The US Multi-Society Task Force (USMSTF) has approved six methods at varying intervals for colorectal cancer screening (USMSTF).1 Four of these—colonoscopy, CT (computed tomography) colonography, flexible sigmoidoscopy, and capsule endoscopy, which the US Food and Drug Administration (FDA) approved as adjunctive testing in certain situations)—require some degree of bowel prep. The other two tests—fecal immunohistochemistry (FIT) and FIT-fecal DNA—do not require bowel prep. Of note, the FDA still approves the fecal occult blood test for colon cancer screening, though the USMSTF did not endorse it given the higher sensitivity rates of FIT testing.1 The recent FDA approval of the home commercial combined FIT-fecal DNA test (Cologuard), presents a highly attractive option for patients reluctant to perform bowel prep; take time off work, possibly both to prep as well as the day of the procedure; and undergo conscious sedation.
Overall rates of colorectal cancer incidence and deaths both have declined on average 2% per year for the last 10 years.2 One major reason is increased screening rates and earlier detection prompting timely investigation and treatment, depending on which screening test was performed. An important feature of this statistic that should be considered is that the declining incidence rate is likely due to benign polypectomy at the time of screening colonoscopy, preventing evolution to cancer. A concerning recent trend is the increased colorectal cancer rates, specifically in young patients (< 50 years old) population, prompting the screening age to be lowered to 45 years old.3 Therefore, with half of the eligible screening population participating in the workforce, many patients may specifically inquire about in-home, prep-free testing. This is a brief review of the scientific basis of these tests and comparison of their detection rates.
Colorectal Cancer Genetic Alterations
Vogelstein first described a sequence of adenoma to carcinoma in 1988 as a series of well-defined histologic stages that arise after a sequence of genetic mutations.4 The genomic changes include activation of proto-oncogenes (K-Ras, 12p) and inactivation of many tumor suppression genes, such as APC (5q), p53 (17p), and DCC (18q). Each step of this process is associated with histologic changes in a polyp from early adenoma to immediate, late, dysplasia, and ultimately carcinoma. It is thought that this transformation typically spans approximately 10 years, which is the basis of the intervals of certain screening tests (colonoscopy, flexible sigmoidoscopy).
Since the adenoma to carcinoma sequence theory was introduced, two other pathways have been established in which tumorigenesis is driven by other genetic alterations. The microsatellite instability pathway involves alterations in genes crucial to mismatch repair during DNA replication. The other pathway is the CpG island methylator phenotype (CIMP). CpG islands are DNA methylation regions in promoters known to regulate gene expression. When methylation occurs, the result is silencing of promoter regions and dysregulation of downstream gene expression. The timeframe for this type of process is not well-defined but occurs in 12%–15% of colon cancers.
In 2014, the FIT-fecal DNA test gained FDA approval. It is an assay for different DNA mutations in the stool sample. The test examines whole gene mutations, including: 7 KRAS mutations, methylation of bone morphogenetic protein 3 (BMP3) and N-Myc downregulated gene 4 (NDRG4), and presence of hemoglobin.5 In other words, this test detects methylation, mutation, and hemoglobin. The total result that comes back to the provider is "positive" or "negative" but does not report which of these abnormalities were detected.
Comparison of Detection Rates
One must parse the data regarding what "detection" is desired. The sensitivity of detection of carcinoma is a remarkably acceptable comparison. The multi-targeted stool DNA test is 92% sensitive for finding cancers, which is almost equal to colonoscopy, reportedly at 95%. Reasons for missed cases include folds obscuring vision or inappropriately identifying the hepatic flexure as the cecum.2
However, in terms of polyp detection, the comparison is vastly different. Here, the FIT-fecal DNA test proved a detection rate for high-grade dysplasia of 62%, which then fell to 42% for detecting any type of polyp.6 Comparatively, colonoscopy is 75%–93% sensitive for finding any type of polyp smaller than 6 mm.7
The USMSTF's extensive report highlights that FIT testing alone, without the multi-targeted DNA, had a 73.8% sensitivity for cancer detection, suggesting that most cancer sensitivity of the FIT-fecal DNA test is not due to the genetic markers.2 Unfortunately, they also note that FIT testing alone has a reported 30% advanced adenoma detection and concern over detection of serrated lesions. Because yearly FIT testing has a cumulative sensitivity equivalent to FIT-fecal DNA for cancer screening, this test is listed as a "first tier" designation, along with colonoscopy over the "second tier" multi-targeted stool DNA testing every three years.
False positive rates for the FIT-DNA test are higher than for FIT alone (13% versus 5%, respectively).6 With erroneous results in one out of seven positive multi-targeted stool tests, appropriate counseling regarding accuracy and dependability of screening methods must be given when discussing fecal test results or endoscopy results with patients.
Patient Population and Costs
The multi-targeted stool DNA is indicated, tested, and FDA approved only for average-risk, 50-year-old patients. In 2019, the FDA also approved these tests for adults ages 45 and older as the screening guidelines changed. Patients in a high-risk category (personal history of colorectal cancer or adenomas, family history of colorectal cancer, inflammatory bowel disease, suspected familial genetic cancer syndromes) are recommended to undergo colonoscopy for screening purposes.
Another significant consideration when ordering the appropriate screening test is the cost, and what qualifies as "screening" varies between states and insurance companies. Typically, one screening test is covered without any out-of-pocket expenses. Once a FIT-DNA test is positive , the recommended colonoscopic evaluation becomes a diagnostic study.
Diagnostic colonoscopies are only slightly more expensive, but not covered as preventive screening in some states. This may be an issue in underserved or rural areas that may have a shortage of endoscopists or where patients may have difficulty accessing healthcare. An example of a recent attempt to reduce this burden can be seen in the Kentucky legislature, which has amended regulations to include the follow-up colonoscopy under "screening." This is certainly not the case in many states, and many media outlets have reported unexpected costs resulting from further investigative studies.
On the other hand, for patients who do not have insurance and have no prospects of obtaining it, the cost of FIT-DNA testing is $500–$600 versus $2,750 for colonoscopy (national average), and $24 for FIT alone.2 Clearly, in this instance, FIT alone is most cost effective, with an additional acceptable cost of FIT-DNA with a higher sensitivity and a slightly better polyp detection rate.
When choosing the best test for your patient, there are two practical mantras: some screening is better than no screening, and the best test is the one that will get done. While cancer detection rates may be nearly equivalent between FIT-fecal DNA and colonoscopy, colonoscopy is the clear choice for advanced polyp detection and removal before cancer is established.
References
- Rex DK, Boland CR, et al. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. GI Endosc. 2017; 86(1):18-33.
- SEER database https://seer.cancer.gov/statfacts/html/colorect.html. Accessed on 1/1/2022.
- US Preventive Services Task Force. Screening for Colorectal Cancer US Preventive Services Task Force Recommendation Statement. JAMA. 2021;325(19):1965-1977. doi:10.1001/jama.2021.6238
- Vogelstein B, Fearon ER, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525-532. doi: 10.1056/NEJM 198809013190901.
- Dhaliwal A, Panagiotis J, et al. Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives. World J Gastrointest Oncol. 2015;7(10):178-183.
- Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal- cancer screening. N Engl J. Med. 2014;370:1287–1297.
- Lin JS, Piper MA, et al. Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 201621;315(23):2576-2594. doi: 10.1001/jama.2016.3332.
