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) 正在成为肿瘤学中的一种生物标志物，具有多种用途 变革性的临床应用。一项应用可能是能够检测临床上无法检测到的最小量 治愈性治疗后的残留病灶（MRD）。在 III 期结直肠癌 (CRC) 中，原发性 治愈的方法是手术切除，但如果手术后仍有任何肿瘤细胞残留，这可能会导致最终 复发。在 III 期 CRC 中，辅助化疗也可降低复发风险，但 30% 的患者仍会复发 复发。 ctDNA 检测可以预测哪些患者的复发风险最高，但一个关键问题是是否 检测 MRD 的有效方法还可以识别可能受益于额外治疗的患者 提高治愈率。在目标 1 和 2 中，有 500 名患者参与，多机构 III 期 CRC 试验 ACT3，由 Stand Up 2 Cancer，我们将测试 ctDNA 识别无需额外治疗即可复发的患者的能力 并评估额外的治疗是否允许 ctDNA“清除”。 ctDNA“清除”将被用作快速 读出辅助治疗效果，然后评估“清除”是否与改善相关 无复发生存期。通过 ACT3，我们还将评估用于 MRD 检测的新兴技术并识别 MRD 检测的最佳时机。这可以为辅助临床试验创造一种新方法，提供 挽救更多治疗方法的机会。 ctDNA 的第二个潜在变革性临床应用是实时的 监测对全身治疗的反应。虽然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，检测治疗反应早期证据的能力或 在标准放射成像显示失败之前，临床医生可以快速调整治疗方法 优化患者治疗效果。患者可以尽早从无效的治疗转为潜在的治疗 有效的治疗可实现更快速的获益，同时最大限度地减少继续无效治疗带来的毒性 治疗。在目标 3 中，我们将检验以下假设：连续 ctDNA 监测可以提供实时、非侵入性的数据。 是指在一项 200 名患者参与的前瞻性研究中追踪转移性胃肠道癌症的早期治疗反应。我们将 将 ctDNA 变化与标准肿瘤标志物的变化以及患者报告的结果进行比较，评估 每种方式单独或组合预测放射照相反应的能力。同时，我们将评估 用于反应预测的 ctDNA 新技术。主要工作将在马萨诸塞州综合医院进行 医院并扩展了我与国际导师团队建立的关系 液体活检和临床试验领域公认的专家（主要导师：医学博士 Ryan Corcoran 和共同导师 Luis M. Diaz（医学博士）和 David B Ryan（医学博士）。具有互补专业知识的科学咨询委员会将 还提供指导（John Iafrate，医学博士、博士和 Keith Flaherty 医学博士）和生物统计学（Nora Horick，MS）。 K08 支持将为我提供时间和资源，以进一步发展并实现我成为一名 具有生物标记专业知识的独立研究者发起了胃肠道癌症的研究。