DEVELOPMENT OF BLOOD-BASED, CANCER-ASSOCIATED BIOMARKERS FOR EARLY DETECTION OF COLORECTAL CANCER: SIGNIFICANT DIFFERENCES BETWEEN RESULTS FROM SYMPTOMATIC AND SCREENING SUBJECTS.
Jakob Kleif1, Linnea Ferm1, Gerard J. Davis2, Ib J. Christensen1, Hans J. Nielsen*1
1Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre, Danmark, Denmark; 2Abbott Laboratories, Abbott Park, IL
Introduction: Research in early detection of colorectal cancer has focused on development of blood-based, cancer-associated biomarkers, including proteins, ctDNA, miRNA, nucleosomes, metabolomes, etc. At present, a number of significant results have emerged suggesting blood-based test concepts as useful in early detection, not only of colorectal cancer, but also of extra-colonic cancers. Indeed, the CancerSEEK combinations of ctDNA mutations and certain proteins published recently (1) appear as a valuable test for those subjects that refuse to undergo screening by direct colonoscopy, gFOBT or FIT. It should be considered however, whether results generated from subjects with symptoms of cancer or even diagnosed with cancer can be interpreted and immediately implemented to subjects undergoing screening. The aim of the present study was to evaluate differences in results generated from patients with symptoms of colorectal cancer and subjects undergoing FIT screening for the disease.
Methods: Results of protein analyses of plasma from two large studies on early detection of colorectal cancer were compared. The E II study included subjects (n=4,698) at risk of colorectal cancer due to symptoms of the disease (2), and the E III study included subjects (n=4,048) undergoing FIT screening (3), and who had a hemoglobin level above the cut-point of 100 ng/ml. All study subjects underwent colonoscopy, and results of that and results from possible immediate or subsequent intervention were recorded. The proteins, including CEA, hsCRP, CyFra21-1, Ferritin, Galectin-3 and TIMP-1, were determined at the Abbott COE in Amsterdam, The Netherlands using the Architect® platform. The AUCs were used to assess discrimination. Comparisons of protein levels between the two studies were done by linear modeling adjusting for age, gender and pathology.
Results: Focusing on CRC vs all other subjects the E II AUC was 0.83 and the E III AUC was 0.69 (p<0.0001). Overall, the protein levels among E II subjects were significantly different compared to the levels among E III subjects. The magnitude of these differences was significantly larger for patients with disease contra those with a clean colorectum. Major differences were observed in the levels of CEA, hsCRP, and CyFra21-1 (p<0.0001, E II vs E III).
Conclusions: The present results demonstrate substantial differences in the ability to detect CRC between symptomatic subjects and subjects undergoing screening for bowel cancer. The significant differences in levels of cancer-associated proteins between the two groups underline that results achieved among subjects with symptoms cannot be directly transferred to early detection or screening of subjects without symptoms.
References:
1. Cohen JD, et al. Science 2018;359:926-30.
2. Wilhelmsen M, et al. Int J Cancer 2018;140:1436-46.
3. Rasmussen L, et al. JMIR Res Protoc 2016;5:e182.
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