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

摘要-项目3 通过将手术延迟到新辅助化疗（NAC）后，可以评估治疗的影响 真实的进行乳腺肿瘤的研究。对NAC反应良好的侵袭性疾病妇女， 比那些没有反应的女性更容易预后。需要有一种方法来早期识别高风险的无应答者 并确定哪些替代或额外的治疗可能对他们有益。先前分子 谱分析研究已经确定了预测化疗反应或结果的标记物， 治疗活检。然而，治疗引起肿瘤生物学的显著变化;其中一些变化是由肿瘤细胞的生长和分化引起的。 变化与对治疗的反应有关。因此，我们假设，询问动态 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（mRNA和DNA）和反相蛋白质阵列（蛋白质/磷酸化）。 蛋白）进行综合分子表征的系列活检从I-SPY 2患者治疗 毕业的实验特工在目标1中，我们将评估残留的可药物化/可操作途径 接受标准或靶向药物/组合治疗的无应答患者的疾病。在 目标2：我们将纳入早期治疗引起的变化，以改善治疗的预测模型 电阻/灵敏度。在目标3中，我们将利用这一数据概要来动态描绘关键 随着患者从治疗前到治疗过程中的手术， 和受体亚型。我们的目标是确定目标1中确定的残留疾病特征 在早期治疗或治疗前时间点是明显的，并且为了评估早期 预测/阻力信号。这些努力将为治疗中期评估患者的反应提供信息， 治疗和发展一种分子合理化的策略，用于转换预测的无应答 患者获得更有效的治疗，作为整个计划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.