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The selection of serological markers for the<br />
determination of a prognostic profile predicting<br />
cancer-specific death in colorectal cancer<br />
Ib Jarle Christensen<br />
Hvidovre Hospital, Department of Gastroenterology, Hvidovre, Denmark<br />
Introduction: The prognostic value of serological markers sampled preoperatively<br />
in patients with colorectal cancer (CRC) has been established. This study combines<br />
a panel of these markers in order to select a prognostic profile independent of<br />
the clinical baseline covariates: stage, localization, gender and age at diagnosis.<br />
The markers selected for this study are plasminogen activator inhibitor-1 (PAI-1),<br />
soluble urokinase plasminogen activator receptor (suPAR), tissue inhibitor of matrix<br />
metalloproteinase-1 (TIMP-1), tetranectin, YKL-40, soluble vascular endothelial<br />
growth factor (VEGF), molecules of the mannan-binding lectin pathway of innate<br />
immunity MBL and its associated protease MASP-2, carcinoembryonic antigen (CEA)<br />
and the acute phase response marker C-reactive protein (CRP). In addition, cathepsin<br />
B and the cysteine proteinase inhibitors stefin A, stefin B and cystatin C have been<br />
analysed in a subset of this dataset.<br />
Methods: Six-hundred and fifty-four CRC patients undergoing elective surgery<br />
have been followed for 7.9 years (median, 6.8-9.1 years). No patients received<br />
adjuvant chemotherapy or radiation therapy. The primary end-point was cancerspecific<br />
death and 308 patients were registered with CRC as primary cause of death.<br />
Multiple imputation was used to manage missing values and the time to cancerspecific<br />
death was subsequently analysed with the multivariable Cox proportional<br />
hazards model. Serological markers were scored as continuous variables on the log<br />
scale or dichotomised using previously determined cut-points. The selected model<br />
was assessed using cross validation techniques and Schoenfeld and martingale<br />
residuals.<br />
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Results: The mannan-binding lectin pathway molecules were not associated to any of<br />
the other markers. No pair of markers were shown to have a correlation higher than 0.7.<br />
Univariable analysis of the serological markers has shown all to be significant predictors<br />
of cancer-specific death with the exception of MBL and stefin B. All markers have been<br />
entered into the multivariable analysis and the final model was selected including<br />
only covariates which are significant in the analysis and independent of the baseline<br />
clinical characteristics. The final multivariable analysis showed that TIMP-1 (p
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