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: 10523117
• 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/10523117
• 关键词: Adjuvant; Adjuvant Chemotherapy; 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; Eligibility Determination; Exposure to; Functional Magnetic Resonance Imaging; Genetic Fingerprintings; Genomics; Goals; Hormone Receptor; Image; In complete remission; Infrastructure; Magnetic Resonance Imaging; Measures; Metastatic to; Metastatic/Recurrent; Modality; Molecular; 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 Neoplasm; Risk; Risk Assessment; Risk Marker; Serial Magnetic Resonance Imaging; Testing; Therapeutic; Time; Toxic effect; Treatment outcome; Tumor Burden; Tumor Volume; Validation; advanced disease; cancer subtypes; cohort; companion diagnostics; deep sequencing; diagnostic biomarker; drug efficacy; efficacy evaluation; experience; high risk; improved; improved outcome; liquid biopsy; malignant breast neoplasm; multimodality; novel therapeutics; patient response; phase II trial; predicting response; predictive marker; predictive tools; primary endpoint; prognostic model; prognostic tool; prognostic value; real time monitoring; relapse risk; response; risk stratification; standard of care; 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) 是手术前进行的治疗，已成为一种标准治疗 NAC 为诊断患有局部晚期疾病的乳腺癌患者提供了独特的机会。 时间监测肿瘤反应并评价达到病理完全的患者。 因此，NAC 的挑战是让每位患者达到 pCR； 在无反应者中，确定那些在辅助治疗中很有可能复发的人 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。 我们寻求一种多模式方法来监测 NAC 期间的肿瘤负荷，即通过磁性 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——可以产生对 NAC 反应和转移复发的稳健且准确的预测因子；以及 反过来，帮助做出有关升级或降级治疗的治疗决策，以改善患者的情况 在这里，我们提出了一项新辅助 I-SPY 2 试验的相关研究，这是一项多中心、适应性的研究。 随机化 II 期试验，评估新疗法与标准 NAC 组合的疗效。 I-SPY 2 中集成了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因子， 以及用于发现和验证伴随诊断标记（包括 ctDNA）的基础设施。 拟议研究的目的是：(1) 对接受 NAC 的患者进行连续 ctDNA 分析；(2) 结合连续分析； ctDNA 图谱与可用的 FTV 数据一起开发 pCR 的乳腺癌亚型特异性预测因子，以及 (3) 构建 结合 ctDNA 和 FTV 信息的预后模型可提高残差的预测性能 手术时评估癌症负担（RCB）。 这项拟议研究的成果包括：(1) 一大群早期乳腺癌患者的连续 ctDNA 谱 癌症患者；(2) 计算 pCR（或残余癌症负担，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 用于 NAC（非 pCR 或 RCB 1/2/3）后有残留疾病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 pCR 预测工具来识别良好的反应者 可能有资格接受早期手术治疗，以减少不必要的额外接触带来的毒性 治疗方法；以及反应不佳的人，他们可能会从治疗的转变中受益，以增加实现目标的可能性 此外，我们预计这里开发的预后工具将有助于指导治疗选择。 辅助试验设置，为早期癌症高危患者提供积极的辅助治疗 转移性复发，同时对那些可能治愈的患者进行降级治疗或放弃进一步治疗 因此NAC和手术治疗不太可能复发。