Strategy for combining circulating tumor DNA (ctDNA) and magnetic resonance imaging (MRI) measures of tumor burden for prediction of response and outcome in neoadjuvant-treated early breast cancer

结合循环肿瘤 DNA (ctDNA) 和肿瘤负荷磁共振成像 (MRI) 测量来预测新辅助治疗的早期乳腺癌的反应和结果的策略

• 批准号: 10311505
• 负责人: Wen Li
• 金额: $ 65.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-03 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10311505
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Biological Assay; Biological Markers; Blood; Breast; Breast Cancer Patient; Breast-Conserving Surgery; Cancer Burden; Characteristics; Clinical; Clinical Trials; Correlative Study; DNA analysis; Data; Detection; Diagnosis; Disease; Disease-Free Survival; Distant; Drug Evaluation; ERBB2 gene; Exposure to; Functional Magnetic Resonance Imaging; Genetic Fingerprintings; Genomics; Goals; Hormone Receptor; In complete remission; Infrastructure; Magnetic Resonance Imaging; Measures; Modality; Monitor; Mutation; Neoadjuvant Therapy; Nodal; Operative Surgical Procedures; Outcome; Pathologic; Patient risk; Patient-Focused Outcomes; Patients; Performance; Prediction of Response to Therapy; Primary Neoplasm; Probability; Randomized; Recurrence; Residual Cancers; Residual Tumors; Risk; Risk Assessment; Serial Magnetic Resonance Imaging; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; Tumor Burden; Tumor Volume; Validation; advanced disease; base; cancer subtypes; chemotherapy; cohort; companion diagnostics; diagnostic biomarker; drug efficacy; efficacy evaluation; experience; high risk; improved; improved outcome; liquid biopsy; malignant breast neoplasm; molecular imaging; multimodality; novel therapeutics; patient response; phase II trial; predicting response; predictive tools; primary endpoint; prognostic model; prognostic tool; prognostic value; real time monitoring; relapse risk; response; risk stratification; standard of care; tool; treatment choice; treatment response; tumor; tumor DNA

ABSTRACT/PROJECT SUMMARY Neoadjuvant chemotherapy (NAC), which is treatment given before surgery, has become a standard-of-care for breast cancer patients diagnosed with locally advanced disease. NAC offers a unique opportunity for real- time monitoring of tumor response and evaluation of drug efficacy. Patients who achieve pathologic complete response (pCR) have an excellent outcome. Thus, the challenge of NAC is to bring each patient to pCR; and, among non-responders, to identify those with a high probability of recurring for additional therapy in the adjuvant setting. Biomarkers that accurately predict NAC response and metastatic recurrence are key to achieving these objectives. We hypothesize that a multimodal approach for monitoring of tumor burden during NAC—i.e., by magnetic resonance imaging (MRI)-based functional tumor volume (FTV) and liquid biopsy-based circulating tumor DNA (ctDNA) analyses—can yield robust and accurate predictors of response to NAC and metastatic recurrence; and in turn, aid in therapeutic decisions regarding escalation or de-escalation of treatment to improve patient outcomes. Here, we propose a correlative study to the neoadjuvant I-SPY 2 TRIAL, a multicenter, adaptive randomization phase II trial that evaluates the efficacy of novel therapies in combination with standard NAC. Integrated within I-SPY 2, is an ongoing study that evaluates MRI FTV as predictor of response and outcome, and an infrastructure for discovery and validation of companion diagnostic markers, including ctDNA. The proposed study aims to: (1) perform serial ctDNA profiling in patients receiving NAC; (2) combine serial ctDNA profiles with available FTV data to develop breast cancer subtype-specific predictors of pCR, and (3) build prognostic models that combine ctDNA and FTV information to improve on the predictive performance of residual cancer burden (RCB) assessed at surgery. The deliverables of this proposed study include: (1) serial ctDNA profiles in a large cohort of early breast cancer patients; (2) a prediction tool that will calculate the probability of pCR (or residual cancer burden, RCB 0) at an early time point during treatment, and (3) a prognostic tool that will provide accurate risk assessment for early metastatic recurrence in patients who have residual disease after NAC (non-pCR or RCB 1/2/3). Our ultimate goal is to use the pCR prediction tool in the clinical trial setting to identify good responders who may be eligible for early surgical treatment to reduce exposure to toxicities from unnecessary additional therapies; and poor responders who may benefit from a switch in therapy to increase the likelihood of achieving a pCR. Furthermore, we envision that the prognostic tool developed here will help guide treatment choices in the adjuvant trial setting by providing aggressive adjuvant therapies to patients who are at high-risk of early metastatic recurrence, while de-escalating or forgoing further treatment for those who were potentially cured by NAC and surgical treatment and, therefore, not likely to recur.

摘要/项目摘要 新辅助化疗(NAC)是在手术前进行的治疗，已经成为一种标准的护理 适用于被诊断为局部晚期疾病的乳腺癌患者。南汽提供了一个独特的机会，真正- 肿瘤反应时间监测和药物疗效评价。完成病理检查的患者 反应(PCR)有一个很好的结果。因此，NAC的挑战是将每个患者都带到PCR；以及， 在无反应者中，识别那些有很高复发概率的人，以进行辅助治疗 布景。准确预测NAC反应和转移复发的生物标志物是实现这些目标的关键 目标。 我们假设，在NAC期间监测肿瘤负荷的多模式方法--即通过磁力 基于磁共振成像(MRI)的功能性肿瘤体积(FTV)和基于液体活检的循环肿瘤DNA (CtDNA)分析--可以提供对NAC和转移复发反应的可靠和准确的预测指标；以及 反过来，帮助做出关于治疗升级或降级的治疗决策，以改善患者 结果。在这里，我们建议对新佐剂i-spy 2试验进行相关研究，这是一个多中心、适应性的试验。 随机第二阶段试验，评估新疗法与标准NAC联合治疗的疗效。 集成在I-SPY 2中的是一项正在进行的研究，该研究评估MRI FTV作为反应和结果的预测指标， 以及发现和验证伴随诊断标记的基础设施，包括ctDNA。 这项拟议的研究旨在：(1)在接受NAC治疗的患者中进行序列ctDNA分析；(2)结合序列 CtDNA图谱和可用的FTV数据来开发乳腺癌亚型特异性预测因子的聚合酶链式反应，和(3)建立 结合ctDNA和ftv信息以改善残差预测性能的预测模型 手术时评估癌症负担(RCB)。 这项拟议研究的成果包括：(1)一大批早期乳房的连续ctdna图谱。 癌症患者；(2)将计算聚合酶链式反应(或残留癌症负担，RCB)概率的预测工具 0)在治疗期间的早期时间点，以及(3)提供准确风险评估的预后工具 对于NAC(非聚合酶链式反应或RCB1/2/3)后有残留病变的患者的早期转移复发。 我们的最终目标是在临床试验环境中使用聚合酶链式反应预测工具，以确定谁是好的应答者 可能有资格接受早期手术治疗，以减少因不必要的额外 治疗；以及反应不佳的人，他们可能从改变治疗中受益，以增加实现 一份聚合酶链式反应。此外，我们设想，这里开发的预后工具将有助于指导治疗选择 为早期高危患者提供积极的辅助治疗的辅助试验环境 转移性复发，同时降级或放弃对那些有可能通过 NAC和手术治疗，因此，不太可能复发。