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

I-SPY2试验是一项针对高风险早期乳腺癌的多中心、II期新辅助平台试验，旨在 快速确定新的治疗方法和治疗组合，在标准护理背景下提高疗效 (紫杉醇每周连续一次，然后阿霉素/环磷酰胺(T-AC)化疗)。它被认为是 适应性平台试验的原型，使多种新的治疗方案能够同时进行评估， 以激素受体和人表皮生长因子为靶向治疗乳腺癌亚型 受体-2(HER2)的表达和MammaPrint(预后标志)的高危状态。自2010年推出以来，有24个新的 已经测试了治疗方法或组合，其中7种被发现显著改善了病理完全应答(PCR)， 导致了几个最终的第三阶段试验。然而，随着这一成功的到来，人们意识到在8个预定义的 子类型并不是每个人都受益。通过该项目，我们设计并实现了下一代I-SPY2.2 以患者为中心的临床用药方法在早期乳腺癌治疗中的应用 发展。I-SPY2.2允许通过基于以下条件的治疗升级或降级来优化个别治疗 通过基于MRI的评估来衡量治疗反应，在有效评估的试验背景下进行 新的潜在一线养生法。项目3在推动我们对动态的理解方面发挥了重要作用。 生物学的反应和治疗抗药性，并增强我们的能力，以更好地针对个别生物的药物通过 改进高危肿瘤生物学分层。在与Project 4的合作下，我们制定了更完善的应对措施- 模型显示，预测性亚型‘RPS’将导致PCR率提高15%以上。刻画 了解2期和3期乳腺癌治疗无反应的生物学和动力学有助于 合理设计治疗转换策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，并基于我们的 在计划项目的早期工作和以后，我们现在假设一个全面的方法来理解非 跨多个组学级别的响应(目标1)，并与动态成像功能(来自项目2)集成，将 在试验治疗过程中为升级或降级提供最佳策略(目标2； 项目1)。我们扩展了我们的实验平台，增加了几个基于液体活检的平台(例如 CtDNA、免疫细胞因子分型和蛋白质/磷蛋白的外切体分析)。这一点与一个 扩展我们在当前拨款中已经采用的技术，将为我们提供优先选择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的治疗(目标3)。由此揭示的可用药目标将告知项目4 用于创新的药物选择。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 对观察到的早期无反应或强烈反应的患者进行升级或降级治疗。最终目标是 使所有高危患者得到完全反应，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.