Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients

Abstract

Background: There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI).

Methods: Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni- and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA.

Results: Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.03-2.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI.

Conclusions: High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.

Figure 1

ROC curve analysis. ROC curve analysis calculated with the use of survival data (OS), showing AUC on s-TATI compared to s-CEA in all patients (A), curatively treated patients (B). Cut-off based on the point farthest to the northwest (black arrow) extracted from ROC curves data table (data table not shown).

Figure 2

Distribution of s-TATI according to disease stage. Box plots displaying s-TATI distribution in TNM Stage and subcategories. Boxes show 25^th, 50^th, 75^th percentiles, whiskers show 5^th and 95^th percentile. Outliers are represented with circles while black dots represent extreme outliers. Distribution of s-TATI according to TNM stage (A), tumour stage (B), nodal stage (C) and metastatic stage (D). Kruskal Wallis test was used for statistical analysis.

Figure 3

Prognostic value of s-TATI in all patients. Kaplan Meier estimates of disease free survival and overall survival in strata of s-TATI levels according to the cut-off derived from the ROC analysis (A, C) and quartiles (B, D).

Figure 4

Prognostic impact of s-TATI in Stage II and Stage III disease. Kaplan Meier estimates of disease free survival according to high and low s-TATI levels derived from ROC-analysis in Stage II (A) and Stage III patients (B), and overall survival in Stage II (C) and Stage III patients (D), respectively.