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UPAR(I) AND TYPE IV COLLAGEN OUTPERFORM CEA AS PROGNOSTIC BIOMARKER IN PRIMARY COLORECTAL CANCER
Hans Christian Rolff*1, Ib J. Christensen1, Hans J. Nielsen1, Gerard J. Davis2, Frans Martens3, Gunilla A. Hoyer-Hansen4, Michael Wilhelmsen1, Linnea Ferm1
1Department og Surgery, Hvidovre Hospital, Virum, Denmark; 2Abbott Laboratories, Chicago, IL; 3Department of Clinical Biochemistry, VU Medical Center, Amsterdam, Netherlands; 4The Finsen Laboratory, Copenhagen N, Denmark
Aim: The aim of the study was to evaluate the prognostic and predictive value of a serological biomarker panel consisting of carcinoembryonic antigen (CEA), the soluble urokinase-type plasminogen activator receptor (suPAR) forms (suPAR (I-III), suPAR(I-III)+(II-III) and uPAR(I)) and type IV collagen in primary colorectal cancer (CRC).
Materials and methods: Retrospective evaluation of two independent cohorts of CRC patients included prospectively in 2004-2005 (training set) and 2006-2008 (validation set). Plasma samples were available from 297 (training set) and 482 (validation set) patients. The biomarkers were determined in plasma samples collected preoperatively using validated analysis platforms. The biomarker determinations and statistical analyses were performed retrospectively. Clinical data were retrieved from patient files and computerized national registries.
Results: All of the investigated serological biomarkers showed prognostic value upon univariable analyses. A multivariable analysis including age, disease stage and tumor localization and the serological biomarker levels were performed. The analysis showed that only uPAR(I) and type IV collagen remained statistically significant independent, prognostic biomarkers with HRs of 1.55 (95% CI:1.02-2.33, p=0.038) and 1.57 (95% CI:1.14-2.15, p=0.0053), respectively in the training set. These findings were again tested in a reduced multivariable model excluding the non-significant serological biomarkers. In this reduced model uPAR(I) and type IV collagen had HRs of 1.92 (95% CI: 1.39-2.65, p<0.0001) and 1.69 (95% CI: 1.26-2.27, p=0.0005), respectively. This model was tested in the validation set and showed HRs of 1.58 (95% CI: 1.24-2.02 p=0.0002) for uPAR(I) and 1.62(95% CI: 1.25-2.11, p=0.0003) for type IV collagen.
The combined HR of uPAR(I) and type IV collagen was 3.24 (95% CI: 2.44-4.30, p<0.0001) in the training set and 2.61 (95% CI:1.99-3) in the validation set
The interactions between uPAR(I) and type IV collagen with adjuvant anti-neoplastic therapy were non-significant (p=0.21 and 0.42, respectively) with regards to overall survival in the training set and reproduction was therefore not attempted in the validation set.
Conclusion: uPAR(I) and type IV collagen had a strong prognostic significance which outperformed CEA. Predictive values for uPAR(I) and type IV collagen, respectively, could not be shown.
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