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

基本信息

批准号：
9338930
负责人：
KENNETH W. KINZLER
金额：
$ 21.62万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-07 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9338930
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 Diagnostic Neoplasm Staging Disease Disease-Free Survival Early Detection Research Network Early Diagnosis Early identification Evaluation Feces Genomics Health 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 Patients Performance Population Populations at Risk Primary Neoplasm Probability Process Prognostic Marker Quality of life Recruitment Activity Recurrence Recurrent disease Reproducibility Research Resistance Risk Screening for cancer Secondary to Sensitivity and Specificity Specimen Staging 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 cost early detection biomarkers liquid biopsy mortality neoplastic cell next generation sequencing personalized medicine prognostic prototype resistance mutation response screening specific biomarkers survival outcome targeted treatment tool treatment response tumor tumor DNA uptake

项目摘要

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）：用于早期检测癌症的血液测试将为筛查高危人群提供一种有价值的额外手段。用于监测癌症的血液生物标志物可以通过更早地识别有复发风险的受试者来加强护理。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，因此，用于早期检测和治疗期间对肿瘤和肿瘤特征进行非侵入性评估的“液体活检”将代表重大的医学进步。循环肿瘤DNA (ctDNA) 是源自凋亡或坏死肿瘤细胞更新的小核酸片段，是恶性过程的特征，可以在血浆中评估 ctDNA，并为包括诊断或治疗在内的许多应用提供敏感和特异性生物标志物的潜力。肿瘤的早期检测、无病生存或总体生存的预后信息以及耐药性和治疗无反应概率的预测信息是通过识别原发肿瘤中的特征突变并随后询问来自血浆的 DNA 来实现的。评估 ctDNA 作为筛查方式的下一步是构建一组适合在血浆中检测的突变（“PlasmaSeq”组），以评估血浆 ctDNA 在识别中的敏感性和特异性。在目标 1 中，我们将前瞻性地招募结直肠癌 (CRC) 患者、无病对照者和之前患有腺瘤的受试者。明确的手术或内窥镜治疗，并系统地评估 PlasmaSeq 组合，以探索 ctDNA 作为早期检测标记的效用。在目标 2 中，ctDNA 可用于监测接受治疗或有复发疾病风险的受试者的癌症。我们将招募新诊断的 III 期 CRC 患者，了解他们的肿瘤突变谱，并每 3 个月系统地收集大量（>10 ml）连续血浆样本，持续长达 4 年，用于确定 ctDNA 和同时进行 CEA 测量。将跟踪结果和生存，并根据临床结果评估 ctDNA 评估参数，包括绝对水平、变化速度和波动程度，并按肿瘤分期分类（IIIA-III 期）进行分层。所得数据将允许。 ctDNA 作为无病生存和总体生存的预后标志物的评估将进一步推进 ctDNA 在 CRC 早期检测和监测中的应用，因此，这项技术的进步。是潜在的对癌症治疗影响很大。