Evaluation of a New Blood-based Test to Detect Colorectal Cancer and Its Precursors
Condition: Colorectal Cancer; Colorectal Neoplasms; Colorectal Carcinoma; Colorectal Polyp; Colorectal Adenoma
MeSH terms: Colorectal Neoplasms; Adenoma
Study type: Interventional

Summary: 
      The CELTiC panel is a potential blood-based test for detecting colorectal cancer (CRC) and
      precursors of CRC. This can be useful for CRC screening, since this requires tests that
      detect cancer in an early stage to maximize the chances of successful treatment.

      CELTiC combines four markers that can be detected in blood. These markers are composed of
      so-called messenger RNA (mRNA) and can be viewed as the instructions of our genes to the cell
      to make certain proteins. Cancer is the result of mutation in these genes. Thus, the mRNA in
      cancer patients is, depending on the type of mRNA, often abnormal. In earlier studies, the
      developers of CELTiC found four mRNA's that are different in patients with CRC compared to
      healthy individuals. However, CELTiC has not yet been extensively studied in individuals for
      whom the test is intended: a population undergoing CRC screening.

      The current study aims to fill this gap. We will assess the ability of CELTiC to detect CRC
      and precursors of CRC in a population of individuals between 50 and 75 years old in the
      Netherlands and Italy. This population has already been preselected by having a positive
      fecal immunochemical test (FIT), a test that is frequently used in CRC screening. This
      population will undergo a colonoscopy, a procedure where a doctor enters the large bowel
      through the anus using a flexible camara to assess whether the patient has cancer. Prior to
      this colonoscopy, we will collect blood samples from the individuals to assess their CELTiC
      score. After the colonoscopy and the blood analysis, we can assess whether the test
      adequately detects CRC and precursors of CRC in this population.
    

Detailed description: 
      1. BACKGROUND

           Colorectal Cancer (CRC) is one of the leading causes of cancer in developed regions
           around the world and its incidence is rising(1,2). Many nations or regions have
           introduced CRC population screening programmes to detect cancerous lesions before
           symptoms arise or to detect precursor lesions whose eradication may prevent CRC (3).

           The Faecal Immunochemical Test (FIT) is used to screen for CRC in many nations and
           regions around the world. Its advantages include ease of use, the ability to be
           performed at home and to be sent by mail to a laboratory, and its cost-efficiency (4).
           Moreover, these characteristics enable population-wide screening without the need for
           all participants to undergo a colonoscopy.

           However, a downside of the FIT is its performance. In the Netherlands, where a FIT
           cut-off concentration of 47 mcg Hb/g faeces is used, the FIT produces a negative result
           in 15% of people who have CRC (5). For the detection of CRC and Advanced Adenomas (AA),
           referred to as Advanced Neoplasia (AN), the FIT falsely provides a negative result in up
           to 70% of people with AN. In addition, more than half of the people with a positive FIT
           result in the Netherlands do not have any (pre)cancerous lesions at colonoscopy.

           One way to improve the efficiency of CRC screening is to introduce a second test to
           FIT-positive screening participants, to further select individuals for a colonoscopy.
           Ideally, this test should have a high sensitivity since a false negative result would
           lead to denying a colonoscopy to a FIT-positive individual with a (pre)cancerous lesion.
           In addition, the specificity of this test should be high enough to substantially reduce
           the number of FIT-positive individuals without AN undergoing colonoscopy.

           The CELTiC panel is a blood-based test comprising of four mRNA markers (LGALS4, CEACAM6,
           TSPAN8, and COL1A2) (6). In a sample of 128 individuals the panel reached an are under
           the curve (AUC) of 0.82 in discriminating individuals with AN (n = 92; AA n = 25, CRC n
           = 67) from individuals with a positive FIT result but a normal colonoscopy (n = 36). The
           CELTiC panel could potentially function as a second test for individuals with a positive
           FIT result and reduce the number of unnecessary colonoscopies (7). Furthermore, by
           simultaneously lowering the cut-off concentration of the FIT and introducing the CELTiC
           panel, screening programs may potentially detect more individuals with AN without
           increasing the number of colonoscopies performed.

        2. QUALITY ASSURANCE

           This cross-sectional diagnostic test study will examine the CELTiC panel in a population
           of 800 FIT-positive individuals in Italy and the Netherlands. Sites in both nations will
           adhere to the same protocol, including blood sample collection, processing, and data
           collection. Monitoring will be put in place at both sites to ascertain adequate data
           collection and storage. Laboratory personnel and endoscopy staff will be blinded to the
           results of the colonoscopy and lab analysis respectively.

        3. OBJECTIVES

           Primary Objective: to estimate the sensitivity of the CELTiC panel for detecting AN at a
           cut-off with an expected sensitivity of 90%. Secondary Objective(s) include: (i) to
           estimate the specificity of the CELTiC panel for detecting AN at a cut-off with an
           expected sensitivity of 90%; (ii) to estimate the positive predictive value of the
           CELTiC panel for detecting advanced neoplasia at a pre-specified threshold with an
           expected sensitivity of 90%; (iii) to estimate the specificity of the CELTiC panel for
           detecting advanced neoplasia and CRC at an observed sensitivity of 90%; (iv) to estimate
           the positive predictive value of the CELTiC panel for detecting advanced neoplasia and
           CRC at on observed sensitivity of 90%; (v) to estimate the Area under the receiver
           operator characteristic curve (c-statistic); (vi) to estimate the association between
           CELTiC score and FIT concentration.

        4. SAMPLE SIZE

      The CRC screening programs of Italy and the Netherlands differ in multiple aspects: in Italy,
      individuals between 50 and 69 years old are screening every two years with FIT set at a
      threshold of 20 ug Hb/g feces. In contrast, the Netherlands screens individuals between 55
      and 75 years old every two years with FIT set at a threshold of 47 ug Hb/g feces. Therefore,
      if we were to analyse the results from a combination of these two populations, the results
      may not be externally valid; the population would consist of more individuals with a
      relatively high FIT results compared to any other FIT-population in the world. Since FIT is
      an important risk factor for AN, this may induce selection bias.

      Therefore, we have opted to perform two analyses: one with all individuals recruited in Italy
      (FIT >= 20), and one with all individuals with a FIT of 47 ug Hb/g or higher (both in the
      Netherlands and Italy). We will aim to estimate a cut-off of CELTiC with a sensitivity of 90%
      for detecting AN. In addition, we are interested in an estimate with a 95% confidence
      interval that is not wider than 5% at either side and, for practical reasons, to split the
      recruiting between Italy in the Netherlands in a 3:2 ratio. Given the positive predictive
      value of FIT in both screening programs at their respective cut-offs, we will need in total
      800 participants for this trial, 347 of whom need to be diagnosed with AN.
    

Intervention name(s): CELTiC test
Intervention type(s): Diagnostic Test
Intervention description(s): The CELTiC test is a blood-based test consisting of four mRNA markers and the risk factor age.
Intervention model: Single Group Assignment
Intervention model description: We will cross-sectionally assess the CELTiC test in a group of FIT-positive individuals.
Masking: None (Open Label)
Primary purpose: Screening