Project 2: Non-invasive imaging metrics to optimize early treatment switching decisions and prognostic modeling of long-term outcomes

该计划项目的总体目标是优化每个患者达到病理完整性的可能性。 通过使用成像、组织病理学和分子生物标志物来指导其治疗，来评估pCR。项目二重点是 在I-SPY 2.2的进化设计中推进成像方法，以识别可能从I-SPY 2.2的变化中受益的患者。 疗程在I-SPY 2试验设计中，功能性肿瘤体积（FTV）的MRI测量值是生物标志物 用于为药物组评价的纵向模型提供信息。在I-SPY 2.2中，FTV用于个体患者水平 定制治疗，提高了对MRI性能变化的更大控制的需求。我们一直致力于 通过国家癌症研究所资助的努力，在临床环境中进行的MRI标准化所涉及的许多要素， 定量成像领域。我们还对990名随机分配到一个 到2016年完成的9个实验药物组，以更好地了解变异性对FTV性能的影响， 生物标志物和这些发现已被用于引入I-SPY 2 MRI检查协议的改进。具体目标1 和2侧重于对降级策略和预RCB以及升级策略的迭代改进， 分别虽然基于FTV的反应提供了考虑治疗变化的初始信号，但不同的 考虑到MRI，需要制定策略来提高建议升级或降级的确定性水平， 在显示广泛疾病方面的相对优势，以及在检测微小疾病方面的局限性。在RCB之前， 升级策略，在选择省略之前，需要在12周时对肿瘤床进行核心活检的阴性结果 AC提供。在升级的情况下，我们使用3周时MRI反应低于30%来标记潜在的不良反应。 反应，并建议在6周时重复成像，其中升级到块B的阈值是<65% FTV 反应我们将以几种方式在这些初步战略的基础上再接再厉。目前的MRI预测模型是基于来自 最初的990例患者在I-SPY 2下入组，并在HR和HER 2定义的亚型内进行了优化。我们 将使用生物学上更相关的反应预测亚型模式和使用扩展的I- SPY患者队列。更全面的MRI预测模型有待开发，整合形状分类器， 异质性和正常组织特征，可以从用于测量FTV的相同MRI数据导出。使用 项目3研究人员，我们将提出ctDNA在降级和升级中的附加值问题 策略，在多个时间点调查ctDNA的使用。具体目标3涉及潜在的附加效益 一系列FTV测量的组织病理学终点残留癌负荷（RCB）已得到充分确立 作为新辅助治疗的预后指标。认识到I-SPY 2的独特设置，在该设置中，对所有患者进行MRI检查， 患者，并且系列MRI在所有临床环境中均不可行，我们将专门研究 按亚型和治疗组分类，以确定是否有增加预后信息的患者亚组 特别是信息量大，可以推荐MRI。具体目标4将探索使用成像标记物， 来自I-SPY 2.2子研究中接受内分泌治疗患者的18 F-氟雌二醇（FES）专用乳腺PET。

The overall objective of the Program Project is to optimize every patient’s likelihood of reaching a pathologic complete response (pCR) by using imaging, histopathology and molecular biomarkers to guide their treatment. Project 2 focuses on advancing the imaging methods in the evolved design of I-SPY2.2, to identify patients that might benefit from a change in course of treatment. In the I-SPY2 trial design, MRI measurements of functional tumor volume (FTV) are the biomarker used to inform the longitudinal model for evaluation of drug arms. In I-SPY2.2, FTV is used at the individual patient level to tailor treatments, raising the need for greater control over variability in MRI performance. We have been addressing many of the elements involved in standardization of MRIs performed in the clinical setting through NCI-funded efforts in the area of quantitative imaging. We also performed retrospective studies using data from 990 patients randomized to one of 9 experimental drug arms completed by 2016 to better understand the impact of variability on FTV’s performance as a biomarker and those findings have been used to introduce refinements to the I-SPY2 MRI exam protocol. Specific Aims 1 and 2 focus on iterative improvements to the de-escalation strategy and pre-RCB, as well as the escalation strategy, respectively. While FTV-based response provides the initial signal for considering a change in treatment, different strategies are required to improve the level of certainty for recommending escalation or de-escalation, given MRI’s relative strength in demonstrating extensive disease, and limitation in detecting minimal disease. In the pre-RCB de- escalation strategy, a negative finding on core biopsy of the tumor bed at 12-weeks is required before the option to omit AC is offered. In the scenario of escalation, we use MRI response of less than 30% at 3-weeks to flag potential poor response and recommend repeat imaging at 6-weeks, where the threshold for escalation to Block B is <65% FTV response. We will build on these initial strategies in several ways. Current MRI prediction models are based on data from the initial 990 patients enrolled under I-SPY2 and have been optimized within subtypes defined by HR and HER2. We will refine these models using the more biologically-relevant Response-Predictive Subtype schema and using expanded I- SPY patient cohorts. More comprehensive MRI prediction models twill be developed, integrating classifiers of shape, heterogeneity and normal tissue features that can be derived from the same MRI data used to measure FTV. Working with Project 3 investigators, we will pose the question of added value of ctDNA in both the de-escalation and escalation strategies, investigating the use of ctDNA at multiple timepoints. Specific Aim 3 addresses the potential additive benefit of serial FTV measurement to the histopathologic endpoint residual cancer burden (RCB) which has been well-established as prognostic in the neoadjuvant setting. Recognizing the unique setting of I-SPY 2 in which MRI is performed for all patients, and that serial MRI is not feasible in all clinical settings, we will specifically investigate the differential benefit by subtype and treatment arms to determine if there are sub-groups of patients for whom added prognostic information is particularly informative and MRI can be recommended. Specific Aim 4 will explore the use of imaging markers derived from 18F-fluoroestradiol (FES)dedicated breast PET for patients receiving endocrine treatment in an I-SPY2.2 substudy.