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

项目 2：非侵入性成像指标，用于优化早期治疗转换决策和长期结果的预后建模

• 批准号: 10628610
• 负责人: Nola M. Hylton-Watson
• 金额: $ 37.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628610
• 关键词: Address; Algorithms; Area; Beds; Biological Markers; Biopsy; Breast; Breast Cancer Treatment; Breast Magnetic Resonance Imaging; Cancer Burden; Classification; Clinical; Clinical Drug Development; Core Biopsy; Data; Decision Modeling; Dedications; Disease; Disease-Free Survival; Drug Evaluation; ERBB2 gene; Early Diagnosis; Early treatment; Elements; Eligibility Determination; Endocrine; Estrogen receptor positive; Evaluation; Funding; Goals; Heterogeneity; Histopathology; Image; In complete remission; Individual; Kinetics; Label; Magnetic Resonance Imaging; Mammary Neoplasms; Measurement; Measures; Methodology; Modeling; Molecular; Negative Finding; Neoadjuvant Therapy; Nodal; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Probability; Prognostic Marker; Protocols documentation; Randomized; Recommendation; Regimen; Research Personnel; Residual Cancers; Retrospective Studies; Sequential Treatment; Serial Magnetic Resonance Imaging; Shapes; Signal Transduction; Standardization; Testing; Time; Training; Treatment Protocols; Tumor Volume; Tumor-Derived; Update; Widespread Disease; arm; biomarker development; cohort; contrast enhanced; design; drug development; drug efficacy; effectiveness evaluation; imaging biomarker; imaging modality; improved; individual patient; individualized medicine; malignant breast neoplasm; molecular marker; molecular subtypes; next generation; non-invasive imaging; novel; participant enrollment; patient subsets; personalized medicine; predicting response; predictive marker; predictive modeling; prognostic; prognostic model; programs; quantitative imaging; radiomics; radiotracer; relapse risk; response; response biomarker; success; targeted biomarker; tool; treatment arm; treatment effect; treatment response; trial design; tumor; tumor DNA; tumor heterogeneity; uptake

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.

该计划项目的总体目标是优化每位患者达到病理完全状态的可能性 项目 2 的重点是通过使用影像学、组织病理学和分子生物标志物来指导其治疗。 在 I-SPY2.2 的进化设计中推进成像方法，以确定可能受益于改变的患者 在 I-SPY2 试验设计中，功能性肿瘤体积 (FTV) 的 MRI 测量是生物标志物。 用于为药物组评估的纵向模型提供信息 在 I-SPY2.2 中，FTV 用于个体患者水平。 定制治疗方案，提高了对 MRI 性能变异性的更好控制的需求。 通过 NCI 资助的工作，在临床环境中进行的 MRI 标准化涉及的许多要素 我们还使用 990 名患者随机分组的数据进行了回顾性研究。 到 2016 年完成 9 个实验药物组，以更好地了解变异性对 FTV 作为药物性能的影响 生物标志物和这些发现已用于改进 I-SPY2 MRI 检查方案 1。 2 重点关注降级策略和预 RCB 以及升级策略的迭代改进， 虽然基于 FTV 的响应提供了考虑改变治疗的初始信号，但不同。 鉴于 MRI 的情况，需要采取策略来提高建议升级或降级的确定性水平 在预 RCB 检测中，显示广泛疾病的相对强度和检测微小疾病的局限性。 升级策略，在选择省略之前需要在 12 周时对瘤床进行核心活检获得阴性结果 在升级的情况下，我们使用 3 周时低于 30% 的 MRI 响应来标记潜在的不良情况。 反应并建议在 6 周时重复成像，其中升级至 B 组的阈值 <65% FTV 我们将以多种方式建立在这些初始策略的基础上，当前的 MRI 预测模型基于以下数据。 最初的 990 名患者在 I-SPY2 下入组，并已在 HR 和 HER2 定义的亚型内进行了优化。 将使用更具生物学相关性的响应预测子类型模式并使用扩展的 I- 来完善这些模型 将开发更全面的 MRI 预测模型，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 数据中得出。 项目 3 的研究人员，我们将提出 ctDNA 在降级和升级中的附加值问题 策略，调查 ctDNA 在多个时间点的使用，解决了潜在的附加效益。 连续 FTV 测量对组织病理学终点残留癌症负荷 (RCB) 的影响已得到充分证实 认识到 I-SPY 2 对所有人进行 MRI 的独特设置。 患者，并且连续 MRI 并非在所有临床环境中都可行，我们将专门研究不同的益处 按亚型和治疗组确定是否存在需要补充预后信息的患者亚组 可以推荐特别提供信息的 MRI 特定目标 4 将探索成像标记物的使用。 来自 I-SPY2.2 子研究中接受内分泌治疗的患者的 18F-氟雌二醇 (FES) 专用乳房 PET。