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

项目摘要：循环肿瘤DNA(CtDNA)正在成为肿瘤学中的一个生物标志物，有几个 变革性的临床应用。一种应用可能是能够检测到临床上无法检测到的最低限度 治疗意向治疗后的残留疾病(MRD)。在III期结直肠癌(CRC)中，原发于 治愈的方法是手术切除，但如果手术后仍有肿瘤细胞，这可能导致最终的 复发。在III期结直肠癌中，辅助化疗也可以降低复发风险，但30%的患者仍将 复发。CtDNA检测可以预测哪些患者有最高的复发风险，但关键问题是 检测MRD的有效方法还可以确定哪些患者可能受益于额外的治疗和 提高治愈率。在AIMS 1和2中，有500名患者，多机构III期CRC试验，Act3，由 站起来2癌症，我们将测试ctDNA识别不需要额外治疗就能复发的患者的能力 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，并随后评估“清除”是否与改善相关 无复发存活率。通过Act3，我们还将评估MRD检测的新兴技术并确定 MRD检测的最佳时机。这可以为辅助临床试验创造一种新的方法，提供一种 挽救更多治疗方法的机会。CtDNA的第二个潜在的变革性临床应用是实时 监测对系统治疗的反应。虽然放射成像仍然是测量的黄金标准 治疗反应和疾病进展，检测治疗反应或早期证据的能力 失败--在通过标准的放射成像表现出来之前--可能会让临床医生迅速调整治疗方法 以优化患者的治疗结果。患者可以在早期从无效的治疗切换到潜在的治疗 有效的治疗，以达到更快的收益，同时将持续无效的毒性降至最低 心理治疗。在目标3中，我们将检验这一假设，即连续的ctdna监测可以提供实时的、非侵入性的 在一项200名患者的前瞻性研究中，追踪转移性胃肠道癌症的早期治疗反应。我们会 将ctDNA变化与标准肿瘤标志物的变化和患者报告的结果进行比较，以评估 每种模式单独或组合预测放射学反应的能力。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，并扩展了我与我的指导团队建立的关系，该团队由国际 液体活检和临床试验方面公认的专家(主要导师：Ryan Corcoran、医学博士和共同导师 医学博士路易斯·M·迪亚兹和医学博士大卫·B·瑞安)。一个具有互补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 支持将提供时间和资源，以进一步发展和实现我成为一名 独立调查员在生物标志物驱动的调查员方面具有专业知识，发起了对胃肠道癌症的研究。

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.