Detection of Minimal Residual Disease through Analysis of Genetic Alterations in the Circulation of Stage II Colorectal Cancer Patients

 描述（由申请人提供）：结直肠癌（CRC）是发达国家第三大常见癌症和第三大癌症死亡原因，每年新发病例超过120万例，死亡人数超过608，000例。CRC患者根据其疾病的程度分为I期至IV期。大约25%的CRC患者被诊断为局部II期癌症，在发达国家每年有300，000例新发病例，在美国每年有35，000例。II期CRC的标准治疗包括手术切除肿瘤，然后对高危患者进行辅助治疗。目前的风险分层方法，包括标准的TNM分期方法，只能提供有限的准确性，如约20-25%的II期CRC患者复发，主要是不可治愈的疾病，不接受辅助治疗。因此，迫切需要新的、更准确的方法来识别高风险患者。循环无细胞肿瘤衍生DNA（ctDNA）由肿瘤释放并携带肿瘤专有的遗传改变。假设：我们假设使用ctDNA直接和早期检测微小残留病（MRD）将比基于切除肿瘤分析预测复发的当前方法更准确地识别高风险CRC患者。初步数据：我们率先开发了ctDNA评估技术，并将ctDNA确立为肿瘤负荷和MRD的特异性和敏感性标志物。与该提议最相关的是，我们已经证明>75%的局部CRC释放可检测的ctDNA，并且手术后ctDNA水平是预后性的。具体目标：在第一阶段SBIR中，我们建议开发和验证CRCDetect，这是一种使用手术后4-6周收集的II期CRC患者外周血中的ctDNA检测MRD的分子测试。CRCDetect可以识别仅通过手术无法治愈的患者，具有高复发风险，并可能从辅助治疗中受益。在具体目标1和2中，我们将重点关注CRCDetect的开发和分析验证。在具体目标3中，我们将评估CRCDetect在II期CRC患者队列中的预后性能。总体影响：总之，这些研究将证明使用CRCDetect从术后简单抽血中检测早期CRC患者的MRD的可行性，从而识别具有高复发风险的II期CRC患者，并告知患者是否应该接受辅助治疗。

 DESCRIPTION (provided by applicant): With over 1.2 million new cases and over 608,000 deaths annually, colorectal cancer (CRC) is the third most common cancer and the third highest cause of cancer death in the developed world. CRC patients are classified into stage I through IV depending on the extent of their disease. Approximately 25% of CRC patients are diagnosed with localized stage II cancer, amounting to 300,000 new cases in the developed world and 35,000 in the U.S. annually. The standard of care for stage II CRC includes surgical removal of the tumor followed by adjuvant therapy in high risk patients. The current risk stratification approaches, including the standard of care TNM staging method, offer only limited accuracy, as evidenced by the approximately 20-25% of stage II CRC patients who recur with predominantly incurable disease and do not receive adjuvant therapy. Therefore, novel, more accurate approaches to identify high risk patients are urgently needed. Circulating cell-free tumor-derived DNA (ctDNA) is released by tumors and carries tumor-exclusive genetic alterations. Hypothesis: We hypothesize that direct and early detection of minimal residual disease (MRD) using ctDNA will more accurately identify high risk CRC patients than the current approaches that predict recurrence based on analyses of the resected tumors. Preliminary Data: We have pioneered the development of technologies for evaluation of ctDNA, and established ctDNA as an exquisitely specific and sensitive marker for tumor burden and MRD. Most relevant to this proposal, we have demonstrated that >75% of localized CRC release detectable ctDNA and that post-surgery ctDNA levels are prognostic. Specific Aims: In this phase I SBIR, we propose to develop and validate CRCDetect, a molecular test for the detection of MRD using ctDNA in the peripheral blood of stage II CRC patients collected 4-6 weeks after surgery. CRCDetect can identify patients who are not cured by surgery alone, have a high risk of recurrence, and may benefit from adjuvant therapy. In Specific Aims 1 and 2, we will focus on the development and analytical validation of CRCDetect. In Specific Aim 3, we will evaluate the prognostic performance of CRCDetect in a cohort of stage II CRC patients. Overall Impact: Together, these studies will demonstrate the feasibility of using CRCDetect to detect MRD in early stage CRC patients from a simple blood draw after surgery, thereby identifying the stage II CRC patients with a high risk of recurrence and informing whether a patient should receive adjuvant treatment.