Peripheral Blood Monocytes as Predictive Marker for Colorectal Cancer Diagnosis: A Comparative Study of a Stool Based Versus Blood Based Screening Test

Colorectal cancer (CRC) is the second leading cause of cancer death (approximately 9% of cancer deaths). In Belgium, a country with a population of 11,2 million people, every year 8600 patients get diagnosed with CRC. The cumulative risk is 5,1% for males and 3,5 % for females. Five-year survival of these patients is around 60%. Most colorectal cancers arise from polyps that progress from dysplasia to cancer. This adenoma - carcinoma sequence approximately takes several years. The slow transition from polyps to cancer allows opportunities to prevent CRC by removing polyps and early cancer. Although colonoscopic screening for CRC is currently the most reliable screening tool, the invasive nature and the incurred cost have hampered the wide application of this procedure. On the other hand, the fecal occult blood test (FOBT) and the most recently used fecal immunohistochemical test (FIT) are non-invasive screening tests that can be used prior to colonoscopy. However, they both lack the sensitivity or specificity required for an effective screening. Thus, there is a pressing need to identify specific non-invasive biomarkers for CRC early diagnosis.

Peripheral blood is an easily accessible tissue and therefore suitable for screening of disease biomarkers. Among the cells circulating in peripheral blood, monocytes are an interesting target as they represent a source of macrophages and dendritic cells, contributing to tumor growth, metastasis and angiogenesis as well as anti-tumor immune response.

Investigators from the Vlaams Instituut voor Biotechnologie (VIB) have over the years built an international network and team (UZ Leuven (Belgium), Jules Bordet Institute (Belgium), San Filippo Neri Hospital (Italy), University Hospital of Heidelberg (Germany)). With the initial aim to characterize different monocyte/macrophage phenotypes, the outstanding collaboration led to the development of an innovative test for the diagnosis of CRC that combines transcriptomic data with an efficient predictive model, the so-called "Monomark" test. In the Monomark study, VIB defined a genetic signature, which is induced specifically in circulating monocytes at early disease onset by soluble signals derived from transformed colon epithelium (in comparison to benign colon epithelium or other cancer histotypes). This gene signature was validated in a case-control study including 360 samples from the four European oncological centers with outstanding diagnostic accuracy, showing a sensitivity of about 90% and a specificity of about 95% (even when stratifying patients in stage I, II, III and IV) compared to other tests previously described or currently in use in the clinic (6,7). Moreover, preliminary data suggest the test can also detect relapse - an application that is being further developed.

Within this study investigators propose to further develop the Monomark test for the screening application, in order to maximize the interest from potential licensees. Investigators will need to show that the assay is superior to existing assays in casu the FOBT/FIT assays. Therefore, we will compare the sensitivity and specificity of this test head to head to the FIT stool test currently used in clinical screening for CRC. These findings will showcase Monomark's potential as a novel, non-invasive, cheap and safe assay for early detection of CRC, thus increasing the cure rate of CRC patients and reducing costs for the public health. The outstanding network built around the Monomark diagnostic platform will strongly support and speed up its validation and commercialization with specialized methodologies and analyses.

In this prospective study, the main goal is to evaluate the strength of the Monomark test in patients with a positive FIT test. Therefore, in parallel to the routine FIT screening, blood samples will be harvested and the monocyte genetic profile will be determined. This fundamental study, will disclose the diagnostic power of this biomarker panel head to head with the well-established FIT diagnostic test, a core prerequisite for the commercialization of the Monomark test as an alternative and more reliable CRC screening tool.