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

验证用于预测巴雷特食管是否会发生以下情况的生物标志物：i) 进展为癌症，或 ii) 消融后复发

• 批准号: 10708890
• 负责人: CHETAN BETTEGOWDA
• 金额: $ 102.83万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708890
• 关键词: Aberrant DNA Methylation; Ablation; Algorithms; Aneuploidy; Award; Barrett Esophagus; Biological Assay; Biological Markers; Biopsy; Breakthrough device; Cessation of life; Chromosomes; Classification; Clinical; Complication; DNA; DNA Markers; DNA Methylation; DNA analysis; Detection; Devices; Diagnosis; Diagnostic; Disease; Disease Progression; Disease remission; Distal; Dysplasia; Early Detection Research Network; Early Diagnosis; Effectiveness; Endoscopy; Enrollment; Esophageal Adenocarcinoma; Esophageal Neoplasms; Esophagectomy; Esophagus; Excision; FDA approved; Face; Frequencies; Future; Guidelines; High grade dysplasia; Histology; Image; Immunohistochemistry; Incidence; Individual; Intestinal Metaplasia; Laboratories; Lesion; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of esophagus; Medical; Methods; Methylation; Molecular; Morbidity - disease rate; Natural History; North Carolina; Pathologist; Patients; Periodicals; Phase; Prevention; Prospective Studies; Publishing; Recommendation; Recording of previous events; Recurrence; Recurrent disease; Residual Neoplasm; Retrospective Studies; Risk; Role; Sampling; Societies; Squamous Epithelium; TP53 gene; Technology; Testing; Tissues; Universities; Validation; Vimentin; biobank; biomarker panel; biomarker performance; biomarker validation; commercialization; cost; digital imaging; disorder risk; epigenetic marker; falls; follow-up; high risk; liquid biopsy; molecular marker; mortality; neoplastic; new epidemic; next generation sequencing; overtreatment; patient stratification; patient subsets; phase 3 study; phase 4 study; predictive marker; premalignant; prevent; progression risk; prospective; risk stratification; routine practice; surveillance study; validation studies

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.

抽象的 此EDRN-CVC建议旨在验证分子生物标志物，以区分高与低 冒着食管肿瘤（巴雷特的食管）的风险，以指导选择和管理 内窥镜根除治疗（EET）的患者。提出了两项​​验证研究：第一个，第4阶段 前瞻性研究以识别一个可以免于EET的患者群体的患者群体；第二个阶段 3回顾性研究，以区分遵循EET的个体处于低风险与疾病的高风险 复发。巴雷特的食道（BE）是食管腺癌（EAC）的前体病变，一种癌症 在过去的三十年中，有80％的致命性增加了7倍以上。取得进展 EAC以逐步的方式从非塑性BE到低级发育不良（LGD），再到高级发育不良（HGD）， 最后是癌症。 EAC预防是基于使用EET来消融HGD，然后才能进展到EAC。 但是，越来越多的EET也成为LGD的默认疗法，这是一个高度暗示的诊断。 哪些专家病理学家经常不同意，并且在某些人中适用于多达40％的患者 他们的过程中的点。由于EET的并发症发生率为9％，因此结果是过度治疗的流行病 与LGD在一起。在先前的EDRN-BDL奖中，我们的团队开发了“不良”技术，用于早期发现 是进步。在不良情况下，我们使用刷牙装置对患者的全部为食管段进行了品尝。然后我们 使用下一代测序技术分析了该样品中的DNA（开发用于液体活检 测定）相反，要检测出在特定驾驶员上获得收益或损失的克隆的存在 与EAC相关的染色体。检测驾驶员染色体变化（称为非常糟糕），典型的EAC 和HGD。相反，LGD的28％完全没有任何染色体异常克隆（称为 不错）。现在，我们将验证不要将BAD视为一种生物标志物，该生物标志物识别出低进展风险的LGD 不需要EET。我们将通过与幸存的审判合作来做到这一点，这将是美国的首次前瞻性研究 跟随通过监视而不是消融管理的LGD患者。 EET的第二个主要挑战是 消融后25％的患者重复出现（高风险BE，HGD或EAC）。这些患者面临大量 毕业后监视内窥镜的负担，最初在每个3个月的间隔内。在我们先前的Edrn-BDL中 团队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（目前 授予FDA突破设备名称）。我们进一步确定这些标记仍然保留 在一部分患者中。因此，我们现在提出了一项回顾性3期研究，以进一步验证 这些DNA标记物用于最小残留疾病的分子评估，其后消除鉴定 在疾病复发的低风险下，实现BE的完全分子辐射的个体，而不是 需要强烈的毕业后监视。我们通过与独特的UNC-Beecab生物库合作来做到这一点 来自疾病后疾病或没有复发的患者的饮食后食管活检。