Progress in the field of noninvasive diagnostics for colorectal cancer: a systematic review for the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions

ABSTRACTBackground Early detection of pre-cancerous adenomas through screening can reduce colorectal cancer (CRC) incidence. Fecal immunochemical tests are commonly used, but have limited sensitivity for pre-cancerous lesions. Blood-based screening may improve test sensitivity. This systematic review and meta-analysis was conducted to evaluate the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions.Research design and methods We present the accuracy of blood-based biomarkers for detection of advanced pre-cancerous lesions. EMBASE, Web of Science and PubMed databases were searched, with study populations limited to adults diagnosed with advanced pre-cancerous lesions at colonoscopy, who had a blood-based biomarker test analyzed with reports of sensitivity and specificity.Results 69 studies were identified, which assessed 133 unique biomarkers sets. The best performing test was a panel of 6 miRNAs, with a sensitivity of 95% and specificity of 90% for advanced pre-cancerous lesions. Only 6 biomarkers demonstrated sensitivity ≥ 50% and specificity ≥ 90% for the detection of advanced pre-cancerous lesions.Conclusion Many different blood-based biomarkers have been assessed for detection of advanced pre-cancerous lesions, but few have progressed beyond the discovery stage. While some biomarkers have reported high sensitivity and specificity, larger prospective studies in unbiased intended-use screening populations are required for validation.KEYWORDS: Blood biomarkerctDNAadvanced adenomacolorectal cancerscreeningearly detectionsensitivitypreventionDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Declaration of InterestsErin L Symonds reports grants and in-kind support from Eiken Chemical Co. Ltd. and Clinical Genomics Pty Ltd. Graeme P Young was a paid consultant to Clinical Genomics and reports in kind support from Eiken Chemical Co. Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosurePeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contributionsAll authors have substantially contributed to the conception and design of the manuscript, and interpreting the relevant literature. All authors have been actively involved in writing and revising the manuscript for intellectual content. Rishabh Goyal (conceptualization, data collection, analysis and interpretation of results, writing and reviewing the article). Molla M Wassie (conceptualization, data collection, analysis and interpretation of results, writing and reviewing the article). Jean Winter (conceptualization, data collection, analysis and interpretation of results, writing and reviewing the article). Timothy JH Lathlean (conceptualization, data collection, analysis and interpretation of results, writing and reviewing the article). Graeme P Young (conceptualization, analysis and interpretation of results, reviewing the article). Erin L Symonds (conceptualization, data collection, analysis and interpretation of results, writing and reviewing the article). All authors reviewed the results and revised the manuscript before approving the final version.AcknowledgementsThis manuscript was previously presented as an abstract at Gastroenterological Society of Australia (GESA) Australian Gastroenterology Week (AGW), International Convention Centre Sydney (ICC Sydney), 9-11 September 2022.Ethical approval and participant consentEthical approval and participatory consent was not required as this manuscript involved the collection and synthesis of information from previously published studies, and did not directly involve human participants.Article HighlightsMany countries use fecal immunochemical tests (FIT) for colorectal cancer (CRC) screening. However, to achieve effective CRC prevention as well as detection, it is important that there is high sensitivity for detection of both advanced pre-cancerous lesions and CRC.Due to many countries reporting poor participation in FIT-based screening programs, there has been an increase in the development and validation of blood biomarkers for CRC screening.We identified 69 studies that assessed 133 unique blood biomarkers or panels of biomarkers for detection of advanced pre-cancerous lesions, with the main classes of biomarkers being protein, methylated DNA and microRNA.Only 6 studies included a prospective design conducted in the intended screening population (i.e. asymptomatic individuals undergoing colonoscopy for screening purposes).The pooled sensitivity for detection of advanced pre-cancerous lesions ranged from 15% to 78% and pooled specificity ranged from 75% to 100% for all classes of biomarkers. Only 6 different sets of biomarkers were reported to have a sensitivity ≥50% and a specificity ≥90%, but only one of these studies had a sample size of more than 100 advanced pre-cancerous lesions.Further work is needed to validate the most promising blood-based biomarkers in a screening population, to ensure that their performance and cost effectiveness is appropriate for screening programs.Figure 1: PRISMA flow diagram for selection of included studies for review and/or meta-analysis.Display full sizeFigure 2: Scatter plot of the sensitivity and specificity of different classes of biomarkers for detection of advanced pre-cancerous lesions in studies with a sample size over n=100. Size of the dot represents the sample size of the cohort. miRNA; microRNA.Display full sizeFigure 3. Forest plot demonstrating estimates of sensitivity and specificity for advanced pre-cancerous lesions for protein biomarkers assessed in studies with at least 100 cases of pre-cancerous lesions.Display full sizeFigure 4. Forest plot demonstrating estimates of sensitivity and specificity for advanced pre-cancerous lesions for methylated DNA biomarkers assessed in studies with at least 100 cases of pre-cancerous lesions.Display full sizeAdditional informationFundingThis manuscript was not funded.