Precision Screening for Hepatocellular Carcinoma in Patients with Cirrhosis

项目总结/摘要 肝细胞癌（HCC）的死亡率正在上升，预计将成为第三大病因。 到2030年美国的癌症死亡率。考虑到早期肿瘤检测和提高生存率之间的关联， 多个国家的专业协会建议使用腹部超声进行筛查， 血清生物标志物，甲胎蛋白（AFP），每6个月在高危个体，包括所有患者 肝硬化然而，由于我们目前早期诊断的局限性，大多数肝癌患者在晚期才被诊断出来。 检测策略所有肝硬化患者的超声和AFP的策略是不够的，原因有3个：1） 它忽略了肝硬化患者之间HCC风险的异质性; 2）它忽略了当前诊断的准确性差。 筛查试验; 3）它忽略了患者之间筛查试验表现的可靠性差。 我们的提案的目标是开发和评估一种用于早期HCC检测的精确医学策略， 肝硬化患者的最佳筛查试验与个体风险和筛查试验性能相匹配。 我们将在2000例肝硬化患者中进行前瞻性队列研究， 风险分层和纳入新生物标志物的早期检测模型。具体而言，我们建议： 目的1：开发和验证风险分层模型的性能， 分子标记小组对肝硬化患者发生HCC的风险进行分层 目的2：表征和比较两种基于生物标志物的早期HCC检测策略的性能， 多尔斯敦Plus和纵向生物标志物算法在不同肝硬化患者队列中的应用 目标3：使用微观模拟建模，比较量身定制的早期检测策略的成本效益 根据个体HCC风险和当前标准策略的预期筛查测试性能， 所有肝硬化患者的超声和AFP 我们的建议利用两项前瞻性队列研究，2000例肝硬化患者，以评估新的 基于生物标志物的HCC风险分层和早期检测模型我们使用这些数据来比较 针对所有患者的超声和AFP当前策略的定制早期检测策略的有效性 使用微观模拟建模。根据个体风险和筛查测试调整早期HCC检测工作 绩效超越了目前的“一刀切”战略，并使HCC筛选符合以下原则 精准医疗的一部分。我们提出的HCC早期检测策略将最大限度地提高筛查益处， 最大限度地减少每个患者的筛查危害，从而优化美国HCC筛查价值。

PROJECT SUMMARY / ABSTRACT The mortality of hepatocellular carcinoma (HCC) is rising, and it is projected to become the 3rd leading cause of cancer death in the U.S. by 2030. Given the association between early tumor detection and improved survival, multiple national professional societies recommend screening using abdominal ultrasound with or without a serum biomarker, alpha fetoprotein (AFP), every 6 months in at-risk individuals, including all patients with cirrhosis. However, most HCC patients are diagnosed at a late stage due to limitations in our current early detection strategy. The strategy of ultrasound and AFP for all cirrhosis patients is inadequate for 3 reasons: 1) It ignores heterogeneity in HCC risk between cirrhosis patients; 2) It ignores the poor accuracy of current screening tests; and 3) It ignores poor reliability of screening test performance between patients. Our proposal’s goal is to develop and evaluate a precision medicine strategy for early HCC detection in patients with cirrhosis that matches the best screening test to individual risk and screening test performance. We will leverage prospective cohort studies among 2000 patients with cirrhosis to evaluate the performance of risk stratification and early detection models incorporating novel biomarkers. Specifically, we propose to: Aim 1: Develop and validate the performance of risk stratification models incorporating a blood-based molecular signature panel to risk stratify cirrhosis patients for developing HCC Aim 2: Characterize and compare the performance of two biomarker-based early HCC detection strategies, the Doylestown Plus and a longitudinal biomarker algorithm, in a diverse cohort of patients with cirrhosis Aim 3: Compare the cost effectiveness, using micro-simulation modeling, of a tailored early detection 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 two prospective cohort studies with 2000 cirrhosis patients, to evaluate novel biomarker-based models for HCC risk stratification and early detection. We use these data to compare the effectiveness of a tailored early detection strategy to the current strategy of ultrasound and AFP for all patients using micro-simulation modeling. Tailoring early HCC detection 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 early detection strategy would maximize screening benefits and minimize screening harms for each patient, thereby optimizing HCC screening value in the United States.