Project 03 - Understanding the biology of non-responders to inform treatment selection

摘要--项目3 通过将手术推迟到新辅助化疗(NAC)之后，可以评估治疗的影响。 关于乳房肿瘤的实时信息。对NAC反应良好的侵袭性疾病女性有更好的 预后比没有反应的女性要好。需要有一种方法来及早识别高风险的无反应者 并确定哪些替代疗法或其他疗法可能对他们有益。先验分子 概况研究已经确定了预测化疗反应或结果的标志物，这些标志物使用Pre 治疗活组织检查。然而，治疗会导致肿瘤生物学上的重大变化；其中一些 变化与对治疗的反应有关。因此，我们假设审问动态 治疗过程中的分子变化将使我们能够更好地描述耐药机制 并提高我们预测无反应(或敏感性)的能力。在本项目中，我们将使用(或生成为 需要)下一代测序(信使核糖核酸和DNA)和反相蛋白质阵列(蛋白质/磷酸- 蛋白质)对I-SPY 2患者的系列活检进行全面的分子表征 与毕业的实验特工一起。在目标1中，我们将评估残留物中的可用药/可操作途径 接受标准或靶向药物/组合治疗的无反应患者的疾病。在……里面 目的2我们将纳入早期治疗引起的改变，以改进治疗的预测模型 电阻/灵敏度。在目标3中，我们将利用此数据概要来动态描述如何关键 随着患者从治疗前发展到治疗过程中的手术，分子通路也在不断演变 和受体亚型。我们的目标是确定目标1中确定的残留病特征 均明显在早期治疗或治疗前的时间点，并评估早期的稳定性 预测/阻力信号。这些努力将为患者在治疗期间的反应评估提供信息 预测无反应的转换治疗和分子合理化策略的发展 为患者提供更有效的治疗，作为总体方案项目中其他项目的一部分。

SUMMARY – PROJECT 3 By delaying surgery until after neoadjuvant chemotherapy (NAC), it is possible to assess the impact of therapy on breast tumors in real time. Women with aggressive disease who respond well to NAC have a better prognosis than women who fail to respond. There needs to be a way to identify high risk non-responders early in treatment and determine what alternative or additional treatments may be of benefit to them. Prior molecular profiling studies have identified markers that are predictive of chemotherapy response or outcome using pre- treatment biopsies. However, treatment induces significant changes in tumor biology; and some of these changes are associated with response to therapy. Thus, we hypothesize that interrogating the dynamic molecular changes over the course of treatment will enable us to better characterize resistance mechanisms and improve our ability to predict non-response (or sensitivity). In this Project, we will use (or generate as needed) next generation sequencing (mRNA and DNA) and reverse phase protein arrays (protein/phospho- protein) to perform comprehensive molecular characterization of serial biopsies from I-SPY 2 patients treated with graduated experimental agents. In Aim 1 we will evaluate druggable/actionable pathways in residual disease of non-responding patients undergoing treatment with standard or targeted agents/combinations. In Aim 2 we will incorporate early treatment-induced changes to improve predictive models of treatment resistance/sensitivity. In Aim 3 we will leverage this data compendium to develop a dynamic portrait of how key molecular pathways evolve as patients move from pre-treatment through to surgery in the context of treatment and receptor subtype. Our goal is to determine whether the residual disease characteristics identified in Aim 1 are evident at the early treatment or pre-treatment time points, and to assess the stability of early predictive/resistance signals. These efforts will inform both mid-treatment assessments of patient response to therapy and the development of a molecularly rationalized strategy for switching predicted non-responding patients to more effective treatment, developed as part of other Projects within the overall Program Project.