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 新辅助化学疗法（NAC）是在手术前进行的治疗，已成为护理标准 适用于诊断患有局部晚期疾病的乳腺癌患者。 NAC为房地产提供了独特的机会 肿瘤反应的时间监测和药物效率的评估。完成病理的患者 响应（PCR）的结果很好。那是NAC的挑战是将每个患者带到PCR；和， 在非反应者中，要确定在调整中进行额外治疗的可能性很高的人 环境。准确预测NAC反应和转移性复发的生物标志物是实现这些响应的关键 目标。 我们假设在NAC期间监测肿瘤负担的多模式方法 共振成像（MRI）基于功能性肿瘤体积（FTV）和基于液体活检的循环肿瘤DNA （ctDNA）分析 - 可以产生对NAC和转移性复发反应的强大而准确的预测指标；和 反过来，有助于做出有关升级或降低治疗以改善患者的治疗决定 结果。在这里，我们建议对新辅助I-SPY 2试验（一个多中心，自适应）进行一项相关研究 随机化阶段II试验评估了新疗法与标准NAC结合使用的有效性。 整合在I-SPY 2中，是一项正在进行的研究，评估MRI FTV作为响应和结果的预测指标， 以及用于发现和验证伴侣诊断标记物（包括ctDNA）的基础架构。 拟议的研究旨在：（1）对接受NAC的患者进行连续ctDNA分析； （2）结合串行 具有可用FTV数据的CTDNA曲线，以发展PCR的乳腺癌亚型特异性预测因子，（3）构建 结合ctDNA和FTV信息的预后模型，以改善残留的预测性能 癌症伯嫩（RCB）在手术时进行了评估。 这项拟议的研究的可交付成果包括：（1）在大量早期乳房中的串行ctDNA轮廓 癌症患者； （2）一种预测工具，该工具将计算PCR的概率（或残留癌症Burnen，RCB 0）在治疗期间的早期时间点，以及（3）预后工具，将提供准确的风险评估 在NAC（非PCR或RCB 1/2/3）后患有残留疾病的患者的早期转移性复发。 我们的最终目标是在临床试验环境中使用PCR预测工具来确定好的响应者 可能有资格进行早期手术治疗，以减少不必要的额外的毒性暴露 疗法；还有可能受益于治疗转换以增加实现可能性的差响应者 PCR。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 可调节试验设置，通过为处于早期高风险的患者提供积极的可调疗法 转移性复发，同时降级或忘记了可能治愈的人进一步治疗 NAC和手术治疗，因此不太可能复发。