Cologuard for Colorectal Cancer

The U.S. Food and Drug Administration has approved Cologuard (Exact Sciences, Madison, WI) as a screening test for colorectal cancer. Cologuard detects hemoglobin, KRAS mutations, NDRG3 and BMP3 methylation, and beta actin. These proteins and genes are shed by advanced adenomas and colorectal cancers into stool as it moves through the large intestine and rectum. Patients with positive test results are advised to undergo a diagnostic colonoscopy.

Colonoscopy is considered the gold standard for detection of colorectal cancer. Cologuard was not directly tested against colonoscopy for screening but now is being marketed as an alternative. Instead, the safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 participants for colorectal cancer with Cologuard and a fecal immunochemical test (FIT). Cologuard was more sensitive than FIT. It detected 92% of colorectal cancers and 42% of advanced adenomas, while FIT detected 74% cancers and 24% of advanced adenomas. Cologuard had more false positive results and, therefore, lower specificity than FIT. Cologuard correctly ruled out colon cancer only 87% of the time versus 95% for FIT.  Cologuard’s lower specificity means that an additional 13% of patients will be referred for unnecessary follow-up colonoscopies. 

However, the less invasive nature of Cologuard may mean that more people might be willing to be screened for colorectal cancer. If everyone was screened with Cologuard, 87% of colonoscopies could be avoided. 

Cologuard costs $599 compared to $25 for current stool blood tests. Medicare covers the new test once every three years for Medicare beneficiaries who meet all of the following criteria:

• age 50 to 85 years,
• asymptomatic  and
• average risk of developing colorectal cancer 

Cologuard requires a stool sample collected in a bucket that contains buffer for DNA stability. 

Patients with a positive test result are advised to undergo diagnostic colonoscopy.

In March 2025, launched its Cologuard Plus test after obtaining FDA approval and Medicare coverage. The next-generation test incorporated a new molecular panel including the methylated DNA markers ceramide synthase 4 gene [LASS4], leucine-rich repeat-containing protein 4 gene [LRRC4], serine–threonine protein phosphatase 2A 56-kDa regulatory subunit gamma isoform gene [PPP2R5C], and the reference marker zinc finger DHHC-type containing 1 gene [ZDHHC1]. It also retained fecal hemoglobin.

The addition of new genetic biomarkers reduced its false-positive rate while maintaining its sensitivity in detecting advanced precancerous polyps and tumors. Exact Sciences claims Cologuard Plus detects 95% of colorectal cancer (CRC) at 94% specificity in the U.S. screening population. It also detects 74% of high-grade dysplasia. 

Approval of the Cologuard does not change current practice guidelines for colorectal cancer screening. The United States Preventive Services Task Force (USPSTF) does not recommend stool DNA testing as a method to screen for colorectal cancer. USPSTF recommends adults age 50 to 75, at average risk for colon cancer, be screened using fecal occult blood testing, sigmoidoscopy, or colonoscopy.

For a more complete discussion, see the article entitled: “ Colorectal Cancer Screening.”

Reference

Bosch LJW, et al, Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population. Am J Gastroenterol. 2019 Dec;114(12):1909-1918.

Imperiale TF, et al. Next-generation multitarget stool DNA test for colorectal cancer screening, New Engl J Med, 2024;390:984-993.