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

循环肿瘤DNA（ctDNA）正在成为肿瘤学中的生物标志物， 变革性的临床应用。一个应用可能是检测临床上检测不到的最小的 目的性治疗后的残留疾病（MRD）。在III期结直肠癌（CRC）中，原发性 治愈的手段是手术切除，但如果任何肿瘤细胞仍然手术后，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，但仍有30%的患者 复发。ctDNA检测可以预测哪些患者复发风险最高，但一个关键问题是， 一种检测MRD的有效方法还可以识别可能从额外治疗中获益的患者， 提高治愈率。在目标1和2中，500例患者，多机构III期CRC试验，ACT 3，由 Stand Up 2 Cancer，我们将测试ctDNA的能力，以识别在没有额外治疗的情况下复发的患者 并评估额外的治疗是否允许ctDNA“清除”。ctDNA“清除”将被用作快速 读出辅助治疗疗效，随后评估“清除”是否与改善的 无复发生存。通过ACT3，我们还将评估用于MRD检测的新兴技术，并确定 MRD检测的最佳时机。这可能为辅助临床试验创造一种新的方法， 挽救更多治愈方法的机会ctDNA的第二个潜在的变革性临床应用是实时的 监测对全身治疗的反应。虽然放射成像仍然是衡量 治疗反应和疾病进展，检测治疗反应的早期证据的能力，或 在标准放射成像显示出明显的失败之前， 以优化患者治疗效果。患者可以从无效的治疗早期转换到潜在的治疗。 有效的治疗，以实现更快的利益，同时尽量减少从继续无效的毒性， 疗法在目标3中，我们将检验连续ctDNA监测可以提供实时、非侵入性的 是指在200例患者的前瞻性研究中跟踪转移性GI癌的早期治疗反应。我们将 比较ctDNA变化与标准肿瘤标志物的变化以及患者报告的结局， 每种方式单独或组合预测放射学反应的能力。同时，我们将评估 ctDNA用于反应预测的新技术。主要工作将在马萨诸塞州总医院进行 医院，并扩大了我与我的导师团队组成的国际关系， 液体活检和临床试验领域公认的专家（主要导师：Ryan Corcoran，医学博士和合作导师 路易斯·马里医学博士迪亚兹和医学博士大卫B瑞安）。一个具有互补专长的科学咨询委员会将 还提供指导（John Iafrate，MD，PhD和基思弗莱厄蒂MD）和生物统计学（诺拉霍里克，MS）。K08 支持将提供时间和资源，以进一步发展和实现我的职业目标，成为一个 具有生物标志物驱动研究者发起的GI癌症研究专业知识的独立研究者。

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.