Systematic liquid biopsy to monitor residual disease and treatment efficacy in gastrointestinal cancer patients

系统液体活检监测胃肠道癌症患者的残留病灶和治疗效果

• 批准号: 10697368
• 负责人: Aparna Raj Parikh
• 金额: $ 27.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697368
• 关键词: Adjuvant; Adjuvant Chemotherapy; Adjuvant Study; Adjuvant Therapy; Advisory Committees; Biological Markers; Biometry; Blood; Cancer Patient; Clinical; Clinical Trials; Colon Carcinoma; Colorectal Cancer; DNA analysis; Data; Detection; Detection of Minimal Residual Disease; Disease; Disease Progression; Disease-Free Survival; Doctor of Philosophy; Early Diagnosis; Early Intervention; Early identification; Early treatment; Emerging Technologies; Enrollment; Excision; Funding; General Hospitals; Goals; Image; Immunotherapy; Institution; International; Intervention; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Massachusetts; Mentors; Mentorship; Methods; Modality; Monitor; Oncology; Operative Surgical Procedures; Outcome Assessment; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Postoperative Period; Prediction of Response to Therapy; Prospective Studies; Randomized; Recurrence; Research Personnel; Residual Neoplasm; Resources; Risk; Risk Reduction; Serum; Signal Transduction; Solid Neoplasm; Systemic Therapy; Technology; Testing; Time; Toxic effect; Treatment Effectiveness; Treatment Efficacy; Treatment Failure; Tumor Markers; United States; Work; arm; biomarker driven; career; chemotherapy; clinical application; colon cancer patients; effective therapy; follow-up; high risk; improved; ineffective therapies; large datasets; liquid biopsy; neoplastic cell; new technology; novel; novel strategies; predicting response; prognostic value; prospective; radiological imaging; real time monitoring; response; standard measure; standard of care; targeted treatment; tool; treatment response; trial design; tumor DNA

Project Summary: Circulating tumor DNA (ctDNA) is emerging as a biomarker in oncology with several transformative clinical applications. One application may be the ability to detect clinically undetectable minimal residual disease (MRD) following curative intent treatment. In Stage III colorectal cancer (CRC), the primary means of cure is surgical resection, but if any tumor cells remain post-surgery, this can lead to eventual recurrence. In Stage III CRC, adjuvant chemotherapy also reduces recurrence risk, but 30% of patients will still recur. ctDNA detection may predict which patients have the highest recurrence risk, but a key question is whether an effective method to detect MRD can also identify patients who may benefit from additional therapy and increase cure rates. In Aims 1 and 2 with a 500 patient, multi-institutional Stage III CRC trial, ACT3, funded by Stand Up 2 Cancer, we will test the ability of ctDNA to identify patients who would recur without additional therapy and evaluate if additional treatment allows for ctDNA “clearance.” ctDNA “clearance” will be used as a rapid read-out for adjuvant therapy efficacy and subsequently evaluate if “clearance” correlates with improved recurrence-free survival. With ACT3, we will also evaluate emerging technologies for MRD detection and identify the optimal timing for MRD detection. This could create a novel approach for adjuvant clinical trials, providing a opportunity to salvage more cures. A second potentially transformative, clinical application of ctDNA is real-time monitoring of response to systemic therapy. While radiographic imaging remains the gold standard for measuring treatment response and disease progression, the ability to detect early evidence of treatment response or failure—before it is evident by standard radiographic imaging—could allow clinicians to rapidly adapt therapies to optimize patient outcomes. A patient could be switched early on from an ineffective therapy to a potentially effective therapy to achieve more rapid benefit, while minimizing the toxicity from continuing an ineffective therapy. In Aim 3, we will test the hypothesis that serial ctDNA monitoring may provide a real-time, non-invasive means to track early therapeutic response for metastatic GI cancers in a 200-patient prospective study. We will compare ctDNA changes to changes in standard tumor markers and patient reported outcomes assessing the ability of each modality alone or in combination to predict radiographic response. In parallel, we will evaluate novel technologies of ctDNA for response prediction. The primary work will take place at Massachusetts General Hospital and expands upon my established relationships with my mentorship team consisting of internationally recognized experts in liquid biopsies and clinical trials (primary mentor: Ryan Corcoran, MD PhD and co mentors Luis M. Diaz, MD and David B Ryan, MD). A scientific advisory committee with complementary expertise will also provide guidance (John Iafrate, MD, PhD and Keith Flaherty MD) and biostatistics (Nora Horick, MS). K08 support will provide the time and resources to further develop and achieve my career goal of becoming an independent investigator with an expertise in biomarker driven investigator initiated studies in GI cancers.

项目摘要：循环肿瘤DNA（CTDNA）正在作为肿瘤学中的生物标志物出现，有几种 变革性临床应用。一种应用可能是检测到临床上无法检测到的最小值的能力 治愈性治疗后残留疾病（MRD）。在第三阶段结直肠癌（CRC）中，主要 治愈的手段是手术切除，但是如果任何肿瘤细胞在手术后仍然是手术切除术，这可能会导致最终 复发。在第三阶段CRC中，调整化疗也降低了复发风险，但30％的患者仍将 复发。 CTDNA检测可能会预测哪些患者的复发风险最高，但一个关键问题是是否是 检测MRD的有效方法还可以识别可能从其他疗法中受益的患者 增加治愈率。在AIMS 1和2中，有500名患者，多机构的III阶段CRC试验，ACT3，由 站立2个癌症，我们将测试ctDNA识别未经其他治疗的患者的能力 并评估其他治疗是否允许ctDNA“清除率”。 ctDNA“清除率”将用作快速 读出可调节疗法有效性的启用，随后评估“清除”是否与改进相关 无复发生存。使用ACT3，我们还将评估新兴技术以进行MRD检测并确定 MRD检测的最佳时机。这可能会为可调临床试验创建一种新颖的方法，从而提供 挽救更多治疗的机会。 ctDNA的第二个潜在变化，临床应用是实时的 监测对系统治疗的反应。射线照相成像仍然是测量的黄金标准 治疗反应和疾病进展，检测早期治疗反应证据或 失败 - 在标准射线照相成像的证据之前 - 诊断者可以快速适应疗法 优化患者预后。患者可以尽早从无效的疗法转变为潜在的 有效的疗法以获得更快的益处，同时最大程度地减少了继续无效的毒性 治疗。在AIM 3中，我们将检验以下假设：串行ctDNA监测可能会提供实时，无创的 在200名患者的前瞻性研究中跟踪转移性胃肠道癌的早期热反应的手段。我们将 比较ctDNA的变化与标准肿瘤标记的变化和患者报告的结果评估 单独或组合每种模态的能力预测射线照相响应。同时，我们将评估 ctDNA的新技术用于响应预测。主要工作将在马萨诸塞州将军举行 医院并扩展了我与我与我的Mentalship团队建立的关系，包括国际 公认的液体活检和临床试验专家（主要导师：Ryan Corcoran，MD博士和CO指导者 医学博士Luis M. Diaz和医学博士David B Ryan）。具有完善专业知识的科学咨询委员会将 还提供指导（John Iafrate，MD，PhD和Keith Flaherty MD）和生物统计学（Nora Horick，MS）。 K08 支持将为进一步发展和实现成为我的职业目标的时间和资源 具有生物标志物驱动的研究者专业知识的独立研究者在GI癌症中启动了研究。