgery have very good outcomes. The I-SPY2 clinical trial is an innovative multicenter, multi-agent clinical platform trial that uses an adaptive randomized study design to accelerate the development of new agents and paired biomarkers of response in women with locally advanced breast cancer. To date, 10 novel agents have begun evaluation, and 3 have `graduated' having a high (>85%) probability of success in a phase III trial; over 1000 patients have enrolled, with 250 more each year. Despite these advances, may women still fail to reach pCR. Driven by advances in MRI imaging assesments, this Program Project aims to improve pCR rates by modifying I-SPY 2 to include non-invasive identification of patients with insufficient response to NAC, then redirecting their treatment to another, biologically targeted therapy selected based upon the presence of biomarkers of response present in their tumor. In this project, we will use the substantial archived specimens and data sets from I-SPY 2 to identify new biomarkers and develop the framework for evidence-based selection of substitute treatments. Our hypothesis is that tumor characteristics at time of presentation will assist in the identification drug strategies that will successfully convert a “non-responder” into a patient with a pCR. To achieve our goals of identifying successful drug regimens that can be used to redirect patient's therapies, we will follow a research plan consisting of three specific aims: 1) utilize the I-SPY2 qualifying biomarker evaluation (QBE) framework to identify biomarkers of drug response based upon tumor immune microenvironment analyses, and assign probability scores to each drug-biomarker pair; 2) expand the I-SPY2 predicted drug sensitivity portfolio to single agents or combination therapies not yet within the I-SPY 2 drug portfolio, based on gene expression profiles of responders/non- responders and drug-gene expression databases from breast and other cancer cell lines; and 3) create an integrated drug response prediction matrix from all sources, and establish quantitative and qualitative strategies for the rational, evidence-based selection of agents for reassignment.. We will work closely with the Project 1 clinical team to refine our models in a way that maintains clinical context. We anticipate a unique and important synergy to emerge through collaborations with Project 3, the goal of which is to characterize the dynamics of molecular pathways of resistance under therapeutic pressure. This project will also leverage the broad experience of the investigators and the bioinformatics expertise within the shared cores. The clinical goals of the overall program project are a significant motivating factor for this study, which will result in the development of important new information resources that will find utility within the I-SPY 2+ TRIAL and beyond.