Early Detection and Recurrence of Colorectal Adenomas by Combination of Eight Cancer-Associated Biomarkers in Plasma

Abstract

Introduction

Plasma levels of eight combined proteins have shown value as biomarkers for detection of colorectal cancer (CRC). However, their value in identifying colorectal adenoma needs further evaluation. The aim was to evaluate the eight proteins (AFP, CA19-9, CEA, CyFra21-1, Ferritin, Galectin-3, hs-CRP and TIMP-1) in detection of high-risk adenoma (HRA) and in prediction of recurrence of adenoma. Furthermore, the discrimination between HRA and low-risk adenoma (LRA) or CRC lesions was evaluated.

Methods

The study included 4698 individuals undergoing diagnostic colonoscopy. Automated ELISA platforms were used in the determination of protein levels in samples collected just before colonoscopy.

Results

Univariably, five proteins (AFP, CEA, CyFra21-1, hs-CRP and TIMP-1), respectively, significantly discriminated individuals with HRA from individuals with non-malignant findings. Multivariably, the combination of CEA and hs-CRP improved performance; AUC= 0.63 (sensitivity=0.19 at specificity=0.90). CyFra21-1, Ferritin and TIMP-1 demonstrated significant discrimination between individuals with HRA and LRA in univariable analyses, respectively. Performance was improved in multivariable analysis; AUC=0.61 (sensitivity=0.13 at specificity=0.90). Discrimination between individuals with colorectal adenomas and healthy individuals was significant for CA19-9, CEA, hs-CRP and TIMP-1, respectively, in univariable analyses. Multivariable analysis improved performance; AUC=0.63 (sensitivity=0.17 at specificity=0.90). All proteins except AFP demonstrated significant discrimination between individuals with HRA and CRC. Combination of CEA, CyFra21-1, Ferritin, hs-CRP and TIMP-1 in multivariable analysis improved discrimination; AUC=0.78 (sensitivity=0.34 at specificity=0.90). Association between plasma levels of any of the eight proteins and recurrence of colorectal adenomas after endoscopic removal could not be demonstrated.

Discussion

The protein panel shows a promising potential in detection of colorectal adenomas in general, but specifically of HRA. However, improvements are needed for the panel to be valuable as a screening test. Finally, plasma levels of the eight proteins were not predictive of recurrence of colorectal adenomas.

Keywords:

• biomarkers
• tumor
• neoplasm recurrence
• local
• colorectal adenomas
• colorectal neoplasms
• alpha-feto protein
• cancer antigen 19-9
• carcino embryogenic antigen
• cytokeratin fragment 21-1
• Ferritin
• Galectin-3
• high sensitivity C-reactive protein
• tissue inhibitor of metalloproteinases-1

Abbreviations

AFP, alpha-feto protein; AUC, area under the ROC curve; CA19-9, cancer antigen 19-9; CEA, carcino embryogenic antigen; CRC, colorectal cancer; CyFra21-1, cytokeratin Fragment 21-1; ELISA, enzyme-linked immunosorbent assay; HR, hazard ratio; HRA, high-risk adenoma; Hs-CRP, high sensitivity C-reactive protein; LRA, low-risk adenoma; OR, odds ratio; ROC, receiver operating characteristic; TIMP-1, tissue inhibitor of metalloproteinases-1.

Ethics Approval and Informed Consent

The Ethics Committee of the Capital Region of Denmark (H‐3‐2009‐110) and the Danish Data Protection Agency (2007‐58‐0015) approved the study, which was performed according to the Declaration of Helsinki II. Informed consent was signed by all participating individuals on the day of the colonoscopy.

Data Sharing Statement

All data can be presented by contacting corresponding author.

Acknowledgments

The research nurses, secretaries and technicians at the participating hospital departments and laboratories are thanked for their skillful work.

Abbott Laboratories Inc. (Abbott Park, Il, USA) is thanked for the protein analyses at their Center of Excellence (VUMC, Amsterdam, The Netherlands).

Disclosure

Hans Jørgen Nielsen reports grants and non-financial support from Abbott Laboratories Inc., Chicago, USA, outside the submitted work. The authors report no other potential conflicts of interest for this work.

Additional information

Funding

The study received financial support from The Andersen Isted Fund, The Augustinus Foundation, The Beckett Fund, The Inger Bonnén Fund, The Hans & Nora Buchard Fund, CEO Jens Bærentsen (private donation), The Walter Christensen Family Fund, The P.M. Christiansen Family Fund, The Aase & Ejnar Danielsen Fund, The Erichsen Family Fund, The Knud & Edith Eriksen Fund, The Svend Espersen Fund, The Elna and Jørgen Fagerholt Fund, The Sofus Carl Emil Friis Fund, The Torben & Alice Frimodt Fund, The Eva & Henry Frænkel Fund, The Gangsted Fund, The Thora & Viggo Grove Fund, The H Foundation, The Erna Hamilton Fund, The Sven & Ina Hansen Fund, The Søren & Helene Hempel Fund, The Henrik Henriksen Fund, The Jørgen Holm Family Fund, Foundation Jochum, The KID Fund, The Kornerup Fund, The Linex Fund, The Dagmar Marshall Fund, The “Midtjyske Bladfund”, The Axel Muusfeldt Fund, The Børge Nielsen Family Fund, The Michael Hermann Nielsen Fund, The Arvid Nilsson Fund, The Obel Family Fund, The Krista & Viggo Petersen Fund, The Willy & Ingeborg Reinhard Fund, The Kathrine & Vigo Skovgaard Fund, The Toyota Fund, The Vissing Fund, The Wedell-Wedellsborg Fund and Hvidovre University Hospital (The Capital Region of Denmark).