Elsevier

European Journal of Cancer

Volume 46, Issue 18, December 2010, Pages 3323-3331
European Journal of Cancer

Preoperative plasma TIMP-1 is an independent prognostic indicator in patients with primary colorectal cancer: A prospective validation study

https://doi.org/10.1016/j.ejca.2010.06.009Get rights and content

Abstract

Background

Previous studies have suggested plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) as a stage independent prognostic marker in colorectal cancer (CRC) patients. The aim was to validate plasma TIMP-1 and serum carcino-embryonic antigen (CEA) levels as prognostic indicators in an independent population-based cohort of patients with CRC.

Patients and methods

During 2000–2003, plasma and serum were collected preoperatively from 322 patients treated for primary CRC. TIMP-1 and CEA levels were determined by validated ELISA platforms.

Results

High TIMP-1 and CEA levels each associated with poor overall survival (OS); TIMP-1 (hazard ratio (HR) 2.1; 95% confidence interval (CI) 1.6–2.7) and CEA (HR 1.2; 95% CI 1.1–1.3), and disease-free survival (DFS); TIMP-1 (HR 2.0; 95% CI: 1.5–2.6) and CEA (HR 1.2; 95% CI: 1.1–1.4) in univariate analyses. In stratified analyses of stages II and III, TIMP-1 levels associated significantly with OS and DFS in stages II and III, associations were not found for CEA. Multivariate analysis for OS, including TIMP-1 and CEA levels and clinico-pathological baseline variables, revealed significant association of TIMP-1 (HR 1.8; 95% CI 1.3–2.4) but not CEA levels.

Conclusions

This independent prospective validation study confirms the significant association between preoperative plasma TIMP-1 levels and survival of CRC patients: TIMP-1 provided stronger prognostic information than CEA. Thus, this study brings plasma TIMP-1 to the next level of evidence for its clinical use as a prognostic marker in CRC patients.

Introduction

Colorectal cancer (CRC) is the most common cancer in Europe and ranks second as the cause of cancer-related deaths in developed countries.1 Although survival has improved, almost half of the patients with CRC are expected to die from their disease. About one-fifth of patients have non-curable metastatic disease at diagnosis and for those with curable disease, one-third will develop recurrent disease leading to death, despite the most modern surgical and oncological treatments.

Major expectations are laid on biomarkers for providing more precise prognostic information than the current tumour, lymph node and metastasis (TNM) staging system. Carcino-embryonic antigen (CEA), which has been studied as a marker of CRC since the 1960s, is the only soluble biomarker recommended for use in CRC, being recommended primarily for monitoring after primary surgery.2 As yet, no serological biomarkers have obtained sufficient evidence for routine clinical use in identifying poor prognosis stage II CRC patients, who might be candidates for adjuvant treatment, or good prognosis stage III patients, who could be saved from adjuvant chemotherapy or receive a more mild form for adjuvant treatment other than the oxaliplatin-based treatment generally used for stage III disease. The latest European Group on Tumour Markers (EGTM) recommendations failed to identify additional biomarkers for separating stage II CRC patients into different prognostic groups.3 However, the EGTM proposes tissue inhibitor of metalloproteinases-1 (TIMP-1) as a promising new prognostic biomarker, although TIMP-1 needs to be validated before any conclusion on its use can be drawn.

TIMP-1 regulates the activity of matrix metalloproteinases (MMP), which are enzymes involved in degradation of the extracellular matrix (ECM), and thus, may be involved in cancer invasion and metastasis.4 CRC patients have higher levels of plasma TIMP-1 than healthy controls,5, 6, 7 whereas, patients with premalignant adenomas have similar plasma TIMP-1 levels as those of the healthy people.8 Furthermore, high preoperative plasma TIMP-1 levels are associated with poor prognosis in CRC, independent of stage,9, 10 an observation also seen for high postoperative levels of TIMP-1.11 If plasma TIMP-1 can be used to reliably identify stage II and stage III CRC patients in whom adjuvant treatment is indicated and whether it should be single-drug 5FU or an oxaliplatin-based combination, it may have high potential for guiding individualised treatment of these patient groups. However, the use of plasma TIMP-1 as a prognostic parameter in CRC requires that the previous results be validated independently with patients and patient samples external to the original institutions. In this context, there are research groups that have already confirmed the association of high plasma TIMP-1 levels with poor prognosis in CRC.12, 13, 14 In a medical society where TNM staging of CRC patients has improved with the help of CT and MRI scans and where better surgical and oncological treatments are offered, together with improved pathological examination, it is necessary to continue evaluation of promising biomarkers such as TIMP-1 on a current CRC cohort.

Therefore, the aim was to validate the plasma TIMP-1 and the serum CEA levels as prognostic indicators in a population-based cohort of patients with CRC.

Section snippets

Patients

The study was prospective and the cohort was population based, including patients treated for CRC at the Department of Surgery, Central District Hospital, Västerås, County of Västmanland, Sweden, which has 260,000 inhabitants in the region. The study period was between August 2000 and December 2003 and the inclusion criterion was histologically verified adenocarcinoma of the rectum or colon. Acceptance to participate and to provide blood samples for tumour marker studies was by informed consent.

Patient characteristics

The total number of patients included in the study was 322 and the median observation time for surviving patients was 6.5 years (range 4.9–8.2 years). Major clinico-pathological characteristics and marker levels of the cohort are presented in Table 1. The median age was 73 years (range 34–94 years) and the median number of lymph nodes analysed were 15 (range 1–55). Two older patients with rectal cancer and one with colon cancer in a polyp had a local excision of the tumour and one patient with

Discussion

This prospective study confirmed the significant associations between high preoperative plasma TIMP-1 levels and poor survival of patients with primary CRC. These associations were observed for both DFS and OS analyses of the entire cohort, in the stratified analyses of stages II and III disease and in the multivariate analyses including conventional clinico-pathological baseline parameters.

Thus, this study can be considered as an independent prospective validation study that confirmed our

Conflict of interest statement

None declared.

Acknowledgements

Research nurse Eva Strand, for obtaining informed consent from the patients, and docent Kennet Smedh, Head of the Colorectal section for supporting this study at the clinic, both work at the Department of Surgery, Central District Hospital, Västerås, Sweden. This study was funded by the research fund of the county of Västmanland against cancer, Lions Cancer Foundation Uppsala, the Swedish Cancer Society, the Danish Cancer Society, the Danish Strategic Research Council and the Redaktoer

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