Colorectal Cancer Detection

About

Colorectal cancer (CRC) is a global problem affecting millions of people. CRC grows slowly, and it can take decades before symptoms emerge. This defines a wide window of opportunity for detecting and treating CRC early. It is well proven that population screening prevents CRC-associated death. Among methods used for CRC diagnosis, colonoscopy is the accepted gold standard. However, it is complex, invasive and expensive. Colonoscopy use for CRC screening may be excessively costly. Therefore non-invasive CRC screening tests followed by colonoscopies in positive cases are employed as the most popular CRC screening strategy. Colorectal tumours often bleed. Blood presence in stool is a frequent early sign of CRC, hence various versions of faecal occult blood test (FOBT) detecting minute amounts of blood in stool are employed for CRC screening. The basic guaiac FOBT is cheap, but unreliable. Now it is being replaced with more sensitive immunochemical FOBT (iFOBT or FIT), but blood is not always detectable in stool of CRC patients, therefore test sensitivity remains limited. Many attempts to develop tests based on CRC biomarker detection in stool were undertaken. The most impressive results were achieved using a multitarget stool DNA test that clearly outperformed iFOBT (Imperiale et al. N Engl J Med 2014;370:1287-97). This test was recently launched by EXACT Sciences as a commercial product (‘cologuard’) in the US, but it remains technically complex and prohibitively expensive (over $500 per test) for a routine CRC screening tool. These approaches present the main segments of CRC screening market valued at $600M worldwide. Stool tests are non-invasive, but the need to collect stool makes them unattractive for patients, causing compliance problems. The on-going NHS Bowel Cancer Screening Programme in the UK shows that test uptake is limited to about 50% of subjects invited (Logan et al. Gut 2012;61:1439-46). This reflects the fact that stool collection is inconvenient and often unpopular with patients and screening subjects. Diagnostically informative substances found in stool derive from either colonocytes exfoliated from normal or malignant epithelium or free inflammatory cells migrating into the lumen of the gut in neoplasia or inflammation (Loktionov. Int J Cancer 2007;120:2281-9). Upon leaving the mucosal surface cells and biomolecules enter a layer of secreted mucus that constitutes the protective intestinal barrier (Johansson et al. Proc Natl Acad Sci USA 2011;108:4659-65). The abundant presence of human cells in the mucus collected intra-rectally was repeatedly demonstrated in patients with CRC and Inflammatory Bowel Disease (IBD) (Loktionov et al. Int J Oncol 2009;34:301-11; Anderson et al. Int J Colorectal Dis 2011;26:1287-97). It was logical to hypothesize that immediately following defaecation a significant proportion of excreted colorectal mucus remains on the surface of the external anal area and can be easily sampled. On the basis of this hypothesis we have developed and patented (US patent 94481454) a new method of colorectal mucus self-sampling followed by biomarker analysis. This method was successfully tested in a clinical study addressing IBD detection and monitoring (Loktionov et al. J Gastroenterol Hepatol 2016;31:326-33; Bandaletova T, et al. APMIS 2016;124:160-8; Loktionov et al. J Gastroenterol Hepatol 2017;32:992-1002). It could be assumed that the new approach is perfectly suitable for detecting CRC as well, and early results of our on-going pilot study strongly confirm this assumption. Having analysed a ‘training set’ of sqamples from patients with known diagnoses, we were able to identify several highly promising protein biomarkers. These biomarkers are currently being tested in a blinded case-control study. Biomarker quantification is currently performed using ELISA assays, but the ultimate goal of this project is to develop a rapid ‘point of care’ (POC) test. Once the optimal biomarkers are selected, product development will be initiated. The future POC product will be initially introduced to clinical practice for triage of symptomatic patients with suspected CRC, but its eventual use for CRC screening constitutes the main target of this project.