Diagnostic Accuracy of M3 in Predicting Colorectal Advanced Adenoma Recurrence (M3-AA)

Colorectal Adenoma Clinical Trial

— M3-AA  

Official title:

A Prospective Study to Assess the Diagnostic Accuracy of a Panel of Bacterial Gene Markers (M3) in Predicting Colorectal Advanced Adenoma Recurrence

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05144152
• Other study ID #: 2021.558
• Status: Recruiting
• Start date: December 13, 2021
• Est. completion date: June 15, 2025

Study information

• Verified date: March 2023
• Source: Chinese University of Hong Kong
• Contact: Min Dai
• Phone: +85260490760
• Email: mindai[@]link.cuhk.edu.hk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The investigators aim to evaluate the diagnostic accuracy of FIT and the novel panel of four bacterial gene markers collectively named as M3, to detect recurrent advanced adenomas in patients with history of colonic adenomas.

Description:

Colorectal cancer (CRC) is the most common cancer in Hong Kong with more than 5,600 new cases annually. There is prevailing evidence of increasing trend of young onset CRC globally. Early detection and endoscopic resection of pre-malignant colonic adenomas has shown to reduce CRC-related mortality.

After the index colonoscopy, a surveillance colonoscopy will be required at regular intervals, depending on the number, size and histology of colonic polyps. Studies have reported the use of faecal immunochemical test (FIT) to reduce the burden on surveillance endoscopy service. However, approximately 30-40% of interval CRC and 40-70% of advanced adenomas (AA) could be missed by this strategy. The major limitation of this widely used non-invasive stool test is its unsatisfactory sensitivities for CRC (79%) and 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 colonic adenomas is warranted.

Multitarget stool DNA test and faecal microbial DNA markers appear to be the most promising stool-based diagnostic biomarkers for screening CRC. 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%). The combination of these 4 bacterial gene markers (known as M3) has recently been proven to be useful in detecting adenoma recurrence after polypectomy in a retrospective study. The hypothesis is that it would be effective in the detection of recurrent advanced adenomas.

This prospective cohort study aims to evaluate the diagnostic accuracy of FIT and the novel panel of four bacterial gene markers (Fn, m3, Ch and Bc) collectively named as M3, to detect recurrent advanced adenomas in patients with history of colonic adenomas.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: June 15, 2025
• Est. primary completion date: December 15, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Known colorectal adenomas during index colonoscopy;

2. Available baseline M3 and FIT results before index colonoscopy;

3. Aged =18 years old;

4. Written informed consent obtained.

Exclusion Criteria:

1. Refusal or unfit to undergo surveillance colonoscopy;

2. Incomplete colonoscopy, incomplete removal of colorectal adenomas, or inadequate bowel preparation (defined as Boston Bowel Preparation Scale score 0 or 1 in any colonic segment) at index colonoscopy;

3. Previous colonic resection;

4. Personal history of colorectal cancer;

5. Personal history of polyposis syndrome;

6. Personal history of inflammatory bowel disease;

7. Known pregnancy or lactation;

8. Advanced comorbid conditions (defined as American Society of Anesthesiologists grade 4 or above);

Related Conditions & MeSH terms

• Adenoma
• Advanced Adenoma
• Colorectal Adenoma
• Colorectal Polyp
• Recurrence

Intervention

Diagnostic Test:
• M3
A panel of four bacterial gene markers (Fn, m3, Ch and Bc)
• FIT
faecal immunochemical test

Locations

Country	Name	City	State
Hong Kong	Prince of Wales Hospital	Shatin	New Territories

Sponsors (1)

Lead Sponsor	Collaborator
Chinese University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (12)

Amitay EL, Werner S, Vital M, Pieper DH, Hofler D, Gierse IJ, Butt J, Balavarca Y, Cuk K, Brenner H. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis. 2017 Aug 1;38(8):781-788. doi: 10.1093/carcin/bgx053. — View Citation

Flanagan L, Schmid J, Ebert M, Soucek P, Kunicka T, Liska V, Bruha J, Neary P, Dezeeuw N, Tommasino M, Jenab M, Prehn JH, Hughes DJ. Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. Eur J Clin Microbiol Infect Dis. 2014 Aug;33(8):1381-90. doi: 10.1007/s10096-014-2081-3. Epub 2014 Mar 6. — View Citation

Hassan C, Antonelli G, Dumonceau JM, Regula J, Bretthauer M, Chaussade S, Dekker E, Ferlitsch M, Gimeno-Garcia A, Jover R, Kalager M, Pellise M, Pox C, Ricciardiello L, Rutter M, Helsingen LM, Bleijenberg A, Senore C, van Hooft JE, Dinis-Ribeiro M, Quintero E. Post-polypectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2020. Endoscopy. 2020 Aug;52(8):687-700. doi: 10.1055/a-1185-3109. Epub 2020 Jun 22. — View Citation

Heitman SJ, Ronksley PE, Hilsden RJ, Manns BJ, Rostom A, Hemmelgarn BR. Prevalence of adenomas and colorectal cancer in average risk individuals: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009 Dec;7(12):1272-8. doi: 10.1016/j.cgh.2009.05.032. Epub 2009 Jun 10. — View Citation

Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014 Feb 4;160(3):171. doi: 10.7326/M13-1484. — View Citation

Liang JQ, Li T, Nakatsu G, Chen YX, Yau TO, Chu E, Wong S, Szeto CH, Ng SC, Chan FKL, Fang JY, Sung JJY, Yu J. A novel faecal Lachnoclostridium marker for the non-invasive diagnosis of colorectal adenoma and cancer. Gut. 2020 Jul;69(7):1248-1257. doi: 10.1136/gutjnl-2019-318532. Epub 2019 Nov 27. — View Citation

Liang JQ, Wong SH, Szeto CH, Chu ES, Lau HC, Chen Y, Fang J, Yu J, Sung JJ. Fecal microbial DNA markers serve for screening colorectal neoplasm in asymptomatic subjects. J Gastroenterol Hepatol. 2021 Apr;36(4):1035-1043. doi: 10.1111/jgh.15171. Epub 2020 Jul 15. — View Citation

Liang Q, Chiu J, Chen Y, Huang Y, Higashimori A, Fang J, Brim H, Ashktorab H, Ng SC, Ng SSM, Zheng S, Chan FKL, Sung JJY, Yu J. Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer. Clin Cancer Res. 2017 Apr 15;23(8):2061-2070. doi: 10.1158/1078-0432.CCR-16-1599. Epub 2016 Oct 3. — View Citation

Robertson DJ, Lee JK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, Kaltenbach T, Lieberman D, Levin TR, Rex DK. Recommendations on Fecal Immunochemical Testing to Screen for Colorectal Neoplasia: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017 Apr;152(5):1217-1237.e3. doi: 10.1053/j.gastro.2016.08.053. Epub 2016 Oct 19. — View Citation

Wong SH, Kwong TNY, Chow TC, Luk AKC, Dai RZW, Nakatsu G, Lam TYT, Zhang L, Wu JCY, Chan FKL, Ng SSM, Wong MCS, Ng SC, Wu WKK, Yu J, Sung JJY. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut. 2017 Aug;66(8):1441-1448. doi: 10.1136/gutjnl-2016-312766. Epub 2016 Oct 24. — View Citation

Yamaji Y, Mitsushima T, Ikuma H, Watabe H, Okamoto M, Kawabe T, Wada R, Doi H, Omata M. Incidence and recurrence rates of colorectal adenomas estimated by annually repeated colonoscopies on asymptomatic Japanese. Gut. 2004 Apr;53(4):568-72. doi: 10.1136/gut.2003.026112. — View Citation

Yu J, Feng Q, Wong SH, Zhang D, Liang QY, Qin Y, Tang L, Zhao H, Stenvang J, Li Y, Wang X, Xu X, Chen N, Wu WK, Al-Aama J, Nielsen HJ, Kiilerich P, Jensen BA, Yau TO, Lan Z, Jia H, Li J, Xiao L, Lam TY, Ng SC, Cheng AS, Wong VW, Chan FK, Xu X, Yang H, Madsen L, Datz C, Tilg H, Wang J, Brunner N, Kristiansen K, Arumugam M, Sung JJ, Wang J. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut. 2017 Jan;66(1):70-78. doi: 10.1136/gutjnl-2015-309800. Epub 2015 Sep 25. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sensitivity of the panel of bacterial gene markers (M3) or FIT in detection of recurrent colonic advanced adenomas	The proportion of subjects with true positive results of either M3 or FIT among those with one of more advanced adenomas detected during the surveillance colonoscopy examination at year 3	3 years
Secondary	Sensitivity for advanced adenomas (year 3)	The proportion of subjects with true positive results of either M3 or FIT among those with one of more advanced adenomas detected at year 3 colonoscopy	3 years
Secondary	Sensitivity for non-advanced adenomas (year 3)	The proportion of subjects with true positive results of either M3 or FIT among those with non-advanced adenomas detected at year 3 colonoscopy	3 years
Secondary	Sensitivity for all adenomas (year 3)	The proportion of subjects with true positive results of either M3 or FIT among those with all adenomas detected at year 3 colonoscopy	3 years
Secondary	Specificity (year 3)	Proportion of true negative results of M3/FIT among those with no adenoma detected in colonoscopy (year 3)	3 years