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

Completed

• Conditions: Barretts Esophagus With Dysplasia; Esophagus Cancer; Barrett Adenocarcinoma; Barrett Esophagus, Long-Segment; Reflux Disease; Esophageal Cancer Stage; Esophageal Cancer; Barrett Epithelium; Barrett's Esophagus Without Dysplasia; Barretts Esophagus With High Grade Dysplasia
• Interventions: Diagnostic Test: EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)

• Registration Number: NCT06381583
• Lead Sponsor: City of Hope Medical Center

Brief Summary

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.

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 Timeline

• Study Start: 2023-04-15
• Study First Submitted: 2024-04-19
• Study First Submitted QC: 2024-04-19
• Primary Completion: 2024-04-24
• Study Completion: 2024-04-24
• Study First Posted: 2024-04-24
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-08
• Last Update Posted: 2024-05-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 658

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients with Esophageal Adenocarcinoma [Malignant Tissue]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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)
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Training Cohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.
Patients with Esophageal Adenocarcinoma [Matching Normal Tissue]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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)
Patients with Low-Grade Dysplasia or Long Segment Barrett's Esophagus [Test Cohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Test Cohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Training]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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)
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Validation]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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)
Patients with Low-Grade Dysplasia or Long Segment Barrett's Esophagus [ValidationCohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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
Individuals Without Esophageal Adenocarcinoma or Barrett's Esophagus [Validation Cohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	Individuals who underwent endoscopy and were found not to have any Barrett's Esophagus or adenocarcinoma.
Patients with Esophageal Adenocarcinoma or High-Grade Dysplasia Barrett's Esophagus [Test Cohort]	EMERALD (Esophageal MicroRNAs for BaRRett's esophagus, Adenocarcinoma, and Dysplasia)	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)

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States