An Exploratory Study Investigating the Potential of a Rectal Mucus Sample for Development of Biomarker Assays in Subjects With Gastrointestinal Diseases

Colorectal cancer (CRC) is the fourth most common cancer overall worldwide contributing to 9.7% of global cancer burden. It affects 746,000 men (10% of all cancer cases) and 614,000 women (9.2% of all cancer cases) with most cases (55%) occurring in developed countries. Furthermore, in the UK, 42,300 new colorectal cancer cases are diagnosed each year making it the fourth most common cancer overall, and third most common in males and females. In addition, the incidence of colorectal cancer increased between 1991 and 2016 and is attributed to lifestyle, environmental changes, and aging populations. Although bowel cancer incidence has fallen in the UK in the past decade by 4%, the lifestyle risk factors remain. Moreover, the burden of CRC is expected to increase with 2.2 million new cases and 1.1 million deaths expected globally by 2030. In addition, significant challenges remain in managing disease burden.

In England, five-year overall survival for CRC is 58.4% which is lower than the US reported 60-65%. Further challenges remain due to the ageing demographic and advanced presentation of disease. Older patients, above age 75 years, make up 44% of new colorectal cancer diagnoses and an estimated 20-25% of CRC is diagnosed at the metastatic stage with an additional 25% of patients developing metastasis during their illness. As a result, CRC accounts for 8.5% of cancer related deaths worldwide with 16,300 deaths per year in the UK making it the second most frequent cause of cancer related deaths at 10%. Although survival is stage dependent with 92% survival for stage I, compared to 10% in stage IV, there has been an improvement in survival for the 60-69-year age group attributed to screening. Thus, CRC remains a prevalent challenge in cancer management emphasizing the need for early diagnosis.

Declining mortality due to improvements has been shown with early detection through screening and effective treatment. The UK CRC screening program relying on faecal detected occult blood (FOBT) and colonoscopy has led to 16% decline in overall mortality rate without affecting incidence. However, FOBT has reduced sensitivity for advanced adenomas and CRC which may improve with newly implemented immunochemical testing (qFiT). With the pressures on service from the Covid-19 pandemic, qFIT has been implemented into the Two-Week Pathway to attempt to stratify patients at highest risk of colorectal cancer and the NICE-qFiT Study publication is awaited.

Biomarkers are molecular patterns that can be used as a tool for early cancer detection and individualized CRC treatment. They can be divided into diagnostic, prognostic, or predictive categories. Thus, biomarkers provide utility at different stages of the disease to determine disease progression, recurrence, as well as providing a personalized indicator for therapeutic effectiveness.

Firstly, early diagnosis in asymptomatic patients remains a key target to achieve favourable survival outcomes through identification of early CRC as well as pre-malignant lesions including high risk polyps. This forms the basis of the National Bowel Screening Programme. The sensitivity for detecting CRC using current qFIT testing (100ng/mL) is 73.8% versus 92.3% for a stool-based DNA assay screening KRAS, aberrant NDRG4 and BMP3 methylation. Furthermore, qFIT testing sensitivity for advanced precancerous lesions is 23.8% versus 42.4% with stool DNA testing. Moreover, the rate of detection of polyps with high-grade dysplasia is 46.2% with qFIT testing verses 69.2% with stool DNA testing, whereas the detection rate of serrated sessile polyps measuring >1 cm is only 5.1% (qFIT) versus 42.4% with stool DNA sampling. These findings highlight the limits of current diagnostic screening and difficulty in establishing appropriate surrogate markers for early disease detection in asymptomatic individuals.