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: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304444
• 关键词: Address; Adjuvant Therapy; Aftercare; Archives; Biological Assay; Biological Markers; Biopsy; Blood Tests; Blood Volume; Blood specimen; Clinical; Clinical Data; Clinical Trials; Complement; DNA; DNA analysis; Detection; Detection of Minimal Residual Disease; Diagnostic; Disease; Disease Progression; Disease-Free Survival; Drops; Early treatment; Enrollment; Ensure; Estrogen receptor positive; Excision; Goals; Histopathology; Image; In complete remission; Individual; Literature; Malignant Neoplasms; Measures; Metastatic breast cancer; Methods; Microscopic; Molecular; Monitor; Mutate; Mutation; Neoadjuvant Therapy; No Evidence of Disease; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathologic; Patients; Performance; Phase; Phenotype; Plasma; Postoperative Period; Process; Prognostic Marker; Radiology Specialty; Recurrence; Reproducibility; Residual Neoplasm; Residual Tumors; Sampling; Sensitivity and Specificity; Signal Transduction; Somatic Mutation; Specificity; Testing; Therapeutic; Tissues; Tumor Cell Line; Tumor Tissue; Validation; advanced breast cancer; aggressive therapy; base; cancer cell; circulating biomarkers; clinically relevant; design; digital; exome sequencing; follow-up; improved; improved outcome; malignant breast neoplasm; overtreatment; personalized medicine; portability; preservation; prognostic value; prospective; response; survival outcome; treatment optimization; treatment planning; treatment response; tumor; tumor DNA

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.

项目概要 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。最近几年， ELABC 的 5 年总生存率已提高至约 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，大多数接受辅助治疗的患者 手术后治疗已经治愈，不会产生进一步的益处。同样，近三分之一的患者 发现接受新辅助治疗的患者在手术后具有病理学完全缓解（无 组织病理学上的肿瘤证据），表明手术可以安全地省略。一个 微小残留病（MRD）的有效生物标志物可以帮助个性化治疗计划并减少过度治疗 治疗，同时保留乳腺癌患者的治疗结果。 最近的文献表明，术后检测循环肿瘤 DNA (ctDNA) 可以识别复发、 在成像上被识别之前的几个月。然而，由于现有方法缺乏敏感性且有限 随着血液样本量的增加，ctDNA 信号通常会降至检测限以下。目前的 ctDNA 方法 分析没有足够的灵敏度来检测治疗期间和完成后的残留疾病。 为了弥补这一差距，我们开发了定向数字测序 (TARDIS)，这是一种 对 ctDNA 中几种患者特异性突变的多重分析。在此应用中，我们建议首先 分析验证 TARDIS 用于 ctDNA 检测，然后临床验证该方法作为生物标志物 早期和局部晚期乳腺癌的治疗监测和残留疾病检测。在UH2 分析验证阶段，我们将评估分析的灵敏度、特异性、准确性、精密度和 TARDIS 使用参考材料、肿瘤细胞系稀释液和患者血浆样本的重现性 患有乳腺癌。在UH3临床验证阶段，我们将测量基线ctDNA检出率 早期和局部晚期乳腺癌患者，评估新辅助治疗后 ctDNA 水平是否 治疗可预测病理完全缓解并评估 ctDNA 的预后价值 手术切除后检测无病生存率。 我们的目标是提高早期和局部晚期乳腺癌患者的治疗精度。 一旦经过验证，ctDNA 分析和监测将补充现有的诊断方法，例如 影像学和组织病理学有助于优化早期和局部晚期乳腺患者的治疗 癌症。