Project 3: Characterization of the biology of non-responders using Imaging and molecular analysis to inform treatment

I-SPY 2试验是一项针对高危早期乳腺癌的多中心、II期新辅助治疗平台试验，旨在 在标准治疗的背景下，快速识别新的治疗方法和治疗组合， （序贯每周紫杉醇，随后多柔比星/环磷酰胺（T-AC）化疗）。它被认为是 适应性平台试验的原型，能够同时评估多种新型治疗方案， 针对激素受体（HR）和人表皮生长因子定义的乳腺癌亚型的靶向治疗 受体-2（HER 2）表达和MammaPrint（预后特征）高风险状态。自2010年推出以来， 已经测试了治疗或组合，并且发现7种治疗或组合显著改善病理完全反应（pCR）， 导致了几个最终的III期试验。然而，随着这一成功，人们意识到，在8个预定义的 不是每个人都能从中受益。通过本项目，我们设计并实现了下一代I-SPY 2.2 以患者为中心的临床药物治疗方法在早期乳腺癌治疗中的先进个性化药物试验 发展I-SPY 2.2允许通过基于以下因素的治疗升级或降级来优化个体治疗： 通过基于MRI的评估测量的治疗反应，在有效评估的试验背景下这样做 新的潜在一线治疗方案。项目3有助于促进我们对全球气候变化动态的理解， 反应和治疗抗性的生物学，并通过以下方式增强我们更好地将药物靶向个体生物学的能力： 改善高风险肿瘤生物学的分层。在与项目4的合作中，我们开发了更精细的响应- 预测亚型，“RPS”，模型表明将导致超过15%的pCR率的改善。表征 了解2期和3期乳腺癌治疗无反应的生物学和动力学， 合理设计治疗转换战略和制定综合措施的机制基础， 评估治疗反应和复发风险，以指导临床决策。在我们目前的提案中， 早期的工作，在该计划的项目和超越，我们现在假设，一个全面的方法来了解非- 多个组学水平（目标1）的响应，并与动态成像功能（来自项目2）相结合，将 为试验治疗过程中的递增或递减提供稳健结果的最佳策略（目标2; 项目1）。我们已经扩展了我们的实验平台，其中有几个是基于液体活检（如 ctDNA、免疫细胞因子分型和蛋白质/磷蛋白的外来体分析）。这一点，结合一个 我们的技术已经在我们目前的赠款中使用的扩展，将为我们提供优先考虑替代方案的最佳选择。 在早期或后期观察到无反应的情况下进行治疗（目的3）。由此揭示的可药用目标将为项目4提供信息 创新药物的选择。观察到的肿瘤或血液中生物标志物的动态变化将提供稳健性 对于观察到早期无应答或稳健应答的患者，增加或减少治疗。最终目标是 使所有高危患者获得完全缓解，从而显著降低复发和死亡的机会。

The I-SPY2 trial is a multicenter, Phase II neoadjuvant platform trial for high risk, early-stage breast cancer designed to rapidly identify new treatments and treatment combinations with increased efficacy on a standard-of-care background (sequential weekly paclitaxel followed by doxorubicin/cyclophosphamide (T-AC) chemotherapy). It is considered the archetype of the adaptive platform trial, enabling multiple novel treatment regimens to be evaluated simultaneously, targeting treatment to breast cancer subtypes defined by on hormone receptor (HR) and Human Epidermal Growth Factor Receptor-2 (HER2) expression, and MammaPrint (prognosis signature) high risk status. Since launching in 2010, 24 new therapies or combinations have been tested, and 7 found to significantly improve pathologic complete response (pCR), leading to several definitive phase III trials. However, with this success came the realization that within the 8 predefined subtypes not everyone benefitted. Through this program project we designed and implemented a next generation I-SPY2.2 trial to advanced personalized medicine in early breast cancer treatment with a patient-centric approach to clinical drug development. I-SPY2.2 allows the optimization of individual treatments by escalation or de-escalation of therapy based on treatment response measured by an MRI-based assessment, doing so in the context of a trial that efficiently evaluates novel potential first-line regimens. Project 3 has been instrumental in advancing our understanding of the dynamics of the biology of response and treatment resistance and enhancing our ability to better target agents to individual biology by improving stratification of high-risk tumor biology. In collaboration with Project 4, we developed more refined response- predictive subtypes, ‘RPS,’ that modelling suggests will result in improvements in pCR rates of over 15%. Characterizing and understanding the biology and dynamics of treatment non-response in stage 2 and 3 breast cancer provides the mechanistic basis for the rational design of treatment switching strategies and development of composite measures to assess treatment response and recurrence risk to guide clinical decision-making. In our current proposal and based of our earlier work in the program project and beyond, we now hypothesize that a comprehensive approach to understand non- response across multiple omics levels (Aim 1) and integrated with dynamic imaging features (from Project 2), will provide the best strategy for robust results for either escalation or de-escalation in the course of the trial treatment (Aim 2; for Project 1). We have extended our experimental platforms with several that are based on liquid biopsies (such as ctDNA, immune cytokine typing and exosome analyses of protein/phosphoproteins). This, in combination with an extension of our technologies already employed in our current grant, will give us the best option to prioritize alternative therapies in case of early, or later observed non-response (Aim 3). Druggable targets thus revealed will inform Project 4 for innovative drug selection. The dynamic changes in biomarkers in tumor or blood observed will provide the robustness to escalate or de-escalate treatment for patients with observed early non-response, or robust response. The ultimate goal is to get all high-risk patients to a complete response and thereby significantly reducing chance of recurrence and death.