Diagnostic Accuracy of M3 in Predicting Colorectal Advanced Adenoma Recurrence (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

Overview

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.

Detailed 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.

Interventions

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

Primary outcome measures

• Sensitivity of the panel of bacterial gene markers (M3) or FIT in detection of recurrent colonic advanced adenomas [Time frame: 3 years]

Secondary outcome measures (4)

• Sensitivity for advanced adenomas (year 3) [Time frame: 3 years]
• Sensitivity for non-advanced adenomas (year 3) [Time frame: 3 years]
• Sensitivity for all adenomas (year 3) [Time frame: 3 years]
• Specificity (year 3) [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

• Known colorectal adenomas during index colonoscopy;
• Available baseline M3 and FIT results before index colonoscopy;
• Aged ≥18 years old;
• Written informed consent obtained.

Exclusion criteria

• Refusal or unfit to undergo surveillance colonoscopy;
• 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;
• Previous colonic resection;
• Personal history of colorectal cancer;
• Personal history of polyposis syndrome;
• Personal history of inflammatory bowel disease;
• Known pregnancy or lactation;
• Advanced comorbid conditions (defined as American Society of Anesthesiologists grade 4 or above);

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Case-only

Study locations

Hong Kong · 1 center

• Prince of Wales Hospital — Shatin

Publications

• 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 PMID 26408641
• 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. PMID 32633422
• 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. PMID 27697996
• 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. PMID 27797940
• 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. PMID 24599709
• 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. PMID 28582482
• 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. PMID 31776231
• 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. PMID 19523536

Identifiers

NCT: NCT05144152 · 2021.558

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗