A novel prognostic index in colorectal cancer defined by serum carcinoembryonic antigen and plasma tissue inhibitor of metalloproteinases-1

Abstract

Objective. The introduction of stage-independent prognostic markers may play a significant role in future selection for adjuvant treatment for early-stage colorectal cancer (CRC). The purpose of this study was to assess the combination of preoperative serum carcinoembryonic antigen (CEA) and plasma tissue inhibitor of metalloproteinases (TIMP)-1 as a prognostic index in patients with primary, curatively resected CRC. Material and methods. Blood samples were collected before surgery from 422 patients with CRC stage I–III (Dukes’ stage A–C). CEA was determined in serum by a routine analysis and TIMP-1 was determined in plasma using a validated in-house enzyme-linked immunosorbent assay. Disease-free survival (DFS) was registered and its associations with serum CEA and plasma TIMP-1 levels were studied using a Cox multivariate model. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for DFS were calculated. Results. An event was recorded in 186 patients: 75 had local recurrence, 75 had distant metastases, 28 had both local recurrence and distant metastases, and 36 died from their cancer without a registered recurrence. Scoring CEA and TIMP-1 as continuous variables on a logarithmic scale, serum CEA and plasma TIMP-1 were statistically significant in a multivariate analysis with HR = 1.1 (95% CI 1.0–1.2) and HR = 1.5 (95% CI 1.1–2.0), respectively. The two serological markers could be combined to form a prognostic index adjusted for baseline variables. This index showed a 51% increase in HR for a given CEA level if the TIMP-1 level was doubled. Conclusions. Preoperative serum CEA and plasma TIMP-1 levels are independent predictors of DFS in patients with primary resectable CRC. In combination these two proteins could form an index for the assessment of risk of disease recurrence in early-stage CRC.

Key Words::

• Biological markers
• carcinoembryonic antigen
• colorectal cancer
• prognosis
• tissue inhibitor of metalloproteinases-1

Acknowledgements

The authors thank Ms. Vibeke Jensen at the Laboratory of Disease Biology, Institute of Life Sciences, University of Copenhagen, Frederiksberg for analysis of TIMP-1 in plasma and the staff at the Department of Clinical Biochemistry at Hvidovre Hospital for analysis of CEA. In addition, the authors thank Ms. Karen Vibeke Jacobsen for linguistic correction of the final manuscript.

The study received financial support from: The Kornerup Fund (H. J. N. is Kornerup Professor of Experimental Surgical Oncology), The Aase and Ejnar Danielsen Fund, The Aage and Johanne Louis-Hansen Fund, The KID Fund, The Sophus and Astrid Jacobsen Fund, The Friedrich and Else Boehm Fund, The Walter and O. Kristiane Christensen Fund, The Danish Bank Fund, Den Midtjyske Bladfond, The Agnes and Poul Friis Fund, The Bjarne Jensen Fund, The Hartmann Bros. Fund, The Arvid Nilsson Fund, The Willy & Ingeborg Reinhard Fund, The Katrine and Vigo Skovgaard Fund, The Oda & Hans Svenningsen Fund, The Einar Willumsen Fund, The Danish Cancer Society, The Danish Medical Research Counsel, IMK Foundation and The Kaaresen Fund.

Declaration of interest: The authors and their institutions have submitted patent applications on CEA and TIMP-1 as biomarkers in colorectal cancer.