Early Detection of Advanced Adenomas and Colorectal Cancer

Recruiting

• Conditions: Colorectal Cancer; Colorectal Adenocarcinoma; Colorectal Disorders; Colorectal Adenoma With Mild Dysplasia; Colorectal Adenoma and Carcinoma 1; Colorectal Cancer Stage II; Colorectal Neoplasms Malignant; Colorectal Polyp; Colorectal Dysplasia; Colorectal Adenoma With Moderate Dysplasia
• Interventions: Diagnostic Test: DENEB

• Registration Number: NCT06342440
• Lead Sponsor: City of Hope Medical Center

Brief Summary

This study aims to develop a highly sensitive, specific, and cost-effective blood assay for early detection of colorectal adenomas and cancer, using advanced machine learning and state-of-the-art biological analyses.

Detailed Description

Colorectal cancer (CRC) is a significant global health concern, ranking third in diagnosis and second in mortality. Despite being potentially preventable, it remains a leading cause of cancer-related deaths. Traditional screening methods like fecal immunochemical testing (FIT) have shown benefits in reducing late-stage diagnoses but have not effectively prevented CRC incidence. This is because tests like FIT can effectively detect the cancers, but not the precursor lesions, called adenomas. On the other hand, endoscopy-first approaches offer higher sensitivity for such adenomas and, therefore, lower the risk of developing CRC but face 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 CRC and advanced adenomas (AAs). This is likely because they assume the same analyte can detect both CRC and AAs, which may not be accurate due to differences in analyte release and the biological changes that occur during the adenoma-carcinoma sequence.

This study proposes developing an innovative liquid biopsy test tailored for AAs and CRC 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, while those based on exosome-derived microRNA (exo-miRNA) offer high specificity. Therefore, combining both analytes in a single test could maximize sensitivity and specificity.

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

1. Genome-wide profiling of cf-miRNA and exo-miRNA and selecting the best candidates for biomarker panels.

2. Utilizing machine learning to identify promising candidates and train algorithms for detecting AAs and CRC separately, based on results from quantitative polymerase chain reaction (qPCR) analysis.

3. Combining these algorithms to create detection signatures for both conditions.

4. 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 AAs and CRC. Success could transform clinical practice by preventing CRC through early detection of pre-malignant lesions. Innovations include incorporating pre-malignant lesions into screening and combining cf-miRNA and exo-miRNA biomarkers for accuracy. This approach could reduce CRC mortality and incidence and pave the way for new clinical trials.

Study Timeline

• Study Start: 2020-03-15
• Study First Submitted: 2024-03-26
• Study First Submitted QC: 2024-04-01
• Study First Posted: 2024-04-02
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-06
• Last Update Posted: 2024-06-07
• Primary Completion: 2025-12-15
• Study Completion: 2025-12-15

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2000

Inclusion Criteria

• All individuals included in the study need to have had a colonoscopy 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

• Hereditary colorectal cancer syndromes (identified through genetic testing).
• Inflammatory bowel diseases.
• Lack of written informed consent.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Non-disease controls (Validation cohort)	DENEB	Individuals who underwent colonoscopy and were found not to have any adenomas or cancer.
Colorectal Cancer (Validation cohort)	DENEB	Individuals who underwent colonoscopy and were found to have colorectal cancer.
Low-risk Adenoma (Validation cohort)	DENEB	Individuals who underwent colonoscopy and were found to only have low-risk adenomas, defined as: * 1 to 4 adenomas at most. * All adenomas have low-grade dysplasia at most. * All adenomas are \<10 mm in diameter.
Advanced Adenoma (Training cohort)	DENEB	Individuals who underwent colonoscopy and were found to have high-risk adenomas, defined as one or more of the following: * 5 or more adenomas. * One or more adenomas have high-grade dysplasia. * One or more adenomas are \>10 mm in diameter.
Colorectal Cancer (Training cohort)	DENEB	Individuals who underwent colonoscopy and were found to have colorectal cancer.
Low-risk Adenoma (Training cohort)	DENEB	Individuals who underwent colonoscopy and were found to only have low-risk adenomas, defined as: * 1 to 4 adenomas at most. * All adenomas have low-grade dysplasia at most. * All adenomas are \<10 mm in diameter.
Non-disease controls (Training cohort)	DENEB	Individuals who underwent colonoscopy and were found not to have any adenomas or cancer.
Advanced Adenoma (Validation cohort)	DENEB	Individuals who underwent colonoscopy and were found to have high-risk adenomas, defined as one or more of the following: * 5 or more adenomas. * One or more adenomas have high-grade dysplasia. * One or more adenomas are \>10 mm in diameter.

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 (6)

The First Affiliated Hospital of Dalian Medical University; 🇨🇳 Dalian, China

Mie University; 🇯🇵 Mie, Japan

University of California San Diego; 🇺🇸 San Diego, California, United States

IRCCS San Raffaele; 🇮🇹 Milan, Italy

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

Barcelona University; 🇪🇸 Barcelona, Spain