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 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）的目的是指导选择和管理 提议进行两项验证研究：第一项是 4 期研究。 前瞻性研究，以确定进展风险较低的患者群体，他们可以免受 EET 第二阶段； 3 项回顾性研究，用于区分接受 EET 的个体处于低疾病风险还是高疾病风险 巴雷特食管 (BE) 是食管腺癌 (EAC) 的前兆病变。 死亡率为 80%，其发病率在过去三十年中增加了 7 倍以上。 EAC 逐步从非发育不良 BE 到低度发育不良 (LGD)，再到高度发育不良 (HGD)， 最后，预防 EAC 的基础是在 HGD BE 进展为 EAC 之前使用 EET 消除它。 然而，EET 也逐渐成为 LGD 的默认疗法，LGD 是一种非常不精确的诊断。 病理学家专家经常不同意这一点，并且在某些情况下适用于多达 40% 的 BE 患者 由于 EET 的并发症发生率为 9%，其结果是过度治疗的流行。 在之前的 EDRN-BDL 奖项中，我们的团队开发了用于早期检测的“BAD”技术。 在 BAD 中，我们使用刷牙装置对患者的整个 BE 食管段进行取样。 使用下一代测序技术（为液体活检而开发）分析了该样本中的 DNA 化验）来代替检测在特定驱动程序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），以 EAC 为代表。 相比之下，28% 的 LGD 完全不存在任何染色体异常克隆（称为 HGD）。 Not-BAD）。我们现在将验证 Not-BAD 作为识别 LGD 进展风险如此低的生物标志物。 不需要 EET。我们将通过与 SURVENT 试验合作来做到这一点，这将是美国第一个前瞻性研究。 EET 的第二个主要挑战是通过监测而非消融来追踪 LGD 患者。 25% 的患者在消融后复发（具有高风险 BE、HGD 或 EAC）。这些患者面临着巨大的风险。 EET 后监测内窥镜检查的负担，最初每 3 个月一次。 研究小组确定了一组甲基化 DNA 生物标志物，用于敏感的 BE 分子早期检测（目前 授予 FDA 突破性设备称号）我们进一步确定这些标记仍然保留。 因此，我们现在建议进行一项回顾性 3 期研究以进一步验证。 这些用于分子评估微小残留病的 DNA 标记，其 EET 消除后可识别 个体实现完全分子根除BE，因此疾病复发的风险较低，并且不会 需要进行严格的 EET 后监测，我们通过与独特的 UNC-BEECAB 生物样本库合作来做到这一点。 对消融后疾病复发或未复发的患者进行 EET 后食管活检。