It may be an indelicate subject to bring up at the dinner table, but colon cancer screening based on fecal matter merits discussion. The first-generation kit ColoGuard rolled out in August 2014, and now an advanced version, ColoGuard Plus, received FDA approval in October 2024. What’s new?Â
Journey from food to poop. Be it eggs, English muffin, or oatmeal with berries for breakfast, tuna salad or General Tsao’s chicken for lunch and burgundy potato-carrot-beef stew for supper, it all ends up as mushy chyme in our stomach. The next stop is the small intestine where assorted digestive enzymes break the food down and allow 95% of nutrients to be absorbed into the blood stream. The remaining 5%, mostly fiber, heads down the road to the large intestine (colon) where water is removed and food remnants solidify into fecal matter.
sDNA and methyl IDs. What’s in a healthy person’s poop? Besides water, fecal matter consists of undigested fiber, fats, cholesterol, and bacteria. However, there is also something else in the fecal matter from an individual with colon cancer or pre-cancerous polyps. Tumor DNA! It turns out that colon tumors, benign or malignant, shed DNA into the stool stream, labelled as sDNA. This can be extracted, amplified, and analyzed for colon cancer genes as well as rectal cancer genes. By common practice, the two types of cancers are grouped into “colorectal cancer” or CRC. All testing kits simultaneously detect CRC and pre-cancerous polyps. ColoGuard is designed to identify 11 genes whereas ColoGuard Plus zooms in on all but  4 genes but has demonstrated improved testing outcomes. The 4-gene cluster out-performed the 11-gene panel. Less is more! How come?
It turns out that the secret to the better performance by ColoGuard Plus is embedded in DNA methylation: All four biomarkers are genes associated with altered DNA methylation commonly found in colon cancer. A molecule is said to have undergone methylation after a methyl group (CH3) has been incorporated into the molecule. The consequence of methylation is gene silencing. Cancer cells make use of methylation for their survival. Specifically, cancer cells engage in molecular tricks that lead to methylation of tumor suppressor genes (TSGs). That leads to the inactivation of these suppressor genes meaning that the cancer cells can grow uncontrollably. Despite being a universal trait in cancers, methylation biomarkers are highly unique depending on cancer type, subtype, stage, and grade. What’s more, fecal matter is not the only place of methyl residence. In fact, GALLERI, a screening test that analyses DNA methylation status in blood sample is boasting to detect 50 cancers all at once though still waiting for FDA green light.
How good is ColoGuard Plus? The short answer is “It depends”. The molecular holy-grail for medical testing kits are sensitivity (accurate capture of diseases in people with the disease, also called “true positives”) and specificity (accurate detection of no disease in people who are disease-free, termed as “true negatives”).
Here is the performance card for ColoGuard Plus for colorectal cancer (CRC): 95% Sensitivity, meaning 95% of the participants with CRC are accurately detected as such whereas 5% of the people also with CRC received a negative test result, which is untrue, hence “false negatives”. As for the other testing parameter, ColoGuardPlus has 91% Specificity which is interpreted as 91% without CRC are indeed tested negative (which is good news!) while 9% of CRC disease-free patients were erroneously tested positive or “false positives” (which can be unnecessarily stupefying!). Then again, no screening test is perfect.Â
Now, page 2 of ColoGuard Plus performance card on advanced pre-cancerous polyps depicts a mixed picture: The plus side is test Specificity of 94%, that is, 94% of individuals without polyps are accurately tested as “true negatives”, which is remarkable progress compared to the first-generation ColoGuard and to other fecal matter-based screening tests. An area with still considerable room for improvement by ColoGuard Plus pertains to test Sensitivity of advanced pre-cancerous polyps which, at the moment,  is merely 43%. Is it a big deal? Yes. Because it indicates that only 43% of the individuals with polyps of 10 mm or greater in diameter are caught as “true positives” which is great and important. At the same time, it also indicates that the remainder 57% of individuals who have large polyps residing in their colorectal tract go undetected which are “false negatives.” As known, depending on family history, general health status, and polyp size, colorectal polyps can develop into colorectal cancer over time. This is precisely the reason why the National Cancer Institute (NCI), the FDA, and the manufacturer all urge people to use ColoGuard Plus as a screening kit only, instead of a diagnostic tool. What then, IS the gold standard for detection of cancerous tumor and pre-cancerous polyps?
Trust but verify. Questionable results from ColoGuardPlus or other fecal matter-based screening tests all must be verified by the Gold Standard of CRC and polyps detection procedure: COLONOSCOPY. Equipped with a micro camera that offers a panoramic view of the colorectal tract, COLONOSCOPY allows not only detection but also surgical removal of pre-cancerous polyps right there and then during the procedure. Some may ask: If COLONOSCOPY is the ultimate go-to source, why bother with any screening kits in the first place?
Well, despite robust sensitivity and specificity of COLONOSCOPY, the invasive nature of the procedure and the uncomfortable preparation makes many shy away. This is where handy ColoGuard Plus comes in. Despite the screening-only utility of the kit, some level of screening is better than no screening at all! Despite progress made in cancer therapeutics, early detection remains key. “Skate to where the puck is going to be” coined by hockey legend Wayne Gretzky also applies to cancer. Catching cancer early, or better yet, catching cancer before it starts, is pivotal to treatment success.
As for screening test performance improvement in sensitivity and specificity, the crux of the matter resides in the identification of cancer-specific and tumor-unique antigens, also called neo-antigens.  The use of methylation markers by ColoGuard Plus is by all means a big step forward. The advent of A.I. particularly machine learning shall greatly facilitate neo-antigen discovery, in no uncertain terms!
Take-home message:
- Non-invasive, ColoGuard Plus and additional fecal matter-based tests are convenient screening tools for CRC and advanced pre-cancerous polyps
- Albeit invasive and complex in procedures, COLONOSCOPY continues to be the Gold Standard for both detection and prevention of CRC.
Dr. Nancy Liu-Sullivan holds a Ph.D. in biology and served as a senior research scientist at Memorial Sloan Kettering Cancer Center. She currently teaches biology at the College of Staten Island, City University of New York.
This article was revised on Tuesday, November 19th, 2024.
