Clinical Validation Center for Hepatocellular Carcinoma

项目摘要 肝细胞癌（HCC）是美国增长最快的癌症死亡原因之一， 预计到2040年将成为美国癌症死亡的第三大原因， HCC风险分层和早期检测策略。具体而言，建议对所有患者进行HCC筛查 肝硬化，尽管每年HCC风险在1-4%/年之间变化，但需要进行风险分层 生物标志物。肝细胞癌筛查是通过腹部超声和血清标志物甲胎蛋白进行的 (AFP)然而，这种策略在早期阶段错过了超过三分之一的HCC，并导致在早期阶段筛选危害。 很多病人。我们的HCC临床验证中心（CVC-HCC）的目标是验证新的血液， I-III期研究中的成像生物标志物，以改善HCC风险分层和早期检测。 HCC生物标志物的实践转化受到缺乏高质量样本集的阻碍， 储存的血液和成像现有的样本集还主要包括患有肝硬化的患者， 病毒性肝炎，对主要治愈病毒性肝炎的当代人群适用性有限， 肝脏疾病的非病毒原因。我们的CVC将创建一个包含血液和成像数据的现代资源， 允许在I-III期中快速验证用于HCC风险分层和早期检测的有前景的生物标志物 问题研究需要更好的生物标志物的特定人群是不确定性肝结节（ILN）患者， 诊断性CT或MRI，在超过四分之一接受HCC筛查的患者中观察到， 发展为HCC的风险高，但可变（年风险约6-10%/年）。我们小组已经证实了一种新的血液- 用于风险分层的生物标志物PLSec和用于患者早期HCC检测的生物标志物组GALAD 并在此提出进行II-III期生物标志物研究，以评估它们在ILN患者中的作用。 我们的团队包括HCC筛查，成像和生物标志物验证的国家领导者。我们正在努力 评估HCC生物标志物，包括EDRN资助的肝细胞早期检测策略（HEDS）研究， NCI资助的转化型肝癌（TLC）联盟和CPRIT资助的德克萨斯州HCC联盟。我们将 利用五个卫生系统的现有基础设施，创造两个新的资源， 目前的样品集包括（1）具有来自患者的血液和成像数据的生物储存库，具有和不具有 HCC，代表II期研究的肝脏疾病的当代病因，和（2） 在III期研究中，使用以下指标对ILN患者进行HCC风险分层和早期检测生物标志物评估： 前瞻性标本采集、回顾性盲法评价（PRoBE）设计。我们将与BCC合作 和DMCC评估新的生物标志物，促进跨网络项目的贡献。总的来说，我们的CVC- HCC将导致HCC风险分层的新型生物标志物的I-III期验证的重大进展， 早期发现，需要的领域，将促进设计良好的第四阶段临床实用性试验的发展。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is one of the fastest-growing cause of cancer death in the U.S. and it is projected to be the 3rd leading cause of cancer death in the U.S. by 2040 given the poor effectiveness of current HCC risk stratification and early detection strategies. Specifically, HCC screening is recommended in all patients with cirrhosis, despite annual HCC risk varying between 1-4%/year, highlighting a need for risk stratification biomarkers. HCC screening is performed using abdominal ultrasound and the serum biomarker alpha fetoprotein (AFP); however, this strategy misses over one-third of HCCs at an early stage and results in screening harms in many patients. The goal of our Clinical Validation Center for HCC (CVC-HCC) is to validate novel blood and imaging biomarkers in phase I-III studies to improve HCC risk stratification and early detection. Translation of HCC biomarkers to practice has been hampered by a dearth of high-quality sample sets including both stored blood and imaging. Existing sample sets also primarily include patients with cirrhosis from active viral hepatitis, with limited applicability to contemporary populations who primarily have cured viral hepatitis or non-viral causes of liver disease. Our CVC will create a contemporary resource with blood and imaging data to allow for rapid validation of promising biomarkers for HCC risk-stratification and early detection in phase I-III studies. A specific population in need of better biomarkers is patients with indeterminate liver nodules (ILNs) on diagnostic CT or MRI, which are observed in over one-fourth of patients undergoing HCC screening and have a high, yet variable, risk for developing into HCC (annual risk ~6-10%/year). Our group has validated a novel blood- based biomarker, PLSec, for risk stratification and a biomarker panel, GALAD, for early HCC detection in patients with cirrhosis and herein propose to perform a phase II-III biomarker study to evaluate them in patients with ILNs. Our team includes national leaders in HCC screening, imaging, and biomarker validation. We are leading efforts to evaluate HCC biomarkers including the EDRN-funded Hepatocellular Early Detection Strategy (HEDS) Study, NCI-funded Translational Liver Cancer (TLC) Consortium, and CPRIT-funded Texas HCC Consortium. We will leverage existing infrastructure across five health systems to create two novel resources not offered by the current sample sets including (1) a biorepository with both blood and imaging data from patients, with and without HCC, representing contemporary etiologies of liver disease for Phase II studies and (2) a prospective cohort of patients with ILNs to evaluate HCC risk stratification and early detection biomarkers in Phase III studies using a prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) design. We will work with the BCCs and DMCC to evaluate novel biomarkers, facilitating contributions to trans-network projects. Overall, our CVC- HCC will lead to significant advances in phase I-III validation of novel biomarkers for HCC risk stratification and early detection, areas of need that will facilitate development of well-designed phase IV clinical utility trials.