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聽ColoGuard聽rolled out in August 2014, and now an advanced version,聽ColoGuard Plus,聽received FDA approval in October 2024. What鈥檚 new?聽
Journey from food to poop. Be it eggs, English muffin, or oatmeal with berries for breakfast, tuna salad or聽General Tsao鈥檚聽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.聽What鈥檚 in a healthy person鈥檚 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聽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 鈥渃olorectal cancer鈥� or CRC. All testing kits simultaneously detect CRC and pre-cancerous polyps.聽ColoGuard聽is designed to identify 11 genes whereas聽ColoGuard Plus聽zooms in on all but 聽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聽ColoGuard Plus聽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鈥檚 more, fecal matter is not the only place of methyl residence. In fact,聽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聽ColoGuard Plus? The short answer is 鈥淚t depends鈥�. The molecular holy-grail for medical testing kits are聽sensitivity聽(accurate capture of diseases in people with the disease, also called 鈥渢rue positives鈥�) and聽specificity聽(accurate detection of no disease in people who are disease-free, termed as 鈥渢rue negatives鈥�).
Here is the performance card for聽ColoGuard Plus聽for聽colorectal cancer聽(CRC):聽95% Sensitivity, meaning 95% of the participants聽with聽CRC are accurately detected as such whereas 5% of the people also聽with聽CRC received a聽negative聽test result, which is untrue, hence 鈥渇alse negatives鈥�. As for the other testing parameter,聽ColoGuardPlus聽has聽91% Specificity聽which is interpreted as 91%聽without聽CRC are indeed tested negative (which is good news!) while 9% of CRC disease-free patients were erroneously tested positive or 鈥渇alse positives鈥� (which can be unnecessarily stupefying!). Then again, no screening test is perfect.聽
Now, page 2 of聽ColoGuard Plus聽performance card on聽advanced pre-cancerous polyps聽depicts a mixed picture: The plus side is test聽Specificity聽of 94%, that is, 94% of individuals聽without聽polyps are accurately tested as 鈥渢rue negatives鈥�, which is聽remarkable聽progress compared to the first-generation聽ColoGuard聽and to other fecal matter-based screening tests. An area with still considerable room for improvement by聽ColoGuard Plus聽pertains to test Sensitivity of聽advanced pre-cancerous polyps which, at the moment, 聽is聽merely 43%. Is it a big deal? Yes. Because it indicates that only 43% of the individuals聽with聽 polyps of 10 mm or greater in diameter are caught as 鈥渢rue positives鈥� 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聽undetected聽which are 鈥渇alse negatives.鈥� 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聽ColoGuard聽Plus聽as a聽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聽ColoGuardPlus聽or other fecal matter-based screening tests all must be verified by the Gold Standard of CRC and polyps detection procedure:聽COLONOSCOPY. Equipped with a micro camera that offers a panoramic view of the colorectal tract,聽COLONOSCOPY聽allows not only detection but also surgical removal of pre-cancerous polyps right there and then during the procedure. Some may ask: If聽COLONOSCOPY聽is the ultimate go-to source, why bother with any screening kits in the first place?
Well, despite robust sensitivity and specificity of聽COLONOSCOPY, the invasive nature of the procedure and the uncomfortable preparation makes many shy away. This is where handy聽ColoGuard Plus聽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.聽鈥淪kate to where the puck is going to be鈥� 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. 聽The use of methylation markers by聽ColoGuard Plus聽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聽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.
