Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers

Abstract

BackgroundPrograms for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements.ObjectivesThe protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT.MethodsIn Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms.ResultsWe anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination.ConclusionsThe purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers.

Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?

“…At present, the available results of biomarker examinations added to colonoscopy is not sufficient, however, to recommend a blood test in addition to diagnostic colonoscopy. Future results from major studies may lead to such considerations [24].…”

Serological biomarkers in triage of FIT-positive subjects?

“…We recently completed the accrual of Part 1 of the Endoscopy III validation study on blood-based biomarkers for early detection of neoplastic lesions, including CRC [1]. The primary aim of the study, which followed the REMARK guidelines [2], was to collect blood samples and data from >8000 subjects screened positive with FIT; analyses of various biomarkers can be used to develop and validate a blood test for screening of CRC either as single testing or in combination with FIT [1].…”

“…The primary aim of the study, which followed the REMARK guidelines [2], was to collect blood samples and data from >8000 subjects screened positive with FIT; analyses of various biomarkers can be used to develop and validate a blood test for screening of CRC either as single testing or in combination with FIT [1]. The final inclusion comprised blood samples, demographic data, occult blood (FIT) concentration (100 FIT <1000 ng/ml) and subsequent colonoscopy data from 8415 subjects with a positive FIT result and in addition blood samples and demographic data from 5118 subjects with a negative FIT result [35 < FIT <100 ng/ml (35 ng/ml is the detection limit)]; subjects with negative FIT results did not undergo colonoscopy.…”

“…The next steps in further evaluating triage in FIT screening will include analyses of all 13,533 Endoscopy III Part 1 samples, interpretation of the results to settle the optimal FIT cut-off level, inclusion of additional biomarker entities such as proteins, DNA methylations, miRNA, metabolomes, etc. [1,[5][6][7][8][9][10][11][12] in various combinations, focus on logistics including considerations of on-site or regional analyses and the timeframe between FIT result and blood collection, interpretation of the analysis results at the end-user level, and in particular cost/benefit issues. Indeed, based on the present, preliminary results an on-line algorithm will be developed and applied on results of the remaining samples.…”

Triage May Improve Selection to Colonoscopy and Reduce the Number of Unnecessary Colonoscopies

“…The discrepancy may be well explained based on the current achievements, which show significantly higher levels of cancer-associated protein biomarkers among symptomatic subjects compared to screened subjects [ 37 ]. Although future research on biomarker discovery, which may have focus on symptomatic subjects or even patients with a final malignant diagnosis is still acceptable, subsequent training and validation need to concentrate on sufficiently sized and well-performed screening studies [ 38 ].…”