Catch the cancer;
towards a cfDNA-based test for colorectal cancer screening

Introduction of the national screening program for colorectal cancer (CRC) has
improved the prevention and early detection of this disease. (1) The screening
consists of a fecal immunohistochemical test for hemoglobin (FIT), which is
followed by a colonoscopy if positive. Nevertheless, the FIT*s sensitivity and
specificity are still low, leading to unnecessary colonoscopy in half of the
FIT positive individuals.
Patients with Lynch Syndrome (LS), are advised to undergo surveillance
colonoscopies every two years. (2) However, a colonoscopy is burdensome, and it
doesn*t provide detection of extra colonic cancers associated with LS.
A reliable, more efficient test is needed to identify individuals with adenomas
and/or early carcinomas, both sporadic as LS-associated. For this purpose, a
blood test based on cell free DNA (cfDNA) might have potential. This test is
currently used to monitor tumor activity in cancer patients. Also, pregnant
women can be screened for Down syndrome by means of fetal cfDNA. (3-5)
Interestingly, in the national TRIDENT-II study, that evaluates the cfDNA based
Non-Invasive Prenatal Test (NIPT), cfDNA cancer profiles were detected in
pregnant women, leading to early detection of cancer. From these findings, we
hypothesize that cfDNA analysis can also be used as a non-invasive screening
test for precursor lesions and/or early cancer.

The primary objective of the CATCA-study is to develop a cfDNA based
screening/surveillance tool for colorectal adenoma and cancer, both in the
setting of the national CRC screening program and in the surveillance of LS
carriers. Additionally, we want to evaluate the psychological impact of this
new way of cancer screening for patients, especially regarding incidental
findings (secondary objective).

This is a prospective longitudinal cohort study.

After informed consent is given, a colonoscopy is performed (either as
indicated via the national screening program or as biennially surveillance in
LS carriers). At colonoscopy, blood (2x 10 ml) will be obtained from
individuals from both groups via the needle necessary for sedation.
Sequentially, the blood will be stored. If >=1 lesion(s) is/are found during
colonoscopy, cfDNA and DNA will be isolated from the stored blood and detected
lesion(s), respectively. DNA analyses (CRC specific DNA alterations) will be
performed in order to compare the cfDNA profile to the DNA from the lesion(s).
Patients will be included until at least 10 advanced adenomas and 10
Chromosomally Instable (CIN) as well as Microsatellite Instable (MSI)
carcinomas have been detected by colonoscopy. Adenomas will be considered
advanced in case of a villous component, high-grade dysplasia and/or >=10 mm in
size. Also, informed consent will be asked to send questionnaires (and if
indicated, to conduct interviews) to investigate the cfDNA-based test*s
psychological burden, especially regarding possible incidental findings.

A part of this study will be to evaluate patients* perceptions on the new
procedure and the psychological impact of unexpected findings.The extent of the
burden associated with participation therefore consists of filling in two short
questionnaires in case no lesion is found during colonoscopy. If a lesion is
found participants are asked to fill in a third questionnaire. Participants
will (possibly) experience additional burden in case of an incidental finding
like a constitutional chromosomal aberration or malignant cfDNA aberrations
that do not correspond to the colonic lesion*s DNA profile. Then, counseling or
a clinical and molecular workup to detect possible other (pre)malignancies will
be offered. In case of incidental findings participants are invited for an
in-depth interview.
An advantage of this study for participants can be that an (extracolonic) tumor
can be detected in an earlier stage. This could lead to better treatment
options.