Enhanced Neoplasia Detection in Chronic ulcerative colitis: results of the ENDCaP-C Diagnostic accuracy study

Background Chronic ulcerative colitis is an inflammatory condition associated with a pro-neoplastic drive, predisposing to colorectal cancer. Repeated colonoscopy is undertaken to detect preneoplastic change, but cancer diagnosis is still frequently missed. Aims To determine if a predetermined panel of methylation markers could better risk stratify patients, aiding earlier detection of neoplasia. Methods ENDCaP-C () was a prospective multicentre test accuracy study of enhanced large bowel neoplasia detection and cancer prevention in patients with chronic ulcerative colitisAll patients underwent baseline colonoscopy and biopsies that had (on central review) shown no dysplasia on histology were put forward for methylation testing. In a prespecified subgroup of 200 patients without initial dysplasia detection, a second colonoscopy was performed, after 12 months. Results 818 patients underwent a baseline colonoscopy. The methylation assay at baseline (testing non-neoplastic mucosa) was compared with pathology assessment at baseline for neoplasia and showed a diagnostic odds ratio (DOR) of 2.37 (95% CI 1.46, 3.82, P=0.0002). Biopsy analysis was successful in 95% of patients within a multisite routine surveillance programme. The probability of dysplasia increased from 11.1% to 17.7% (13.0%, 23.2%) with a positive methylation result consistent with added value in neoplasia detection. To determine added value above ‘colonoscopy alone’, a second (reference) colonoscopy was performed in 193 patients without neoplasia. This test also showed an increased number of patients harbouring neoplasia but failed to reach statistical significance (DOR=1.50; 95% CI (0.48, 4.45) P=0.45) The results were also non-significant in the per protocol analysis (DOR=3.93; 95% CI (0.82, 24.75) P=0.09). Patients with persistent abnormal methylation findings at both colonoscopies were at further enhanced risk of neoplasia, 22% of cases (4/18), or 3x that of patients without methylation changes (7/98). Conclusion This methylation assay was successfully applied within a routine clinical surveillance programme. Blinded analysis confirmed improved rates of neoplasia detection. Although predetermined levels of statistical significance were not reached, the study has also shown that methylation testing can supplement existing clinical and pathological risk stratification, informing patient consent and anticipated dysplasia detection rates. Although not yet recommended for routine uptake, the finding suggest refined methylation assays could be applied for patient benefit. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial ISRCTN81826545 ### Clinical Protocols ### Funding Statement The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29). ADB was funded by a Cancer Research UK Advanced Clinician Scientist Fellowship (C31641/A23923). The funders had no input into the design or conduct of the study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval for ENDCaP-C was granted by South East Coast Surrey Research Ethics Committees (reference 14/LO/1842). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data not available as confidential health data