Diagnostic Accuracy of a Panel of Bacterial Gene Markers (M3) for Colorectal Advanced Neoplasia (M3-PRO)

A Prospective Cross-sectional Multi-center Study to Assess the Diagnostic Accuracy of a Panel of Bacterial Gene Markers (M3) for Colorectal Advanced Neoplasia

The investigators aim to evaluate and compare the diagnostic accuracy of FIT and the novel panel of bacterial gene markers (Fn, m3, Ch and Bc) collectively named as M3, in detecting colorectal advanced neoplasia.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms; Colorectal Cancer; Colorectal Adenoma
• Intervention / Treatment: Diagnostic test: Fecal immunochemical test (FIT)

Detailed Description

Colorectal cancer (CRC) is the one of the most common cancers in Hong Kong with more than 5,500 new cases annually. There is prevailing evidence of increasing trend of young onset CRC globally. Early detection and resection of pre-malignant colorectal neoplasia has shown to reduce CRC-related mortality.

Non-invasive stool tests including guaiac-based faecal occult blood tests (gFOBT) and faecal immunochemical tests (FIT) are the cornerstones of population-based CRC screening programmes. The major limitation of this widely used strategy is its unsatisfactory sensitivities for CRC (79%) and advanced adenomas (AA; 40%). The sensitivity for non-advanced adenomas is even lower than 10%. A large proportion of advanced and non-advanced adenomas will be missed by FIT alone. Therefore, identification of alternative non-invasive test with better sensitivity to detect colorectal neoplasia is warranted.

Multitarget stool DNA test and faecal microbial DNA markers appear to be promising options for CRC screening. Several bacterial gene markers have been identified by metagenome sequencing and reported to be associated with CRC, including Fusobacterium nucleatum (Fn), Clostridium hathewayi (Ch) and Bacteroides clarus (Bc). However, these molecular markers had low accuracy in distinguishing adenomas from normal tissue. Recently, a new Lachnoclostridium gene marker (labelled as 'm3') has been shown to have high diagnostic yield for the detection of colorectal adenomas. In a case-control study of 1012 subjects, a linear increasing trend of m3 level was observed from fecal samples of healthy subjects to those with adenomas and cancers. The overall sensitivity of m3 was significantly higher than FIT in detecting all adenomas (48% vs 9.3%), AA (50.8% vs 16.1%) and non-advanced adenomas (44.2% vs 0%). The diagnostic accuracy of m3 could be further enhanced by combining with a panel of fecal microbial markers composing of Fusobacterium nucleatum (Fn), Bacteroides clarus (Bc), Clostridium hathewayi (Ch) for CRC (82.3%) and adenomas (64.2%). We hypothesized that the combination of these 4 bacterial gene markers (known as M3) is more sensitive than FIT in detecting colorectal advanced neoplasia.

• Study Type: Observational
• Enrollment (Estimated): 2500

Contacts and Locations

• Study Contact: Name: Connie Seto; Phone Number: 6049 0760; Email: waiyiseto@cuhk.edu.hk
• Study Contact Backup: Name: Min Dai; Phone Number: 6049 0760; Email: mindai@link.cuhk.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Prince of Wales Hospital
    • Contact: Louis Lau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Subjects with average risk of colorectal neoplsia requring screening/surveillance colonoscopy

Description

Inclusion Criteria:

1. They require elective colonoscopy for colorectal cancer screening or polyp surveillance, or investigation of symptoms (e.g. anemia, change of bowel habit, abdominal pain);
2. Aged ≥18 years old;
3. Written informed consent obtained.

Exclusion Criteria:

1. Contraindications to colonoscopy (e.g. perforation, intestinal obstruction, unstable cardiopulmonary status);
2. Contraindication to polyp resection (e.g. active gastrointestinal bleeding, uninterrupted anticoagulation or dual antiplatelets);
3. Known colorectal cancer or adenoma for staged procedure;
4. Previous colonic resection;
5. Personal history of colorectal cancer;
6. Personal history of polyposis syndrome;
7. Personal history of inflammatory bowel disease;
8. Known pregnancy or lactation;
9. Advanced comorbid conditions (defined as American Society of Anesthesiologists grade 4 or above);

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Colorectal neoplasia screening/surveillance cohort; Subjects with average risk of colorectal neoplasias requiring screening/surveillance colonoscopy	Diagnostic test: Fecal immunochemical test (FIT); A kind of stool test; Other Names: Bacterial gene marker test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity of bacterial gene markers panel (M3)	The proportion of subjects with true positive results of M3 among those with one of more advanced neoplasia detected in the index colonoscopy.	1 month
Sensitivity of FIT/FOBT	The proportion of subjects with true positive results of FIT among those with one of more advanced neoplasia detected in the index colonoscopy.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sensitivity of M3 for early-stage (stage 1) or invasive (stage 2-4) colorectal cancers	The proportion of subjects with true positive results of M3 among those with early-stage (stage 1) or invasive (stage 2-4) colorectal cancers detected in the index colonoscopy.	1 month
Sensitivity of M3 for advanced adenomas	The proportion of subjects with true positive results of M3 among those with one or more advanced adenomas detected in the index colonoscopy.	1 month
Sensitivity of M3 for all adenomas	The proportion of subjects with true positive results of M3 among those with all advanced adenomas detected in the index colonoscopy.	1 month
Sensitivity of M3 for sessile serrated lesions (SSL)	The proportion of subjects with true positive results of M3 among those with SSLs detected in the index colonoscopy.	1 month
Sensitivity of FIT/FOBT for early-stage (stage 1) or invasive (stage 2-4) colorectal cancers	The proportion of subjects with true positive results of FIT among those with early-stage (stage 1) or invasive (stage 2-4) colorectal cancers detected in the index colonoscopy.	1 month
Sensitivity of FIT/FOBT for advanced adenomas	The proportion of subjects with true positive results of FIT among those with one or more advanced adenomas detected in the index colonoscopy.	1 month
Sensitivity of FIT/FOBT for all adenomas	The proportion of subjects with true positive results of FIT among those with all advanced adenomas detected in the index colonoscopy.	1 month
Sensitivity of FIT/FOBT for sessile serrated lesions (SSL)	The proportion of subjects with true positive results of FIT among those with SSLs detected in the index colonoscopy.	1 month
Specificity	The proportion of true negative results of M3/FOBT/FIT among those with no adenoma detected in colonoscopy	1 month
Positive predictive value (PPV)	The ratio of subjects truly diagnosed as positive to all those who had positive test results	1 month
Negative predictive value (NPV)	The ratio of subjects truly diagnosed as negative to all those who had negative test results	1 month
Overall diagnostic accuracy	The proportion of correctly classified subjects among all subjects	1 month
Microbiota changes in subjects with adenomas or normal findings after polypectomy	Microbiota change measured by qPCR or metagenomic sequencing	1 month

Collaborators and Investigators

• Sponsor: Chinese University of Hong Kong
• Collaborators: National Taiwan University Hospital; Changi General Hospital; Oxford University Hospitals NHS Trust; Dr Cipto Mangunkusumo General Hospital; Phramongkutklao College of Medicine and Hospital; Osaka International Cancer Institute; St. Mark's Hospital; Aster CMI Hospital; Sano hospital; Thingangyun Sanpya General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2022
• Primary Completion (Estimated): June 15, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 1, 2022
• First Submitted That Met QC Criteria: June 1, 2022
• First Posted (Actual): June 6, 2022

Study Record Updates

• Last Update Posted (Actual): August 27, 2024
• Last Update Submitted That Met QC Criteria: August 26, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Colonoscopy; FIT; Bacterial gene marker
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenoma
• Other Study ID Numbers: 2022.170

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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