Chemoprevention of HCC related to MAFLD

代谢（功能障碍）相关性脂肪肝（MAFLD）现在是最重要的危险因素之一， 目前，没有肝脏特异性疗法被批准用于患有肝细胞癌（HCC）的个体。 MAFLD。可能阻断肝癌发生的治疗-即，化学预防-是唯一可行的解决方案 阻止MAFLD相关HCC的上升趋势。在这种情况下，三类药物（他汀类药物，二甲双胍， 和格列酮）具有很大的前景，因为它们作用于不同的代谢和/或应激反应， 在MAFLD相关肝癌发生中重要的途径，通常用于治疗代谢紊乱， 并且广泛可用。据我们所知，没有研究探讨MAFLD中HCC的化学预防。有 关于这些药物潜在危害的信息也有限，尤其是肝脏相关不良事件（AE） 这在MAFLD患者中可能很常见。化学预防的益处和危害可能是不同的 在不同的分组中。我们的研究将评估用这些药物进行HCC化学预防的益处和危害。 MAFLD患者的三种有前景的疗法。为此，我们将使用、扩大和扩展 先前组装的，充分表征的MAFLD患者的全国队列，具有广泛的纵向临床， 药房和实验室数据与癌症登记处、死亡登记处和临床医生的详细信息相关联 notes.使用这个队列，作为初步工作的一部分，我们显示了MAFLD和 并报道了代谢特征对HCC风险的累加效应。目标1（ 化学预防），我们将进行一系列精心设计的研究，以评估化学预防 他汀类药物（与无他汀类药物相比）、二甲双胍（与无二甲双胍相比）和吡格列酮（与无吡格列酮相比）在 降低HCC发生的风险。我们还将评估化学预防效应的异质性， 重点关注伴有和不伴有肝硬化的MAFLD患者，那些具有不同严重程度的共存代谢特征的患者， 并进行剂量-持续时间分析，以指导量身定制的化学预防。对于目标2（ 化学预防），我们将使用机器学习的创新，然后手动审查医疗图表 对纳入研究的患者中的潜在药物相关AE进行全面比较评价 目标1模拟试验。研究表明，遗传因素有助于对癌症的反应差异 化学预防在目标3（受益的遗传决定因素）中，我们将使用来自一项正在进行的前瞻性研究的数据。 MAFLD-肝硬化患者队列，以检查少数可能改变MAFLD-肝硬化的可疑遗传标记。 二甲双胍和/或他汀类药物在MAFLD-肝硬化患者中的化学预防作用。我们的研究是 重要的是，它将告知指导方针，关于谁，何时以及如何推荐化学预防， MAFLD患者除了阐明在一般MAFLD人群中的潜在化学预防作用外， 我们强调个性化的化学预防是新颖的。

Metabolic (dysfunction) associated fatty liver disease (MAFLD) is now one of the most important risk factors for hepatocellular cancer (HCC) in the U.S. Currently, no liver-specific therapies are approved for individuals with MAFLD. Therapy that may block hepatocarcinogenesis – i.e., chemoprevention – is the only practical solution to stem the rising tide of MAFLD-related HCC. In this context, three classes of medications (statins, metformin, and glitazones) hold substantial promise because they act on different metabolic and/or stress-response pathways important in MAFLD-related hepatocarcinogenesis, are commonly used to treat metabolic disorders, and widely available. To our knowledge, no study has examined HCC chemoprevention in MAFLD. There is also limited information about potential harms of these drugs, especially liver related adverse events (AEs) which may be common in persons with MAFLD. The benefits and harms of chemoprevention are likely different in different subgroups. Our study will evaluate the benefits and harms of HCC chemoprevention with these three promising therapies in individuals with MAFLD. To do so, we will use, expand and extend a previously assembled, well-characterized national cohort of MAFLD patients with extensive longitudinal clinical, pharmacy, and laboratory data linked to detailed information from cancer registry, death registry and clinician notes. Using this cohort, and as part of preliminary work, we showed a strong association between MAFLD and HCC and reported an additive effect of metabolic traits on HCC risk. For Aim 1 (benefits of chemoprevention), we will perform a series of carefully designed studies to evaluate the chemopreventive effects of statins (vs. no statins), metformin (vs. no metformin) and pioglitazone (vs. no pioglitazone) in reducing risk of incident HCC. We will also assess the heterogeneity of chemopreventive effects, with specific focus on MAFLD patients with and without cirrhosis, those with varying severity of co-existing metabolic traits, and perform dose-duration analyses to guide tailored chemoprevention. For Aim 2 (harms of chemoprevention), we will use innovations in machine learning followed by manual review of medical charts to conduct a comprehensive comparative evaluation of potential drug-related AEs among patients included in Aim 1 emulated trials. Studies show that genetic factors contribute to differences in response to cancer chemoprevention. In Aim 3 (genetic determinants of benefits), we will use data from an ongoing prospective cohort of patients with MAFLD-cirrhosis to examine few suspected genetic markers that may modify the chemopreventive effects of metformin and/or statins in individuals with MAFLD-cirrhosis. Our research is significant because it will inform guidelines about who, when and how to recommend chemoprevention in patients with MAFLD. Besides elucidating a potential chemopreventive effect in the general MAFLD population, our emphasis on personalized chemoprevention is novel.