Plasma TIMP-1 and CEA in detection of primary colorectal cancer: a prospective, population based study of 4509 high-risk individuals

Abstract

Objective. The combination of plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) and carcinoembryonic antigen (CEA) may be valuable biomarkers for early detection of colorectal cancer (CRC). A prospective, population based study was performed to validate this hypothesis. Material and methods. Individuals (n = 4509) referred for large bowel endoscopy due to symptoms of CRC were prospectively included. Baseline data and concurrent diseases were recorded. The primary endpoint was detection of CRC and findings at examinations were recorded using International Classification of Diseases-10 codes. Plasma was obtained before endoscopy and TIMP-1 and CEA levels were determined after the inclusion of all individuals. Results. Findings were based on sigmoidoscopy in 1766 and colonoscopy in 2743 individuals. Colon cancer (CC) was detected in 184 and rectal cancer in 110 individuals. Ten individuals with other cancers, 856 with adenomas and 1176 with non-neoplastic findings were also detected. The biomarker levels were increased in a variety of diseases including CRC compared to individuals without any findings at endoscopy. A multivariable analysis demonstrated that both markers were significant and independent detectors of CRC. Combining both biomarkers, independent contributions from each (TIMP-1, odds ratio (OR) = 1.8 (95% confidence interval (CI): 1.4–2.2), p < 0.0001; CEA < 5 ng/ml, OR = 1.6, 1.3–1.9, or ≥5 ng/ml, OR = 2.3, 95% CI: 1.9–2.7 (p < 0.0001)) were obtained. Subgroup analysis of individuals examined by colonoscopy with CC as the endpoint showed that combining both biomarkers, independent contributions from each (TIMP-1, OR = 2.5, 95% CI: 1.8–3.4, p < 0.0001; CEA < 5 ng/ml, OR = 1.4, 95% CI: 1.1–1.8, and CEA ≥ 5 ng/ml, OR = 2.3, 95% CI: 1.8–3.0 (p < 0.0001)) were obtained. Conclusions. This prospective validation study supports the use of the combination of plasma TIMP-1 and CEA protein measurements as a potential aid in early detection of CRC and specifically of CC.

Key Words::

• CEA
• colonoscopy
• colorectal cancer
• detection
• sigmoidoscopy
• TIMP-1

Acknowledgements

The staff at the surgical departments and endoscopy sections at the participating hospitals, at the departments of clinical biochemistry at Odense, Randers, and Aarhus hospitals, and at the departments of clinical biochemistry at Munich and Amsterdam Hospitals are thanked for their skillful work during the entire study period. The authors thank BS Nielsen and V Jensen for their valuable contribution regarding analysis of the samples using the MAC15 TIMP-1 ELISA platform. Finally, KV Jakobsen, MSc is thanked for linguistic corrections of the final manuscript.

Grant support: The Kornerup Fund, The Aase and Ejnar Danielsen Fund, The Aage and Johanne Louis-Hansen Fund, Den Midtjyske Bladfond, The Agnes and Poul Friis Fund, The Glunz and Jensen Fund, The Sophus and Astrid Jacobsen Fund, The Arvid Nilsson Fund, The Walter and O. Kristiane Christensen Fund, The Danish Bank Fund, The Johannes Fog Fund, The Eva and Henry Fraenkel Fund, The Hartmann Bros. Fund, The KID Fund, The Henrik Henriksen Fund, The King Christian X's Fund, The Lily Benthine Lund Fund, The Kathrine and Vigo Skovgaard Fund, The Oda and Hans Svenningsen Fund, The Else and Mogens Wedell-Wedellsborg Fund, The Einar Willumsen Fund, The Willy and Ingeborg Reinhard Fund, The Friedrich and Else Boehm Fund, The Toyota Fund, The IMK Foundation, The Danish Medical Research Council, The Beckett Fund, Hvidovre University Hospital, and The Danish Cancer Society.

Declaration of interest: For Hans J. Nielsen, Nils Brünner and Ib. J. Christensen, institution holds patents on TIMP-1 in colorectal cancer. Petra Stieber and Marinus Blankenstein are Consultants for Abbott Corp., Chicago, USA, Gerard Davis and Barry Dowell are Employees at Abbott Corp., Chicago, USA. Rest of the authors do not have any conflicting interest.