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

该项目的总体目标是推进个性化治疗的科学，以改善 根据对治疗的反应得出结果。新辅助化疗（NAC）提供了机会， 评估高危早期乳腺癌妇女手术前对全身治疗的反应。最优 结果是肿瘤完全根除（病理完全缓解（pCR）），这是强烈的 与改善长期生存相关，是加速药物批准的替代终点。 相反，具有显著残留癌症负荷（RCB 2/3）的女性的无事件生存率小于 3-5年时为60%。在低反应者中重新定向治疗可以显着提高乳腺癌的生存率， 最高风险的女性，并尽量减少早期反应者的毒性。新辅助I-SPY 2适应性临床 试验平台，旨在加速II/III期乳腺癌新药的II期开发， 这是这项工作的理想场所。MRI将作为综合残留癌症负荷评估的基础 工具（“iRCB”），通过肿瘤亚型和途径优化。I-SPY的20年MRI成像研究 该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，作为触发器，重定向到合理选择的，生物靶向的 剂.每个项目的进展都集中在项目1中，我们开发了 - 整合所述片段以确定是否基于通路异常而重新定向治疗，以及 在完全或不良反应的情况下避免化疗剂的额外毒性导致 更好的结果。项目2利用成像技术的进步，为iRCB的优化提供了工具 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，和一个治疗方案间活检，以确认不存在或存在的疾病，并准确分类 极好和差的反应（分别为RCB 0和RCB 2/3）。项目3将提供一个了解 响应和治疗阻力的生物学动力学，项目4将描绘合理的 根据已经或正在使用的药剂的生物学和知识选择“第二次机会”疗法 开发我们将与FDA密切合作，在这个项目的过程中，以建立亚型 iRCB的具体阈值。最终结果将是现有I-SPY试验的演变（成为“I-SPY 2+”）， 采用创新的序贯多重分配随机试验（SMART）设计， 临床影响和知识生成，同时密切反映当前临床实践的现实。采取 这些项目共同利用了一个成熟的、成功的、有效的和高度创新的临床试验 该平台和经验丰富的协作研究团队致力于解决乳腺癌的关键临床问题。 采用的创新方法将标志着在实施个性化医疗的一个里程碑， 乳腺癌，并产生一个前所未有的观点的分子进化的治疗耐药性。

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.