Precision Screening for Hepatocellular Carcinoma in Patients with Cirrhosis

项目摘要/摘要 肝细胞癌的死亡率正在上升，预计它将成为世界上第三大致癌原因。 到2030年，美国的癌症死亡人数。考虑到早期肿瘤检测和提高存活率之间的关联， 多个国家专业协会建议使用腹部超声进行筛查，无论有没有 高危个体每6个月检测一次血清生物标记物甲胎蛋白(AFP)，包括所有患有 肝硬变。然而，由于我们目前早期的局限性，大多数肝细胞癌患者的诊断都是在晚期。 检测策略。对于所有的肝硬变患者，超声和甲胎蛋白的策略是不够的，原因有三：1) 它忽略了肝硬变患者之间肝癌风险的异质性；2)它忽略了当前较差的准确性 筛查试验；3)它忽略了患者之间筛查试验表现的低可靠性。 我们的建议的目标是开发和评估一种用于肝癌早期检测的精确医学策略 与个体风险和筛查测试表现相匹配的最佳筛查测试的肝硬变患者。 我们将利用2000名肝硬变患者的前瞻性队列研究来评估 结合新生物标志物的风险分层和早期检测模型。具体来说，我们建议： 目标1：开发和验证包含以血液为基础的风险分层模型的性能 分子标志物小组对肝硬变患者发生肝细胞癌的风险分层 目的2：比较两种基于生物标志物的肝细胞癌早期检测策略的性能。 Doylestown Plus和纵向生物标记物算法在不同的肝硬变患者队列中的应用 目标3：使用微观模拟建模，比较定制早期检测策略的成本效益 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 我们的建议利用两项前瞻性队列研究，对2000名肝硬变患者进行评估 基于生物标记物的肝细胞癌风险分层和早期检测模型。我们使用这些数据来比较 为所有患者量身定制的早期检测策略与目前的超声和甲胎蛋白检测策略的有效性 采用微观仿真建模。根据个体风险和筛查测试量身定做早期肝癌检测工作 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早期检测策略将最大限度地提高筛查效益和 将每个患者的筛查危害降至最低，从而优化美国的肝细胞癌筛查价值。

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.