DEVELOPMENT OF BLOOD-BASED BIOMARKER TESTS FOR EARLY DETECTION OF COLORECTAL NEOPLASIA: INFLUENCE OF BLOOD COLLECTION TIMING AND HANDLING PROCEDURES
Mathias M. Petersen*1, Hans J. Nielsen2, Niels L. Pedersen2, Jon J. Ladd4, Paul D. Lampe4, Robert S. Bresalier5, Gerard J. Davis6, Christina Demuth3, Claus L. Andersen3, Sarah Ø. Jensen3, Linnea Ferm2, Ib J. Christensen2
1Gastrounit 360 - Surgical Department, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark; 2Hvidovre University Hospital, Hvidovre, Denmark; 3Department of Molecular Medicine, Skejby, Denmark; 4Fred Hutchinson Cancer Research Center, Seattle, WA; 5MD Anderson Cancer Center, Houston, TX; 6Abbott Laboratories, Abbott Park, IL
Introduction: Blood-based, cancer-associated biomarkers are susceptible to a variety of well-known preanalytical factors. The influence of bowel preparation solutions before a diagnostic colonoscopy on biomarker levels is, however, poorly investigated. The present study assessed the influence of bowel-preparation on colorectal cancer-associated biomarkers. In addition, the effect of single versus double centrifugation of plasma biomarkers was assessed.
Methods: Blood samples were collected pre- and post-bowel preparation from 125 subjects scheduled for first -time diagnostic colonoscopy due to symptoms potentially attributable to CRC. The samples were separated into serum and EDTA plasma, and analyzed by four independent collaborators for: 1) the proteins AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1, 2) the proteins BAG4, IL6ST, vWF, CD44 and EGFR, 3) the glycoprotein Galectin-3 ligand, and 4) cell-free DNA (cfDNA). Statistical analysis of biomarker data has been performed using mixed modelling, including repeated measures.
Results: The biomarkers generally showed negligible variation between pre- and post-bowel preparation except for CyFra21-1, Ferritin, BAG4 and cfDNA. CyFra21-1 levels were systematically reduced with 29% (95% CI 21-36%) by bowel preparation (p=<.0001). Ferritin was not significantly different between pre- and post-bowel preparation (p=0.07), however the estimated difference (increase) was 18%. BAG4 was systematically reduced by 12% (95% CI 1-22%, p=0.04), while cfDNA showed a significant increase of 28% (95% CI 17-39%, p<0.0001).
Double centrifugation compared to single centrifugation showed reduced vWF (ratio 0.86, p=<.0001) and CD44 (ratio 0.85, p=0.016), but increased IL6ST levels (ratio 1.18, p=0.014).
Conclusions: Results of the present study demonstrated systematic, statistically significant differences between pre-bowel preparation vs post-bowel preparation levels for three independent blood-based biomarkers (BAG4, CyFra21-1, cfDNA), illustrating the importance of when and how samples are collected for biomarker analyses.
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