ctDNA for the Early Detection and Monitoring of Colorectal Cancer

用于结直肠癌早期检测和监测的 ctDNA

• 批准号: 10375657
• 负责人: KENNETH W. KINZLER
• 金额: $ 39.09万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375657
• 关键词: Address; Adenomatous Polyps; Alternative Therapies; Apoptotic; Biological; Biological Assay; Biological Markers; Blood; Blood Tests; Cancer Detection; Caring; Characteristics; Classification; Clinical; Colonoscopy; Colorectal Cancer; Control Groups; DNA; Data; Detection; Development; Diagnosis; Disease; Disease Marker; Disease-Free Survival; Early Detection Research Network; Early Diagnosis; Early identification; Evaluation; Feces; Genomics; Incidence; Knowledge; Laboratories; Location; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Measurement; Medical; Modality; Monitor; Morbidity - disease rate; Mutation; Necrosis; Newly Diagnosed; Nucleic Acids; Operative Surgical Procedures; Outcome; Patient Monitoring; Patient Recruitments; Patients; Performance; Plasma; Population; Populations at Risk; Primary Neoplasm; Probability; Process; Prognostic Marker; Quality of life; Recurrence; Recurrent disease; Reproducibility; Research; Resistance; Risk; Screening for cancer; Screening procedure; Secondary to; Sensitivity and Specificity; Specimen; Technology; Testing; Translational Research; Tumor Burden; Tumor Tissue; Tumor stage; Universities; adenoma; base; blood-based biomarker; cancer care; cancer therapy; chemotherapy; clinical application; clinical risk; colon cancer patients; comparison group; cost; early detection biomarkers; early screening; liquid biopsy; mortality; neoplastic cell; next generation sequencing; personalized medicine; prognostic; prospective; prototype; public health relevance; recruit; resistance mutation; response; screening; secondary analysis; specific biomarkers; targeted treatment; translational impact; treatment response; tumor; tumor DNA; uptake

 DESCRIPTION (provided by applicant): A blood test for early detection of cancer would provide a valuable, additional means for screening the population at risk. Blood-based biomarkers for monitoring cancer could enhance care by earlier identification of subjects at risk of recurrence, better prognostic assessment, and potentially, improvements in survival or quality of life due to earlier implementation of alternative therapy. Thus, a "liquid biopsy" for early detection and for non-invasive assessment of tumor and tumor characteristics during treatment would represent a significant medical advance. Circulating tumor DNA (ctDNA) are small fragments of nucleic acid that originate from apoptotic or necrotic tumor cell turnover. Characteristic of the malignant process, ctDNA can be assessed in plasma, and offers the potential of a sensitive and specific biomarker for a host of applications including diagnosis or early detection of tumors, prognostic information on disease-free or overall survival, and predictive information on resistance and probability of lack of response to treatment. Previous ctDNA studies have been implemented by identifying characteristic mutations in the primary tumor and subsequently interrogating plasma DNA from the same patient for the presence of those mutations. The next step in evaluating ctDNA as a screening modality is to construct a panel of mutations amenable to detection in plasma (a "PlasmaSeq" panel) to assess the sensitivity and specificity of plasma ctDNA in identifying cancer without prior knowledge of which mutations are present in the tumor of the patient whose plasma is assayed. In Aim 1, we will prospectively recruit patients with colorectal cancer (CRC), disease-free controls, and subjects with adenomas prior to definitive surgical or endoscopic treatment and systematically evaluate a PlasmaSeq panel to explore the utility of ctDNA as a marker for early detection. Previous studies suggest that ctDNA can be used to monitor cancer in subjects under treatment or at risk for recurrent disease. In Aim 2, we will recruit newly diagnosed stage III CRC patients, determine their tumor mutational profile, and systematically collect high volume (>10 ml), serial plasma specimens every 3 months for up to 4 years for ctDNA and concurrent CEA measurement. Clinical outcome and survival will be tracked and parameters of ctDNA assessment, including absolute level, velocity of change, and degree of fluctuation will be evaluated in relation to clinical outcome, stratified by tumor stage classification (stage IIIA-III). The resulting data will permit assessment of ctDNA as a prognostic marker for disease-free and overall survival. This research will further advance study on the use of ctDNA in early detection and monitoring of CRC. ctDNA testing is also applicable to many other cancers. Thus, advancement in this technology is potentially of great impact to cancer care.

 描述（由申请人提供）：用于癌症早期检测的血液检测将为筛查风险人群提供有价值的额外手段。用于监测癌症的基于血液的生物标志物可以通过早期识别有复发风险的受试者，更好的预后评估以及由于早期实施替代疗法而可能改善生存或生活质量来加强护理。因此，用于早期检测和用于在治疗期间非侵入性评估肿瘤和肿瘤特征的“液体活检”将代表显著的医学进步。循环肿瘤DNA（ctDNA）是源自凋亡或坏死肿瘤细胞更新的核酸的小片段。作为恶性过程的特征，ctDNA可以在血浆中进行评估，并为许多应用提供了敏感和特异性生物标志物的潜力，包括肿瘤的诊断或早期检测，无病或总生存期的预后信息，以及对治疗缺乏反应的抗性和概率的预测信息。先前的ctDNA研究已经通过鉴定原发性肿瘤中的特征性突变并随后询问来自同一患者的血浆DNA以确定这些突变的存在来实施。评估ctDNA作为筛选模式的下一个步骤是构建一组适于在血浆中检测的突变（“PlasmaSeq”组），以评估血浆ctDNA在鉴定癌症中的灵敏度和特异性，而无需事先知道哪些突变存在于测定血浆的患者的肿瘤中。在目标1中，我们将前瞻性招募结直肠癌（CRC）患者、无疾病对照和接受明确手术或内镜治疗前的腺瘤受试者，并系统评价PlasmaSeq panel，以探索ctDNA作为早期检测标记物的效用。以前的研究表明，ctDNA可用于监测正在接受治疗或有复发风险的受试者的癌症。在目标2中，我们将招募新诊断的III期CRC患者，确定他们的肿瘤突变谱，并每3个月系统地收集高体积（>10 ml）的连续血浆样本，长达4年，用于ctDNA和同时CEA测量。将跟踪临床结果和生存期，并将根据肿瘤分期分类（IIIA-III期）分层，评价ctDNA评估参数（包括绝对水平、变化速度和波动程度）与临床结果的关系。所得到的数据将允许评估ctDNA作为无病生存期和总生存期的预后标志物。这项研究将进一步推进ctDNA在CRC早期检测和监测中的应用研究。ctDNA检测也适用于许多其他癌症。因此，这项技术的进步可能对癌症护理产生重大影响。

项目成果

Human Blood Autoantibodies in the Detection of Colorectal Cancer.

• DOI: 10.1371/journal.pone.0156971
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Negm OH;Hamed MR;Schoen RE;Whelan RL;Steele RJ;Scholefield J;Dilnot EM;Shantha Kumara HM;Robertson JF;Sewell HF
• 通讯作者: Sewell HF