A Stool DNA Test for Detection of Advanced Colorectal Neoplasia in Asymptomatic Chinese Community Population
Condition: Colorectal Cancer; Colorectal Neoplasm; Advanced Adenoma; Adenoma; Serrated Lesion
MeSH terms: Colorectal Neoplasms; Adenoma; Neoplasms
Study type: Observational

Summary: 
      to determine screening value of stool-based SDC2 DNA methylation test for advanced colorectal
      neoplasia in the asymptomatic Chinese community population.
    

Detailed description: 
      In China, colorectal cancer (CRC) remains to be the leading cancer of the digestive system.
      According to nationwide cancer statistics using population-based cancer registry data in
      China, age-standardized incidence rate of CRC and age-standardized mortality rate increased
      significantly from 2000 to 2015. It induces a substantial financial burden in terms of
      healthcare utilization and quality-adjusted life years (QALY) lost. Fecal Occult Blood Tests
      (FOBT) and colonoscopy have been proposed as the main primary screening modalities for
      asymptomatic subjects by international guidelines and Asia Pacific Consensus Statements.
      Nevertheless, shortage and uneven distribution of colonoscopy resources combined with huge
      population base consisted of the current situation in China. Previous population-based CRC
      screening programs usually employed questionnaires and/or FOBT to assess high-risk groups and
      recommended colonoscopy. This algorithm faced difficulties such as complex traditional
      questionnaires, low colonoscopy adherence, and a high false-positive rate. When the
      Coronavirus disease 2019 pandemic further limited the implementation of colonoscopy, the
      contradictions developed more acute.

      A Hong Kong group had designed and validated a colorectal cancer risk scoring system based on
      age, gender, smoking history, and family history through the results of screening in 11
      Asia-Pacific cities. The Asia-Pacific Colorectal Screening (APCS) score was more concise and
      divided the population into three categories: low risk, intermediate risk, and high risk.
      Compared with the low-risk population, the probability of advanced colorectal neoplasia in
      intermediate-risk and high-risk population increased by 2.6 times and 4.3 times respectively.
      Because of simplicity and efficiency, it was recommended by Asia-Pacific screening guidelines
      and several guidelines in China. Another APCS related multi-center study indicated that by
      selecting high-risk subjects and low/average-risk subjects with a positive fecal
      immunochemical test (FIT) for colonoscopy, the colonoscopy workload could be reduced by 50%
      compared with the strategy of primary colonoscopy in those same subjects. All these
      experiences deserved to be drawn on during the post-pandemic era.

      The recent decade has witnessed a rapid development of non-invasive biomarkers to detect CRC.
      Stool DNA(sDNA) Testing is a novel screening test for CRC, using molecular techniques to
      identify CRC-relevant biomarkers in stool. One of its toolkits, Multitarget Stool DNA Testing
      (FIT-DNA), was first approved by the FDA in 2014 for its application in clinical practice,
      which has been widely promoted in the United States. Subsequently, it was endorsed by
      multiple societies as one of the recommended screening tests.

      Recently, a stool test of methylated Syndecan-2(SDC2) has been developed as a fecal-DNA
      product targeted to improve the diagnostic accuracy of CRC screening. A meta-analysis of
      previous clinical studies reporting the accuracy of stool DNA methylation tests in detecting
      CRC included 46 studies totaling 16,149 patients. The most accurate single gene was found to
      be SDC2 with a pooled sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%,
      93.2%). A recent study involving 1,110 subjects from 2017 to 2018 by three Chinese tertiary
      hospitals assessed the performance of the SDC2 sDNA test. The sensitivity of the SDC2 sDNA
      test was 301/359 (83.8%) for CRC, 16/38 (42.1%) for advanced adenomas, and 134/154 (87.0%)
      for early-stage CRC (stage I-II), while maintaining a specificity of 699/713 (98.0%).
      Nevertheless, there were limitations in the design of these original studies. For instance,
      most involved small, hospital-based CRC cases and controls that might not fill the knowledge
      gap between population screening. Additional clinical trials are required to further validate
      its diagnostic accuracy in other populations, especially community-setting.

      Potential participates would be recruited via community public communication. The subjects
      would be asked to fill in a concise questionnaire obtained through a public WeChat account
      after informed consent. Basic information would be acquired while APCS score and
      correspondent risk categories would be calculated automatically. After sampling education,
      stool collection devices of sDNA and quantitative fecal immunochemical test (qFIT) would be
      distributed to all subjects. Two samples of stool from single defecation would be requested
      to put into the two collection devices according to instructions respectively by the subjects
      themselves at home.

      Efforts would be made by the public WeChat account and the community staff to urge samples
      recover from subjects as quickly as possible (prefer within 24h after defecation). Community
      staff would deliver the samples qualified in the initial evaluation to the standardized
      laboratory for testing as quickly as possible. If APCS be evaluated high-risk or any of qFIT
      or sDNA tests positive, the risk of the subject would be considered increased. Colonoscopy
      would be strongly recommended, and priority and rapid arrangement would be made in the
      corresponding center. For subjects with low/intermediate-risk APCS and negative qFIT and
      sDNA, the project team also encourages the subjects to accept colonoscopy on the basis of a
      clear understanding of benefits and risks. We would help to arrange colonoscopy as early as
      possible.

      All colonoscopy examinations will be performed by experienced endoscopists while monitoring
      quality of colonoscopy (bowel preparation, cecal intubation rate and withdrawal time).
      Full-time recording personnel would be arranged to follow up and record the relevant
      information of colonoscopy. For the subjects diagnosed with colorectal cancer, the
      postoperative diagnosis and tumor-node-metastasis (TNM) staging of the subjects would be
      retrieved.
    

Intervention name(s): Stool-based SDC2 DNA methylation test; quantitative Fecal immunochemical test
Intervention type(s): Diagnostic Test; Diagnostic Test
Intervention description(s): A diagnostic device measuring syndecan 2(SDC2) methylation status in stool DNA to detect colorectal cancer; A diagnostic device using immunoturbidimetric methods to measure fecal hemoglobin concentration
Other intervention name(s): COLOSAFE; OC-Sensor
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Community residents were invited to participate in the evaluation. All the individuals
        involved would undergo APCS evaluation, qFIT, and sDNA tests. A participator would be
        considered with increased CRC risk if any of the three is evaluated high-risk or tested
        positive and would be subsequently recommended to receive timely colonoscopy. When the APCS
        evaluation shows low or Intermediate risk with both negative results of qFIT and sDNA,
        participators would be encouraged to undergo colonoscopy based on patient preferences,
        which could also provide a refference for the prevanlence of advanced colorectal neoplasia
        in low-risk patients.
      
Biospecimen description: 
      Stool sample
    
Keywords: Methylated Syndecan-2(SDC2); Stool DNA; Fecal immunochemical test; Advanced colorectal neoplasia; Asia-Pacific Colorectal Screening score