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

摘要 该EDRN-CVC提案旨在验证用于区分高与低的分子生物标志物。 风险食管肿瘤（巴雷特食管），以指导选择和管理 内镜下根除治疗（EET）的患者。提出了两项验证研究：第一，第4阶段 前瞻性研究，以确定一个患者组在低进展风险谁可以幸免EET;第二，阶段 3项回顾性研究，以区分EET后处于低风险与高风险疾病的个体 复发Barrett食管（BE）是食管腺癌（EAC）的前驱病变，EAC是一种癌症， 致死率为80%，其发病率在过去三十年中增加了7倍以上。BE进展为 EAC以逐步方式从非异型增生BE到低度异型增生（LGD），再到高度异型增生（HGD）， 最后是癌症。EAC预防基于在HGD BE发展为EAC之前使用EET消融HGD BE。 然而，EET也越来越多地成为LGD的默认疗法，LGD是一种高度不精确的诊断， 专家病理学家经常不同意，并且在某些情况下适用于多达40%的BE患者， 在他们的行程中。由于EET的并发症发生率为9%，其结果是过度治疗的流行 与LGD。在之前的EDRN-BDL奖项中，我们的团队开发了“BAD”技术，用于早期检测 BE进展。在BAD中，我们使用了一种刷拭装置对患者的整个BE食管段进行采样。然后我们 我使用下一代测序技术（为液体活检开发的）分析了该样本的DNA 测定）来检测在特定驱动因子上获得增益或损失的BE克隆的存在 与EAC相关的染色体。检测驱动染色体变化（称为Very-BAD），典型的EAC 和HGD。相比之下，28%的LGD显示完全没有任何染色体异常克隆（称为 Not-BAD）。我们现在将验证Not-BAD作为一种生物标志物，可以在如此低的进展风险下识别LGD， 不需要EET。我们将通过与SURVENT试验合作来实现这一目标，这将是美国第一项前瞻性研究。 随访通过监测而非消融治疗的LGD患者。EET的第二个主要挑战是， 25%的患者在消融术后复发（高风险BE、HGD或EAC）。这些患者面临着严重的 EET后监测内镜检查的负担，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DNA生物标志物，用于BE的敏感分子早期检测（目前 获得FDA突破性器械称号）。我们进一步确定这些标记仍然保留在 在EET后的患者亚组中。因此，我们现在提出一项回顾性3期研究，以进一步验证 这些DNA标记物用于微小残留病的分子评估，其EET后消除可识别 个体实现BE的完全分子根除，因此疾病复发风险低， 需要加强EET后的监控我们通过与独特的UNC-BEECAB生物储存库合作来实现这一目标 消融后疾病复发或未复发患者的EET后食管活检。

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.