Multitarget stool DNA testing (mt-sDNA, FIT-DNA), sold under the trade name Cologuard, is a noninvasive screening test developed to detect biomarkers associated with colorectal cancer or precancerous lesions. Multitarget sDNA testing differs from other noninvasive colorectal cancer screening tests in that it looks for both abnormal DNA and hemoglobin in the stool, which can be released from cancerous and precancerous cells or from the underlying blood vessels, respectively. The test is approved by the Food and Drug Administration (FDA) for use in the United States in individuals 50 years or older who have no signs or symptoms of colorectal cancer and have an average risk of developing the disease.
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Medical uses
The multitarget sDNA test is a noninvasive test used to screen for colorectal cancer or precancerous lesions. A positive result should be followed by colonoscopy. The American Cancer Society recommends screening with either multitarget sDNA testing every 3 years, guaiac fecal occult blood test, or fecal immunochemical test every year starting at age 50. Other options include sigmoidoscopy or virtual colonoscopy (CT colonography) every five years or colonoscopy every 10 years.
Screening
Screening can detect precancerous lesions in the colon before they become cancerous, and can identify colorectal cancer in early stages when it is easier to treat. The American Cancer Society and many other organizations recommend colorectal cancer screening beginning at age 50 in general, and earlier in African Americans. While evidence supports the effectiveness of screening for colorectal cancer and the availability of a variety of screening methods, only 59% of the US population aged 50 and older report have been screened as recommended.
Barriers to screening include cost, lack of access to health care, low awareness, inadequate communication by health care providers, differences in patient and provider testing preferences, and fear and embarrassment. Many people are hesitant to undergo a colonoscopy, the primary and most frequently recommended screening method to which other colorectal cancer screening tests are compared) because they fear it will be painful and they feel it is inconvenient, as it involves bowel preparation and the need to take a day off from work. Lack of awareness about noninvasive screening alternatives to colonoscopy also reduces compliance. Noninvasive screening options significantly increases participation in colorectal cancer screening.
The U.S. Preventive Services Task Force published an updated colorectal cancer screening recommendation statement in 2016. It included multitarget stool DNA as one of several equally positioned “A” rated strategies for use every 3 years for average-risk person ages 50–75.
The National Comprehensive Cancer Network (NCCN) included multitarget sDNA test in their NCCN Guidelines Version 2.2016 Colorectal Cancer Screening, updated October 20, 2016.
On October 3, 2016 the National Committee for Quality Assurance (NCQA) issued an update to the Healthcare Effectiveness Data and Information Set (HEDIS) for 2017 that includes the use of multitarget stool DNA test for the screening of CRC during the measurement year and for the two years prior to the measurement year.
Adverse effects
Colorectal cancer screening guidelines vary for people over 75.
Biology
The lining of the colon, or large intestine, sheds cells every day, some of which break apart and release DNA into the colon, which is passed in stool. Some of the human DNA in the stool is altered, reflecting natural aging.
Cancers, and to a lesser extent, precancerous lesions, shed abnormal cells and contribute altered DNA into the stool. Altered DNA may account for as much as 14% to 24% of the total recovered human DNA in the stool of colorectal cancer patients. Cancers and precancerous lesions (polyps) that are ulcerated or rubbed by passing stool also may shed blood into the stool, which can be identified by a hemoglobin assay.
Metrics
The test specifically looks for 3 types of stool biomarkers: 1) mutated human DNA; 2) aberrant human DNA methylation (hypermethylation); and 3) hemoglobin. The resulting 11 biomarkers include 7 mutations in the KRAS gene (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) that have been detected in up to 35% of colorectal cancers and are present to a lesser degree in adenomas. Cologuard also looks for aberrant methylation in the promoter regions of the ‘’NDRG4’’ gene (N-Myc Downstream-Regulated Gene 4) and ‘’BMP3’’ gene (Bone Morphogenetic Protein 3 gene), which are hypermethylated in colorectal cancer, as well as hemoglobin. Another DNA marker, the human beta-actin gene, acts as a reference gene and a measure of total human DNA. Test results, even negative results, can only be generated if sufficient DNA was isolated and analyzed, which is determined by the measurement of human beta-actin DNA.
The 3 marker types are each helpful screening tools, but are more powerful (finding more cancers) when considered together in an algorithm rather than individually.
Procedure
No bowel preparation or dietary restriction is necessary before testing, as the test has no known interfering substances and does not rely on visualization of the colon.A single spontaneously passed stool sample is collected using a kit. The stool is collected into a container, which fits on a toilet seat. A sample for hemoglobin determination is captured with a small wand and placed into a separate sealed tube. A preservative buffer is added to the larger stool sample in the collection container, which is then sealed.
The tube and container are placed into a secure shipping box and shipped to a certified molecular biology laboratory for analysis, where the stool sample is processed for DNA extraction for testing. DNA amplification techniques (ie, polymerase chain reaction [PCR]) are used to identify the presence of ‘’KRAS’’ mutations and hypermethylated DNA, while the presence of hemoglobin from blood in the stool is determined using an enzyme-linked immunosorbent assay (ELISA). Results from the DNA and hemoglobin assays are then combined in a logistic algorithm that calculates a composite score dependent on the relative amounts of each biomarker.
Interpretation of results
A positive result could indicate the presence of a cancerous or precancerous lesion of the colon, warranting a diagnostic colonoscopy. A negative result means that the composite levels of abnormal DNA and blood are below the threshold commonly seen with precancerous lesions and colorectal cancers. Patients with negative test results can continue with routine screening. If beta-actin DNA (the internal control) is insufficient, the test result is not reported as positive or negative and the patient’s stool sample should be recollected to obtain a definitive screening result.
Cost-effectiveness and test interval
A 2016 study used modeling to demonstrate that this testing is cost effective. At an assumed average price of $600 per test and an assumed average cost of $1,500 for colonoscopies following a positive test, three-year sDNA screening costs $11,313 per quality adjusted life year (QALY) compared with no screening. By comparison, triennial cervical and biennial breast cancer screening have been reported to cost $15,500 and $30,000 per QALY, respectively, compared with no screening. The analysis further showed an incidence reduction of 57 percent and mortality reduction of 67 percent, compared to 65 and 73 percent, respectively, for decennial colonoscopy. This study used the Archimedes cost-effectiveness model. The authors conducted a five-arm screening study in a population of 200,000 virtual individuals. The model compared the clinical effectiveness of sDNA screening to colonoscopy performed at 10-year intervals and to no screening during a 30-year period.
History
It was approved in August 2014 by the FDA as a screening test for non-symptomatic, average-risk adults 50 years or older.