I-SPY2 +: Evolving the I-SPY 2 TRIAL to include MRI-directed, adaptive sequential treatment to optimize breast cancer outcomes

该计划项目的总体目标是推进个体化治疗的科学性，以改善 根据对治疗的反应来判断结果。新辅助化疗(NAC)提供了机会 评估高危早期乳腺癌患者手术前对系统治疗的反应。最优的 结果是肿瘤完全根除(病理完全应答(PCR))，这是强有力的 与改善长期存活率相关，是加速药物审批的替代终点。 相反，有显著残留癌症负担的妇女(RCB 2/3)的无事件生存率低于 3-5年为60%。对反应不佳的患者进行重新定向治疗可以显著提高乳腺癌的存活率 风险最高的女性，并将早期应答者的毒性降至最低。新佐剂I-SPY-2适应性临床研究 旨在加速II/III期乳腺癌新药物开发的试验平台是 这是这项工作的理想环境。MRI将作为综合残存癌症负担评估的基础 工具(“iRCB”)，根据肿瘤亚型和途径进行优化。I-SPY磁共振成像研究二十年 计划提供了必要的技术、生物信息学和统计方法以及验证 数据集，以优化iRCB工具，作为重定向到合理选择的生物靶向的触发器 探员们。每个项目的进展都集中在项目1中，我们在项目1中开发了 整合这些片段以确定是否根据通路异常和 在完全或不良反应的情况下避免化疗药物的额外毒性会导致 更好的结果。项目2利用成像方面的进展，贡献了用于优化iRCB的工具 方法(扩散加权成像和乳腺PET)和包括分子数据的纵向模型 从诊断和方案间活组织检查以确认疾病的存在或不存在，并准确地分类 反应良好和差(分别为RCB 0和RCB 2/3)。项目3将提供对 反应和治疗耐药的生物学动态，项目4将描绘理性 基于生物学和已经或正在进行的代理人的知识的“第二次机会”疗法的选择 发展起来的。我们将在该计划项目的过程中与FDA密切合作，以确定亚型 IRCB的特定阈值。最终结果将是现有i-spy审判的演变(i-spy2+)， 采用创新的顺序多任务随机化试验(SMART)设计，最大限度地提高 临床影响和知识生成，同时密切反映当前临床实践的现实。已被占用 总而言之，这些项目利用了成熟、成功、高效和高度创新的临床试验 平台和经验丰富的协作研究团队，以解决乳腺癌的关键临床问题。 所采用的创新方法将标志着个性化医疗在 乳腺癌和治疗耐药的分子进化产生了前所未有的观点。

The overarching goal of this program project is to advance the science of individualizing treatment to improve outcomes on the basis of response to therapy. Neoadjuvant chemotherapy (NAC) provides the opportunity to assess response to systemic therapy prior to surgery in women with high risk early breast cancer. The optimal outcome is the complete eradication of tumor, (pathologic complete response (pCR)), which is strongly associated with improved long-term survival and is a surrogate endpoint for accelerated drug approval. Conversely, women with significant residual cancer burden (RCB 2/3) suffer event free survival of less than 60% at 3-5 years. Redirecting therapy in poor responders could dramatically improve breast cancer survival in the highest risk women and minimize toxicities in early responders. The neoadjuvant I-SPY 2 adaptive clinical trial platform, designed to accelerate phase II development of new agents for stage II/III breast cancer is the ideal setting for this work. MRI will serve as a foundation for an integrated residual cancer burden assessment tool (“iRCB”), optimized by tumor subtype and pathway. Two decades of MRI imaging research in the I-SPY program have provided the necessary technology, bioinformatic and statistical approaches, and validation datasets to optimize the iRCB tool to serve as the trigger to redirect to rationally selected, biologically targeted agents. The advances from each project coalesce in Project 1, where we have developed the mechanics of integrating the pieces to determine whether treatment redirection on the basis of pathway abnormalities and avoiding the additional toxicity of chemotherapeutic agents in the setting of complete or poor response leads to better outcomes. Project 2 contributes the tools for the optimization of the iRCB, using advances in imaging methods (diffusion weighted imaging and breast PET) and a longitudinal model that includes molecular data from diagnosis, and an inter-regimen biopsy to confirm absence or presence of disease and accurately classify excellent and poor response (RCB 0 and RCB 2/3, respectively). Project 3 will provide an understanding of the dynamics of the biology of response and treatment resistance, and Project 4 will delineate the rational selection of `second chance” therapies based on the biology and knowledge of agents already or being developed. We will work closely with the FDA over the course of this Program Project to establish the subtype specific thresholds for iRCB. The final result will be an evolution of the existing I-SPY Trial (into “I-SPY2+”) that employs an innovative Sequential Multiple Assignment Randomization Trial (SMART) design to maximize both clinical impact and knowledge generation, while closely reflecting the realities of current clinical practice. Taken together, these projects leverage an established, successful, efficient, and highly innovative clinical trial platform and an experienced, collaborative research team to address a critical clinical issue in breast cancer. The innovative approach employed will mark a milestone in the implementation of personalized medicine in breast cancer and generate an unprecedented view of the molecular evolution of treatment resistance.