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Treatment monitoring in early and locally advanced breast cancer using circulating tumor DNA analysis

Treatment monitoring in early and locally advanced breast cancer using circulating tumor DNA analysis
使用循环肿瘤 DNA 分析监测早期和局部晚期乳腺癌的治疗
批准号:
10304444
负责人:
Muhammed Murtaza
金额:
$20.69万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-03-01 至 2024-02-29

项目摘要

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中文摘要
翻译
项目总结 早期和局部晚期乳腺癌(ELABC)患者接受联合治疗 手术(新辅助)治疗、手术切除和术后(辅助)治疗。近年来, ELABC的总存活率在5年时已提高到~90%。然而,为了实现这一目标,患者往往 由于缺乏有效的生物标志物而过度治疗。例如,大多数接受佐剂治疗的患者 治疗已经在手术后治愈,不会产生进一步的好处。同样,几乎三分之一的患者 接受新辅助治疗的患者在手术后病理完全缓解(无 组织病理学上肿瘤的证据),这表明手术本可以安全地省略。一个 有效的微小残留病(MRD)生物标志物可以帮助个性化治疗计划,减少过度 治疗,同时保留乳腺癌患者的结果。 最近的文献表明,术后检测循环肿瘤DNA(CtDNA)可以识别复发, 几个月后才能在成像上被识别。然而,由于目前的方法缺乏敏感性和局限性。 血样量、ctDNA信号常降至检测下限以下。当前研究ctDNA的方法 分析没有足够的灵敏度来检测治疗期间和治疗完成后的残留病。 为了解决这一差距,我们开发了目标数字测序(TARDIS),这是一种用于 Ctdna中几个患者特异性突变的多重分析。在本应用程序中,我们建议首先 分析验证TARDIS的ctDNA检测,然后临床验证该方法作为 早期和局部晚期乳腺癌的治疗监测和残留病变检测。在UH2中 分析验证阶段,我们将评估分析的灵敏度、特异度、准确度、精密度和 TARDIS标准物质、肿瘤细胞株稀释液和患者血浆样本的重复性 患有乳腺癌。在UH3临床验证阶段,我们将测量基线ctDNA检测率 早期和局部晚期乳腺癌患者,评估新辅助治疗后ctDNA水平 治疗可预测病理完全缓解并评估ctDNA的预后价值 手术切除后检测无瘤生存率。 我们的目标是使早期和局部晚期乳腺癌患者的治疗更加精确。 一旦得到验证,ctDNA分析和监测将补充现有的诊断方法,如 影像和组织病理学有助于优化早期和局部晚期乳房患者的治疗 癌症。
英文摘要
PROJECT SUMMARY Patients with early and locally advanced breast cancer (ELABC) are treated with a combination of pre- operative (neoadjuvant) therapy, surgical resection and post-operative (adjuvant) therapy. In recent years, overall survival for ELABC has improved to ~90% at 5 years. However, to achieve this goal, patients are often over-treated due to lack of effective biomarkers. For example, a majority of patients who receive adjuvant therapy are already cured after surgery and derive no further benefit. Similarly, almost a third of patients treated with neoadjuvant therapy are found to have pathological Complete Response upon surgery (no evidence of tumor upon histopathology), suggesting that the surgery could have been safely omitted. An effective biomarker for minimal residual disease (MRD) can help personalize treatment plans and reduce over- treatment, while preserving outcomes in patients with breast cancer. Recent literature shows post-operative detection of circulating tumor DNA (ctDNA) can identify recurrence, months before it is recognized on imaging. However, due to lack of sensitivity of current methods and limited blood sample volumes, ctDNA signal often drops below limit of detection. Current approaches for ctDNA analysis do not have adequate sensitivity to detect residual disease during and after completion of treatment. To address this gap, we have developed TARgeted DIgital Sequencing (TARDIS), an approach for multiplexed analysis of several patient-specific mutations in ctDNA. In this application, we propose to first analytically validate TARDIS for ctDNA detection and then clinically validate this approach as a biomarker for treatment monitoring and residual disease detection in early and locally advanced breast cancer. In the UH2 analytical validation phase, we will assess analytical sensitivity, specificity, accuracy, precision and reproducibility of TARDIS using reference material, tumor cell line dilutions and plasma samples from patients with breast cancer. In the UH3 clinical validation phase, we will measure baseline ctDNA detection rates in patients with early and locally advanced breast cancer, evaluate whether ctDNA levels after neoadjuvant treatment are predictive of pathological Complete Response and evaluate the prognostic value of ctDNA detection after surgical resection for disease-free survival. Our goal is to enable greater precision in treatment of patients with early and locally advanced breast cancer. Once validated, ctDNA analysis and monitoring will complement existing diagnostic approaches such as imaging and histopathology to help optimize management of patients with early and locally advanced breast cancer.
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Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
  • 批准号:
    10304711
  • 项目类别:
  • 资助金额:
    $37.11万
  • 财政年份:
    2019
  • 负责人:
    Muhammed Murtaza
  • 依托单位:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
  • 批准号:
    10246983
  • 项目类别:
  • 资助金额:
    $34.93万
  • 财政年份:
    2019
  • 负责人:
    Muhammed Murtaza
  • 依托单位:
Pre-analytical factors affecting ctDNA analysis in early and locally advanced breast cancer
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