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/项目总结 新辅助化疗（NAC），即手术前给予的治疗，已成为一种标准治疗 用于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，真实的- 肿瘤反应的时间监测和药物疗效的评价。达到病理完全性的患者 pCR的结果非常好。因此，NAC的挑战是使每个患者达到pCR;以及， 在无应答者中，识别复发概率高的患者，以进行辅助治疗 设置.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 基于共振成像（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的响应和转移复发的稳健且准确的预测因子;以及 进而有助于关于治疗升级或降级的治疗决定，以改善患者 结果。在这里，我们提出了一个相关的研究，新辅助I-SPY 2试验，一个多中心，适应性 随机化II期试验，评估新疗法与标准NAC联合的疗效。 整合在I-SPY 2中，是一项正在进行的研究，评价MRI FTV作为反应和结局的预测因子， 以及用于发现和验证伴随诊断标志物（包括ctDNA）的基础设施。 本研究旨在：（1）对接受NAC治疗的患者进行连续ctDNA分析;（2）联合收割机连续 ctDNA谱与可用的FTV数据，以开发乳腺癌亚型特异性pCR预测因子，以及（3）构建 结合联合收割机ctDNA和FTV信息的预测模型，以提高残差的预测性能 在手术时评估的癌症负荷（RCB）。 这项拟议研究的成果包括：（1）在一个大型的早期乳腺癌患者队列中的连续ctDNA图谱， 癌症患者;（2）将计算pCR（或残余癌症负荷，RCB）概率的预测工具 0)在治疗期间的早期时间点，和（3）将提供准确风险评估的预后工具 NAC后有残留疾病的患者（非pCR或RCB 1/2/3）的早期转移性复发。 我们的最终目标是在临床试验中使用pCR预测工具来识别良好的应答者， 可能有资格接受早期手术治疗，以减少不必要的额外毒性暴露。 治疗;以及可能受益于治疗转换以增加实现 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， 辅助试验环境，为早期高风险患者提供积极的辅助治疗 转移性复发，而对于那些可能通过以下方法治愈的患者， NAC和手术治疗，因此，不太可能复发。