Validation of Biomarkers for predicting Barrett's esophagus that will or will not: i) progress towards cancer, or ii) recur after ablation

摘要 这项EDRN-CVC提案旨在验证区分高和低的分子生物标志物 高危食道肿瘤(Barrett‘s食道)的选择和治疗 患者接受内窥镜根治治疗(EET)。提出了两项验证研究：第一，阶段4 一项前瞻性研究，旨在确定可以免于EET的低进展风险患者组；第二阶段， 3进行回顾性研究以区分接受EET治疗的患者的低风险和高风险 复发。Barrett‘s食道(BE)是食管腺癌的前驱病变。 其致死率为80%，其发病率在过去30年中增加了7倍以上。BE进展到 EAC以循序渐进的方式从非发育不良BE到低度异型增生(LGD)，再到高度异型增生(HGD)， 最后是癌症。EAC预防的基础是在HGD进展为EAC之前使用EET消融HGD BE。 然而，EET也日益成为LGD的默认治疗方法，这是一种高度不准确的诊断 专家病理学家经常不同意这一点，而且在某些情况下，这种方法适用于多达40%的BE患者 在他们的课程中。由于EET有9%的并发症发生率，结果是出现了一种新的过度治疗流行病 和LGD在一起。在之前的EDRN-BDL奖中，我们的团队开发了用于早期检测 是进步。在BAD中，我们使用刷牙设备对患者的完整BE食管段进行采样。然后我们 使用下一代测序技术(为液体活组织检查开发的)分析了该样本的DNA 化验)，以检测在特定驱动程序上获得收益或损失的BE克隆的存在 与EAC相关的染色体。检测司机染色体变化(称为非常糟糕)，典型的EAC 和HGD。相比之下，28%的LGD患者完全不存在任何染色体异常克隆(称为 还不错)。我们现在将验证不错的生物标志物，以识别进展风险如此低的LGD 不需要EET。我们将通过与SURVENT试验合作来实现这一点，这将是美国第一项前瞻性研究 对LGD患者进行监测，而不是消融。EET的第二个主要挑战是 25%的患者消融后复发(具有BE、HGD或EAC的高危)。这些患者面临着巨大的 EET后监测内窥镜检查的负担，最初每3个月一次。在我们之前的EDRN-BDL中，我们的 研究小组确定了一组甲基化的DNA生物标志物，用于敏感的分子早期检测BE(目前 荣获FDA突破性设备称号)。我们进一步确认，这些标记仍然保留着 在EET后的一组患者中。因此，我们现在建议进行一项回顾的第三阶段研究，以进一步验证 这些用于微小残留病分子评估的DNA标记，其在EET后的消除识别 实现BE分子彻底根除的个人，因此疾病复发和不复发的风险较低 需要严密的EET后监控。我们通过与独特的UNC-BEECAB生物资源库合作来实现这一点 EET后食道活检的患者，其疾病在消融后复发或未复发。

Abstract This EDRN-CVC proposal is aimed at the validation of molecular biomarkers for distinguishing high versus low risk esophageal neoplasias (Barrett’s esophagus) for the purpose of guiding selection and management of patients for endoscopic eradication therapy (EET). Two validation studies are proposed: the first, a phase 4 prospective study to identify a patient group at low progression risk who can be spared EET; the second, a phase 3 retrospective study to distinguish individuals who following EET are at low versus high risk of disease recurrence. Barrett’s esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EAC), a cancer with 80% lethality whose incidence has increased more than 7-fold in the past three decades. BE progresses to EAC in a step-wise fashion from non-dysplastic BE, to low grade dysplasia (LGD), to high grade dysplasia (HGD), and finally cancer. EAC prevention is based on using EET to ablate HGD BE before it can progress to EAC. However, increasingly, EET is also becoming the default therapy for LGD, a highly imprecise diagnosis about which expert pathologists frequently disagree, and which is applied to as many as 40% of BE patients at some point during their course. As EET has a 9% complication rate, the result is an emerging epidemic of overtreatment of BE with LGD. In a prior EDRN-BDL award, our team developed the “BAD” technology for early detection of BE progression. In BAD, we used a brushing device to sample a patient’s full BE esophageal segment. We then analyzed the DNA from this sample using next-generation sequencing technology (developed for liquid biopsy assays) to instead detect presence of BE clones that had acquired gains or losses on specific driver chromosomes associated with EAC. Detection of driver chromosome changes (dubbed Very-BAD), typified EAC and HGD. In contrast, 28% of LGD showed complete absence of any chromosomally aberrant clones (dubbed Not-BAD). We will now validate Not-BAD as a biomarker that identifies LGD at such low progression risk as to not require EET. We will do this by partnering with the SURVENT trial, that will be the first U.S. prospective study to follow LGD patients managed by surveillance, not ablation. A second major challenge with EET is that over 25% of patients recur following ablation (with either high risk BE, HGD, or EAC). These patients face a substantial burden of post-EET surveillance endoscopies, initially at every 3-month intervals. In our prior EDRN-BDL, our team identified a panel of methylated DNA biomarkers for sensitive molecular early detection of BE (currently awarded FDA breakthrough device designation). We have further identified that these markers remain retained in a subset of patients post-EET. We accordingly now propose a retrospective Phase 3 study to further validate these DNA markers for molecular assessment of minimal residual disease, whose post-EET elimination identifies individuals achieving complete molecular eradication of BE, and hence at low risk of disease recurrence and not in need of intense post-EET surveillance. We do this by partnering with the unique UNC-BEECAB biorepository of post-EET esophageal biopsies from patients whose disease did or did not recur following ablation.