Stratification of Cancer Risk in Patients with Non-Dysplastic Barrett's Esophagus using TissueCypher: The SCRiBE study

项目摘要 Barrett‘s食道(BE)，由异常柱状粘膜代替食道 胃食道反流病(GERD)所致的鳞状黏膜损伤是唯一已知的 食管腺癌(EAC)，一种致命的癌症，其发病率在过去几年中增加了八倍以上 在过去的50年里。在此期间，我们预防EAC死亡的主要战略基本上保持不变 不变-使用内窥镜筛查GERD患者的BE，并让BE患者参加 内窥镜检查。这一停滞不前的战略未能阻止EAC频率的上升，因为目前 筛查实践是不够的，而且因为监测依赖于发现异型增生，一种具有 相当大的缺陷，引发了癌症预防干预。新的筛查测试可用于 可以深刻地增加对BE患者的识别，但扩大筛查努力几乎没有意义 只是为了让更多的患者参加昂贵、无效的监测项目。组织密码被检测， 它可以在无不典型增生的BE活检组织中检测癌前分子和细胞的变化，具有 这可能是一种精确的风险分层测试，可能会改变BE患者的实践范式。 回顾病例对照研究，大量患者发展为异型增生和EAC， 结果表明，TisseCypher可以识别高风险和低风险的BE患者的肿瘤进展。但是，如果 TIseCypher将用于临床风险分层，那么这些研究在 “精挑细选”的BE患者群体将需要在普通人群中进行验证 发育不良BE(NDBE)。理想情况下，验证将以随机对照试验(RCT)的形式进行，但 对NDBE的这种研究需要大样本和长时间的跟踪调查 站不住脚。我们建议的研究使用一种替代的创新设计来评估TIseCypher的预测性 准确地执行，没有RCT的站不住脚的要求。我们已经在用活组织检查样本了 在大型社区GI实践中可用来建立一个由2000名连续患者组成的无偏见研究队列 谁在2008年至2011年接受了基线内窥镜检查，活组织检查显示为NDBE，以及谁进行了≥1随访 内窥镜检查一直持续到2021年12月。TIseCypher将在基线活检样本上运行，以及 我们将评估在随后的内窥镜检查中发现的它在预测肿瘤进展方面的表现。 活组织检查。我们还将确定TIseCypher的预测性能是否可以通过将 临床变量和增强的图像分析功能。验证TisseCypher对BE进行风险分层的能力 患者可以改变BE临床实践模式，从昂贵和无效的内窥镜检查 对高危患者早期干预的精准医学试验指导管理的监测 并减少了对低风险患者的监测。这将证明扩大BE筛查工作是合理的，并可能 以具成本效益的方式，遏止东区调校的频率不断上升。

Project Summary Barrett’s esophagus (BE), the condition in which an abnormal columnar mucosa replaces esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD), is the only known precursor of esophageal adenocarcinoma (EAC), a deadly cancer whose incidence has increased more than eight-fold over the past 50 years. During this time, our primary strategy for preventing EAC deaths has remained essentially unchanged - using endoscopy to screen GERD patients for BE, and enrolling BE patients in a program of endoscopic surveillance. This stagnant strategy has failed to stem the rising frequency of EAC because current screening practices are inadequate, and because surveillance relies on finding dysplasia, a biomarker with considerable shortcomings, to trigger a cancer-preventive intervention. New screening tests are available that could profoundly increase identification of BE patients, but it makes little sense to expand screening efforts merely to enter more patients into expensive, ineffective surveillance programs. The TissueCypher BE Assay, which can detect precancerous molecular and cellular changes in BE biopsies without dysplasia, has the potential to be a precision risk-stratification test that could change the practice paradigm for BE patients. Retrospective, case-control studies, heavily enriched with patients who developed dysplasia and EAC, have shown that TissueCypher can identify BE patients at high and low risk for neoplastic progression. However, if TissueCypher is to be used clinically for risk stratification, then the promising results of these studies in a “cherry-picked” population of BE patients will need validation in a general population of patients with non- dysplastic BE (NDBE). Ideally, validation would be in the form of a randomized, controlled trial (RCT), but the large sample size and lengthy follow-up durations required for such a study on NDBE have been deemed untenable. Our proposed study utilizes an alternative, innovative design to assess TissueCypher’s predictive performance accurately without the untenable requirements of an RCT. We will use biopsy specimens already available in a large community GI practice to establish an unbiased study cohort of 2,000 consecutive patients who had baseline endoscopies with biopsies showing NDBE in 2008-2011, and who had ≥1 follow-up endoscopies performed up to December 2021. TissueCypher will be run on baseline biopsy specimens, and we will assess its performance in predicting neoplastic progression as identified in subsequent endoscopic biopsies. We also will determine if TissueCypher’s predictive performance can be improved by incorporating clinical variables and enhanced image analysis features. Validation of TissueCypher’s ability to risk-stratify BE patients could shift the BE clinical practice paradigm from one of expensive and ineffective endoscopic surveillance to one of precision medicine test-guided management with early intervention for high-risk patients and reduced surveillance for low-risk patients. This would justify expanding BE screening efforts, and could stem the rising frequency of EAC in a cost-effective manner.