Precision Risk Stratification and Screening for HCC among Patients with Cirrhosis in the United States

项目摘要/摘要 在美国，与肝细胞癌相关的死亡率正在迅速上升。鉴于两者之间的关联 早期检测和提高存活率，使用超声+/-血清生物标记物甲胎蛋白进行筛查 (AFP)，推荐用于高危人群，包括所有肝硬变患者。然而，大多数肝细胞癌患者 由于这一战略的局限性，在后期被诊断出来。具体地说，超声和AFP的策略 在所有的肝硬变患者中是不够的，因为它忽略了：1)患者之间风险的异质性；2)穷人 筛查试验的准确性；以及3)患者之间筛查试验表现的可靠性较差。这个 目前“一刀切”的肝细胞癌筛查方法导致了对低危肝硬变患者的过度筛查和 对高危患者筛查不足，冲淡了肝细胞癌筛查的整体价值。 我们建议的目标是开发和评估一种对患者早期肝癌进行精确筛查的策略 与个体风险和筛查试验表现相匹配的最佳筛查试验的肝硬变患者。我们会 利用5个患者群体(4个预期队列和1个病例对照数据集)，总共&gt；6000 评价和比较基于生物标记物和成像的肝癌风险分层模型对肝硬变患者的影响 以及及早发现。具体来说，我们建议： 目的1：验证和比较两种风险分层模型对肝硬变患者进行分层的效果 发生肝细胞癌的低、中、高风险 目的2：评价一种简化的MRI方案+/-血清生物标记物(包括AFP、AFP- L3和DCP)与超声+/-血清生物标志物在肝硬变患者早期肝细胞癌检测中的比较 目标3：使用微观模拟建模，比较定制筛选策略的成本效益 基于个体肝癌风险和预期筛查检测性能，以当前的标准策略 所有肝硬变患者的超声和甲胎蛋白检测 我们的建议利用5个不同的患者群体和6000名肝硬变患者，来比较生物标志物-和 基于成像的肝细胞癌风险分层和早期发现模型。我们使用这些数据来比较 为所有患者量身定制的筛查策略对当前超声和甲胎蛋白筛查策略的有效性 采用微观仿真建模。根据个体风险和筛查测试定制肝细胞癌筛查工作 Performance超越了目前的“一刀切”策略，使肝细胞癌筛查符合原则 精准医学。我们建议的肝细胞癌筛查策略将使筛查收益最大化，并将 筛查对每个患者都有危害，从而优化了美国整体的肝细胞癌筛查价值。 2.

PROJECT SUMMARY / ABSTRACT Hepatocellular carcinoma (HCC)-related mortality in the U.S. is rapidly rising. Given the association between early detection and improved survival, screening using ultrasound +/- a serum biomarker, alpha fetoprotein (AFP), is recommended in at-risk individuals, including all patients with cirrhosis. However, most HCC patients are diagnosed at a late stage due to limitations in this strategy. Specifically, the strategy of ultrasound and AFP in all cirrhosis patients is inadequate because it ignores: 1) heterogeneity in risk between patients; 2) the poor accuracy of screening tests; and 3) the poor reliability of screening test performance between patients. The current “one-size-fits-all” approach to HCC screening leads to over-screening of low-risk cirrhosis patients and under-screening of high-risk patients, diluting the overall value of HCC screening. Our proposal's goal is to develop and evaluate a precision screening strategy for early stage HCC in patients with cirrhosis that matches the best screening tests to individual risk and screening test performance. We will leverage five patient populations (4 prospective cohorts and one case-control dataset) with a total of >6000 cirrhosis patients to evaluate and compare biomarker- and imaging-based models for HCC risk stratification and early detection. Specifically, we propose to: Aim 1: Validate and compare the performance of two risk stratification models to stratify cirrhosis patients with low-, intermediate- and high-risk of developing HCC Aim 2: Evaluate the performance of an abbreviated MRI protocol +/- serum biomarkers (including AFP, AFP- L3, and DCP) vs. ultrasound +/- serum biomarkers for early HCC detection in patients with cirrhosis Aim 3: Compare the cost effectiveness, using micro-simulation modeling, of a tailored screening strategy based on individual HCC risk and expected screening test performance to the current standard strategy of ultrasound and AFP in all patients with cirrhosis Our proposal leverages 5 distinct patient populations with >6000 cirrhosis patients, to compare biomarker- and imaging-based models for HCC risk stratification and early detection. We use these data to compare the effectiveness of a tailored screening strategy to the current strategy of ultrasound and AFP for all patients using micro-simulation modeling. Tailoring HCC screening efforts to individual risk and screening test performance moves beyond the current “one-size-fits-all” strategy and aligns HCC screening with the principles of precision medicine. Our proposed HCC screening strategy would maximize screening benefits and minimize screening harms for each patient, thereby optimizing overall HCC screening value in the United States. 2