Improved Diagnosis of Colorectal Cancer Using a Combination of Fecal Occult Blood and Novel Fecal Protein Markers

Abstract

Annual testing for fecal occult blood is recommended as first-line screening for the detection of colorectal cancer (CRC), but is affected by limited sensitivity. We initiated a proteomics-based search for novel biomarkers to improve the sensitivity of detection of CRC in stool samples. Six markers, including immunologic fecal occult blood test (iFOBT), were evaluated in a collective of 551 samples (186 CRC, 113 advanced adenoma, and 252 control patients) to establish the diagnostic performance of each marker and marker combinations. We tested the known stool markers hemoglobin (iFOBT), hemoglobin-haptoglobin, calprotectin, carcinoembryogenic antigen, and the novel fecal markers tissue inhibitor of metalloproteinase-1 (TIMP-1) and S100A12. The best diagnostic performance was found for S100A12 with an area under the curve of 0.95, followed by TIMP-1 (0.92), hemoglobin-haptoglobin (0.92), hemoglobin (0.91), calprotectin (0.90), and carcinoembryogenic antigen (0.66). By using Bayes logistic regression as a mathematic model, the highest sensitivity (88%) for the detection of CRC at 95% specificity was obtained with the marker pair S100A12 and hemoglobin-haptoglobin. Increasing the specificity to 98%, the combination of S100A12, hemoglobin-haptoglobin, and TIMP-1 resulted in a sensitivity of 82%, with the highest increase of sensitivity found in early tumor stages (international union against cancer stage I: 74% sensitivity vs 57% of the best single marker). Depending on the specificity selected, a marker pair, S100A12 and hemoglobin-haptoglobin, or a triple combination including TIMP-1, allowed the detection of CRC at significantly higher rates than can be obtained with iFOBT alone.