ctDNA for the Early Detection and Monitoring of Colorectal Cancer

 描述(申请人提供)：早期发现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记物可以通过更早地识别复发风险的受试者、更好的预后评估，以及由于更早地实施替代治疗而潜在地改善生存或生活质量来加强护理。因此，早期发现并在治疗过程中对肿瘤和肿瘤特征进行非侵入性评估的“液体活检”将代表着一项重大的医学进步。循环肿瘤DNA(CtDNA)是一种小的核酸片段，来源于肿瘤细胞的凋亡或坏死性更新。CTDNA具有恶性过程的特点，可以在血浆中进行评估，并为许多应用提供了一种敏感和特异的生物标志物的潜力，包括肿瘤的诊断或早期检测，关于无病或总体生存的预后信息，以及关于耐药性和治疗缺乏反应的可能性的预测信息。以前的ctDNA研究是通过识别原发肿瘤中的特征突变，然后询问同一患者的血浆DNA是否存在这些突变来实施的。评估ctDNA作为一种筛查方法的下一步是构建一组可在血浆中检测到的突变(“血浆序列”小组)，以评估血浆ctDNA在事先不知道其血浆被检测的患者的肿瘤中存在哪些突变的情况下识别癌症的敏感性和特异性。在目标1中，我们将前瞻性地招募结直肠癌(CRC)患者、无病对照组和腺瘤患者，在确定的手术或内窥镜治疗之前，并系统地评估PlatmaSeq小组，以探索ctDNA作为早期检测标记的应用。先前的研究表明，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期结直肠癌患者，确定他们的肿瘤突变情况，并系统地收集每3个月一次的大容量(&gt；10毫升)连续血浆样本，用于ctDNA和同步CEA检测。临床结果和存活率将被跟踪，ctDNA评估的参数，包括绝对水平、变化速度和波动程度，将根据临床结果进行评估，按肿瘤分期(IIIA-III期)分层。由此得到的数据将允许评估ctDNA作为无病和总存活率的预后标志。这项研究将进一步推进ctDNA在结直肠癌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，这项技术的进步对癌症治疗具有潜在的重大影响。

 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.