A Liquid Biopsy for High-risk Pre-cancer Screening of Esophageal Adenocarcinoma (EMERALD)

A Liquid Biopsy to Screen for Barrett's Esophagus, Dysplasia, and Esophageal Adenocarcinoma: the EMERALD Multi-center Study.

This study aims to develop a highly sensitive, specific, and cost-effective blood assay for the early detection of esophageal adenocarcinoma and its precursor lesions, using advanced machine learning and state-of-the-art biological analyses.

Study Overview

• Status: Recruiting
• Conditions: Esophageal Cancer; Esophageal Neoplasms; Gastroesophageal Reflux; Barrett Esophagus; Esophageal Adenocarcinoma; Reflux Disease; Barretts Esophagus With High Grade Dysplasia; Barrett Adenocarcinoma; Esophagus Cancer; Barrett's Esophagus Without Dysplasia; Barretts Esophagus With Dysplasia; Esophagus Adenocarcinoma; Barretts Esophagus With Low Grade Dysplasia; Esophageal Dysplasia; Barrett's Esophagus With Dysplasia, Unspecified; Esophageal Cancer Stage; Esophagus, Barrett; Esophageal Neoplasms Malignant; Barrett Epithelium; Barrett Esophagus, Long-Segment; Barrett's Esophagus With Esophagitis
• Intervention / Treatment: Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)

Detailed Description

Esophageal adenocarcinoma (EAC) is a significant global health concern, ranking second in lethality (after pancreatic cancer). Despite being potentially preventable, it remains a leading cause of cancer-related deaths. Traditional screening methods have relied on an endoscopy-first approach to screen for the precursor of EAC, which is Barrett's esophagus (BE). After BE detection, BE is then regularly surveiled to monitor the development of dysplasia, which can be treated to prevent malignant transformation. An endoscopy-first approach is sensitive BE and, therefore, it lowers the risk of developing EAC but it also faces challenges such as invasiveness, cost, and patient compliance.

Non-invasive tests are more appealing to patients than invasive tests and can increase participation rates. Biomarker studies have shown promise, but existing tests lack sensitivity for early-stage EAC and, most importantly, to its precursor lesion BE. This is likely because they over-sampled analytes that are primarily expressed at the EAC end of the spectrum, but not in BE yet during the BE to EAC sequence.

This study proposes developing an innovative liquid biopsy test tailored for EAC and BE to address this. An ideal screening test should be minimally invasive, highly sensitive, and cost-effective. This test would optimize patient compliance and resource allocation by detecting both conditions from a single blood draw. More specifically, circulating microRNA (miRNA) analysis shows promise: tests based on cell-free microRNA (cf-miRNA) have demonstrated high sensitivity.

This study will develop a non-invasive blood test for BE and EAC in four phases:

1. In silico genome-wide profiling of tissue miRNA to select the best candidates for biomarker panels.
2. Prioritization of the biomarkers that are differentially expressed across the entire continuum of BE to EAC sequence, compared to the normal mucosa
3. Transition of these biomarkers to a liquid biopsy assay, confirming their detectability in blood as well as their differential expression in cases compared to controls
4. Utilizing machine learning to identify the most promising candidates and train algorithms for detecting EAC and BE, based on results from quantitative polymerase chain reaction (qPCR) analysis.
5. Independently validating these signatures using diverse cohorts to ensure broad applicability and compare the effectiveness of the blood assay to standard care through retrospective and prospective studies.

This study aims to develop a highly sensitive, specific, and cost-effective liquid biopsy for early detection of BE and EAC. Success could transform clinical practice by preventing EAC through early detection of pre-malignant lesions. Innovations include incorporating pre-malignant lesions into screening. This approach could potentially reduce EAC mortality and incidence and pave the way for new clinical trials.

• Study Type: Observational
• Enrollment (Estimated): 1000

Contacts and Locations

• Study Contact: Name: Ajay Goel, PhD; Phone Number: 6262183452; Email: AJGOEL@COH.ORG

Study Locations

• United States
  • California
    • Duarte, California, United States, 91016
      • Recruiting
      • City of Hope Medical Center
      • Sub-Investigator: Alessandro Mannucci, MD
      • Contact: Ajay Goel, PhD; Phone Number: 626-218-3452; Email: AJGOEL@COH.ORG
      • Principal Investigator: Ajay Goel, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Four independent cohorts of individuals who belong to one of the following five

Negative endoscopic findings Barrett's esophagus, at least 3 cm long without low-grade dysplasia (at most) Barrett's esophagus, of any length, with low-grade dysplasia (at most) Barrett's esophagus, of any length, with high-grade dysplasia (at most) Esophageal adenocarcinoma (of any stage, including in situ [Tis]) Colorectal cancer

Description

Inclusion Criteria:

• All individuals included in the study need to have had an endoscopic evaluation at the time of blood sampling.
• Received standard diagnostic and staging (as necessary) procedures as per local guidelines, and at least one sample was drawn before receiving any curative-intent treatment.
• Received standard pathological and endoscopic diagnosis and assessment for cohort assignment.

Exclusion Criteria:

• Lack of written informed consent.
• Short segment Barrett's esophagus with no evidence of dysplasia
• Ultra-short segment Barrett's esophagus with no evidence of dysplasia

Study Plan

How is the study designed?

Number of groups / cohorts

10

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with Esophageal Adenocarcinoma [Malignant Tissue]; Individuals who underwent endoscopy and were found to only have one of the following: Esophageal adenocarcinoma of any stage; Esophageal adenocarcinoma confined to the mucosa (stage Tis)	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Esophageal Adenocarcinoma [Matching Normal Tissue]; Individuals who underwent endoscopy and were found to only have one of the following: Esophageal adenocarcinoma of any stage; Esophageal adenocarcinoma confined to the mucosa (stage Tis)	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Test Cohort]; Individuals who underwent endoscopy and were found to only have one of the following: Barrett's Esophagus, with high-grade dysplasia, independently of Barrett's segment length; Esophageal adenocarcinoma of any stage; Esophageal adenocarcinoma confined to the mucosa (stage Tis)	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Low-Grade Dysplasia or Long Segment Barrett's Esophagus [Test Cohort]; Individuals who underwent endoscopy and were found to only have Barrett's Esophagus, with one of the following: Craniocaudal maximal extension of 3 cm or more; Low-grade dysplasia at most, independently of Barrett's segment length	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Test Cohort]; Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Training]; Individuals who underwent endoscopy and were found to only have one of the following: Barrett's Esophagus, with high-grade dysplasia, independently of Barrett's segment length; Esophageal adenocarcinoma of any stage; Esophageal adenocarcinoma confined to the mucosa (stage Tis)	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Training Cohort]; Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Validation]; Individuals who underwent endoscopy and were found to only have one of the following: Barrett's Esophagus, with high-grade dysplasia, independently of Barrett's segment length; Esophageal adenocarcinoma of any stage; Esophageal adenocarcinoma confined to the mucosa (stage Tis)	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Patients with Low-Grade Dysplasia or Long Segment Barrett's Esophagus [ValidationCohort]; Individuals who underwent endoscopy and were found to only have Barrett's Esophagus, with one of the following: Craniocaudal maximal extension of 3 cm or more; Low-grade dysplasia at most, independently of Barrett's segment length	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Validation Cohort]; Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.	Diagnostic test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia); A panel of circulating microRNA, whose expression level is tested in cell-free derived samples.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity	True positive rate: the probability of a positive test result, conditioned on the individual truly being positive	Through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Specificity	True negative rate: the probability of a negative test result, conditioned on the individual truly being negative	Through study completion, an average of 1 year
Proportion of correct predictions (true positives and true negatives) among the total number of cases (i.e., accuracy)	A measure of trueness: proportion of correct predictions (both true positives and true negatives) among the total number of cases examined	Through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Investigators: Principal Investigator: Ajay Goel, PhD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2023
• Primary Completion (Estimated): June 18, 2026
• Study Completion (Estimated): June 18, 2026

Study Registration Dates

• First Submitted: April 19, 2024
• First Submitted That Met QC Criteria: April 19, 2024
• First Posted (Actual): April 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Screening; miRNA; Artificial Intelligence; Liquid biopsy; Surveillance; Early detection; Dysplasia; Cancer detection; Micro RNA; Long segment Barrett Esophagus
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Gastroenteritis; Head and Neck Neoplasms; Esophageal Motility Disorders; Deglutition Disorders; Esophageal Diseases; Precancerous Conditions; Neoplasms; Hyperplasia; Gastroesophageal Reflux; Adenocarcinoma; Esophageal Neoplasms; Barrett Esophagus; Esophagitis
• Other Study ID Numbers: 23228/EMERALD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No