Second-generation Cologuard colon cancer stool diagnostic test is slightly more accurate

The gold-standard of colorectal cancer (CRC) screening is colonoscopy. Along with nearly perfect diagnostic accuracy (i.e. identifying almost 100% of all patients with colon cancer with very few false positives), the colonoscope can remove advanced adenomas (polyps) that are on their way to becoming cancers. There are alternative non-invasive screening options that involve submitting a stool sample for analysis: the fecal immunochemical test (FIT detects blood in stool) and DNA test (detects cancer-associated DNA mutations). Both the FIT and DNA tests show high sensitivity and specificity in the 80-90% range (QH). But 80-90% accuracy is still worse than close to 100%.

Over time the non-invasive diagnostic tests have become more accurate. A 2020 study claimed that FIT had a sensitivity of 85.1% and a specificity of 83.5%. As a reminder, sensitivity is the true positive rate (i.e. fraction of cancerous polyps that are classified correctly as cancerous), and specificity is the true negative rate (i.e. fraction of non-cancerous polyps classified correctly as non-cancerous). By comparison an early trial (2014) of the Cologuard DNA stool test produced a sensitivity of 92.3% and a specificity of 86.6%, which was superior to FIT (QH).

In the meantime, Exact Sciences, the company that developed Cologuard, has been working on the next-generation CRC DNA diagnostic test in conjunction with the Mayo Clinic. The initial process remains the same with users collecting a fecal sample at home, and then sending it to a laboratory (Figure 1). The subsequent analysis has been modified to scan for more DNA biomarkers in the specimen (e.g. more mutations). In addition, laboratory methods have been improved to bolster the sample's preservation, ensuring the sample remains valid for longer accommodating potential shipping delays.

To assess accuracy, they carried out the BLUE-C study which encompassed over 20,000 individuals aged 40 and above. Recently they reported the results of this trial on their new test (Fierce Biotech):

“When put to the test, the new Cologuard was able to detect signs of colorectal cancer with 94% sensitivity, compared to 92% for the first-generation test. It identified negative cases, meanwhile, with 91% specificity, up from 87% in the original Cologuard. The new test also produced 30% fewer false-positive results than the original.”

The 94% sensitivity and 91% specificity represent a modest but significant improvement over the first generation test. Notably the higher specificity resulted in 30% fewer false positives. There were also gains in the accuracy of diagnosing pre-cancerous polyps. 

The colon polyps can vary in size from diminutive (5 mm or less) to small (6 to 9 mm) to large (1 cm or more). They are classified as neoplastic (cancerous) or non-neoplastic (non-cancerous). Non-neoplastic polyps can exhibit dysplasia which are cellular and nuclear changes that are not normal and represent cells on the pathway to cancer (i.e. pre-cancerous). Polyps with high-grade dysplasia can become malignant over a time period of 10-15 years.

A diagnostic test that is negative for cancer but can detect high-grade dysplasia would be useful (i.e. recommend an immediate colonoscopy). The researchers tested the ability of the new Cologuard to detect these pre-cancerous cells:

"The next-gen and original tests detected high-grade dysplasia—describing an abnormal clump of cells that may become cancerous but haven’t yet—with 75% and 69% sensitivity, respectively, and spotted advanced precancer cases with 43% and 42% sensitivity, respectively."

So there was some improvement, but the DNA stool test is still much less accurate than a colonoscopy which can take a sample of polyp tissue, and then have it biopsied to determine definitively the dysplasia status. Of course an added benefit of colonoscopy is that polyps can be removed.

Regardless, the steady improvement in both FIT and the DNA stool tests (Cologuard) are making non-invasive CRC diagnostics more informative although colonoscopy remains the gold standard.

Figure 1. First generation Cologuard DNA stool test for colorectal cancer (CRC). The kit includes a container for the stool sample, preserving liquid to help preserve the DNA in the stool, and a package to return the sample to the company for analysis (https://www.cologuard.com/).