Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04659590 |
| Other study ID # |
263745 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 6, 2020 |
| Est. completion date |
August 15, 2022 |
Study information
| Verified date |
August 2022 |
| Source |
Origin Sciences |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The identification of patients with colorectal cancer is challenging as they present with a
variable symptom profile and require invasive tests (colonoscopy) for diagnosis (through
histological analysis of biopsies) and complimented by cross-sectional radiology, prior to
commencement of treatment. The biopsy forms the basis of the diagnosis and management
planning for a patient with colorectal cancer through the multidisciplinary team.
The biggest challenge currently faced in the management of colorectal cancer is the accurate
identification of patients who present with various symptoms none of which are specific for
bowel cancer. Currently the NICE referral guidelines are used to determine the
appropriateness of referral pathway, i.e. Fast-Track/Two-Week Wait referral. A recent review
of over 10000 referrals revealed a colorectal cancer diagnosis in 4.1% of referrals. Previous
literature reports rates as high as 8%, but in series of cases with only 72-89% adherence to
the referral guidance leading to at best 40% of all colorectal cases being diagnosed through
this route. The remainder of colorectal cancers being diagnosed through the bowel cancer
screening programme (NBCSP), non-two-week wait referrals and other processes such as
emergency admissions. Inherently the Two-Week Wait pathway refers a large volume of
"symptomatic patients" and it has become a "cancer exclusion pathway." Once cancer has been
excluded, patients are often discharged back to General Practice, yet the patients often
still have symptoms. The current Covid-19 pandemic has had a significant impact on the
already pressed Two-Week pathway impacting on the reduction of endoscopic and radiological
appointments available leading to delays in treatment. Each test performed in the diagnostic
pathway has a significant financial, personal, and institutional resource profile.
It is our aim to develop a novel diagnostic device based upon the identification of genetic
mutations and genomic alterations from material trapped in the rectal mucous layer allowing
focused endoscopic assessment, confirmation/exclusion of cancer diagnosis from
cross-sectional imaging in those unfit for endoscopic examination and identification of
high-risk lesions (dysplasia). This would allow a greater triage, and focus colonoscopic
services onto therapeutic procedures, improving overall care.
Description:
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.
Current non-invasive screening stools are not sensitive to detect pre-cancerous lesions and
regularly miss significant early CRC.
As outlined, the investigator currently have a low threshold in symptomatic patients for
colonoscopy in these patients and further tools are required to support identifying early
pre-malignant lesions (adenomas) and CRC .
The investigator knows from the recognition of the adenoma - carcinoma sequence and the
impact of hyper- and hypomethylation that the local environment that there are a number of
steps both in carcinogenesis and the associated risks.
At an epigenetic level, DNA methylation changes is one of the hallmark events in
carcinogenesis, characterized by global hypomethylation and paradoxical gene-specific
hypermethylation. Hypomethylation is primarily involved in chromosomal instability and global
loss of imprinting, while gene-specific hypermethylation anchors to promoters, it causes
transcriptional silencing of tumour suppressor genes and consequently sets the stage for
neoplastic transformation. Deregulated DNA methylation is well known to be associated with
CRC. The first evidence of DNA methylation contributing to CRC was presented, in which a
global loss in DNA methylation was identified. Then, extensive efforts have been made in
identifying aberrant hypermethylation in promoters of CRC-related suppressor genes, such as
APC, SFRP2, SEPT, and CDH1. Remarkably, a near universal phenomenon that gene-specific
hypermethylation occurred in both pre-neoplastic and neoplastic phase of colorectal cancer
was observed. This might shed light on the process of tumorigenesis. However, few studies
have defined precisely the hierarchy of methylation events during the transformation from
normal epithelial cells to malignant cells in colorectal carcinogenesis.
It is becoming increasingly apparent that the occurrence of molecular alterations could be
found not only in tumour tissue but also in histological normal-appearing tissue adjacent to
the tumour. The presence of such molecular alterations in histological normal-appearing
tissue is commonly known as field cancerization or field effect. This has been thought to
constitute the earliest clone in the carcinogenesis process. In colorectal carcinogenesis, a
few numbers of gene-specific hypermethylation events have been reported in normal-appearing
colonic mucosa from CRC patients (such as APC, DKKI, MGMT, CDKN2A, and SFRP4). In addition,
previous studies have also demonstrated the effect of aberrant DNA methylation on suppressor
genes such as MINT1, MINT31, SLC5A8, and MGMT, during adenoma-carcinoma sequence. These
findings suggest that the presence of field effect in methylation might be a useful
intermediate biomarker in etiologic studies. A better understanding of when these epigenetic
tags occur and how they take part in colorectal progression may represent a practical
opportunity for colorectal cancer risk assessment. The use of a unique biological material
capture device with genomic and epigenetic assessment of the retrieved specimen is the basis
of the trial.
