Screening for Colorectal cancer-Where does the FIT-DNA test fit?

February 21, 2019

By Jamie Oliver

Peer Reviewed

Colorectal cancer (CRC) is the second most common cause of cancer death in the US.[1]Almost all CRC develops from precancerous polyps, and with appropriate colonoscopy screening most polyps can be detected and removed before they transform into cancer. Simply put, CRC screening saves lives.

The US Preventive Services Task Force (USPSTF) recommends CRC screening for all adults aged 50-75;[2] however, over 40% of eligible adults in the US forego routine screening.[3]Perhaps some of this resistance is due to the invasive nature of the mostcommon testing procedure, colonoscopy. Whatever the cause, this avoidance of testing has contributed to as many as 50,000 deaths each year from colorectal cancers in the US.[4]

For many years, the USPTSF has recommended four different CRC screening modalities. Some are more invasive and off-putting than others. Colonoscopy, the gold standard, has the highest sensitivity and specificity for cancer detection but requires patients to forego solid food for a day and drink large volumes of laxatives. Average-risk CRC screening with colonoscopy is currently recommended every ten years. Alternatively, patients can opt for flexible sigmoidoscopy (also invasive) or CT colonography every five years (both requiring bowel preparation), fecal immuno chemical testing (FIT) every year, or sigmoidoscopy every ten years with annual FIT.2

Each of these other screening methods provides at least 90% of the life-year gain as colonoscopy.2 Positive results with CT colonography and FIT require proceeding to colonoscopy for definitive assessment. Therefore, initiating screening with colonoscopy or sigmoidoscopy eliminates the potential intermediate steps associated with these other tests.

In 2016, the USPTSF added a new stool screening test to its recommendations: FIT-DNA.2 It is important that primary care physicians be informed regarding its efficacy and potential role in CRC screening, as it is both USPTSF-recommended and covered by Medicare and most major insurers. This newly available FIT-DNA test, Cologuard®, attempts to improve on the standard FIT by testing cells shed in the stool for altered DNA bio markers. The literature regarding FIT-DNA is limited, since it was only approved by the FDA in 2014.

There are many small studies that investigated FIT-DNA during its early stages of development,but there are only two studies that have assessed the final version of the test used today in CRC screening.[5],[6] The largest of these studies was conducted in 2014, and examined 10,000 asymptomatic adults ≥50 years old at average risk for CRC (no inflammatory bowel disease or personal or family history of CRC).5 Using colonoscopy as the reference standard, FIT-DNA was found to be significantly more sensitive (92.3%) for detecting CRC than FIT alone (73.8%). FIT-DNA was also more sensitive for detecting precancerous lesions (42.4%) than FIT (23.8%). However, FIT-DNA was significantly less specific (86.6%) than FIT alone (94.9%), and led to significantly more false positive results (1231) than did FIT (472). The results of this study were corroborated by a subsequent, but much smaller trial(660 patients).6 The results from these two studies represent the best estimates of the diagnostic performance of FIT-DNA used in CRC screening.

When considering CRC screening methods, one must weigh three primary factors:identifying cancers and the life-years gained, costs, and the consequences of false positive tests: the associated anxiety, further workup, and costs these might entail. Being a relatively new instrument, FIT-DNA has yet to be studied longitudinally with direct assessments of health outcomes and survival.However, several studies have used simulation modeling to estimate the comparative outcomes of different CRC screening strategies.[7],[8],[9]

One of these modeling studies, by Knudsen and colleagues in 2016, was specifically solicited and designed (not by the manufacturer) to inform the USPSTF 2016 screening recommendations.7 FIT-DNA was evaluated using a one-year and three-year screening strategy. Both strategies were found to have at least 90% of the life-year gain of colonoscopy, thus falling within range of other screening tools. Notably, annual FIT-DNA testing was found to have the second-highest life-years gained per 1000 screened—second only to colonoscopy every ten years. It was more effective than sigmoidoscopy with or without FIT testing, CT colonography, or FIT testing alone. However, FIT-DNA testing every three years was at the lower range of effectiveness, only better than flexible sigmoidoscopy alone in terms of life-years gained.

Unfortunately, FIT-DNA ($500 per test) is significantly more expensive than FIT alone ($25 per test). While its costs are similar to an individual sigmoidoscopy or CT colonography scan, it must be performed more frequently than the other screening methods. Modeling analyses note that FIT-DNA screenings lead to higher overall costs.[10]

FIT-DNA also leads to significantly more follow-up colonoscopies than FIT alone, due to its lower specificity and positive predictive value.6 However, these results are somewhat offset by FIT-DNA’s nearly doubled rate of advanced precancerous lesion detection compared to FIT alone. Based on the data currently available, one can expect 23.6% of patients with a positive FIT-DNA to have an advanced precancerous lesion or colorectal cancer on colonoscopy compared to 32.8% of patients following a positive FIT.5 Over 50% of patients with positive results using either test will have a polyp. Modeling has estimated minimal difference, but FIT-DNA may lead to slightly more complications following screening (vs FIT) due to the increased colonoscopy usage (12 versus 10 complications per 1000 screened).7

In its current form, DNA testing for CRC is more an incremental improvement in screening than an answer to the challenges of CRC screening. Many questions must be answered before FIT-DNA is ready for mass application, especially in light of its higher costs. Non-modeled mortality data are needed, and clear screening intervals must be outlined. Such research is in the pipeline; a longitudinal study of FIT-DNA screening every three years is set to be completed in 2019.[11]

The future of CRC screening is likely to entail DNA testing. Stool testing will continue to improve, and blood tests for CRC are in development. Research has demonstrated that blood testing can detect approximately 70% of CRC with a specificity of 90%,[12]and one blood test, Epi pro Colon, was approved by the FDA in 2016. However, it is not currently recommended by the USPSTF.

As this area of research develops, it is important that physicians remain aware of all the currently available USPTSF-approved screening modalities. “One size fits all” may not be the most effective cancer screening approach for all patients. Studies have shown that colonoscopy may be avoided by large numbers of patients averse to the procedure and by underserved persons who prefer at-home stool testing.[13] To these and other patients with intermittent access to healthcare, FIT-DNA may provide the best option for screening. It is the most sensitive stool test, and a positive result could potentially lead at-risk patients to colonoscopy that they would otherwise shun.

Cancer screening saves lives. And colonoscopy remains the gold standard for detecting colorectal cancers. Without it, large numbers of lives will continue to be lost. In lieu of this invasive test, FIT-DNA stool testing with its improved sensitivity is a promising new screening alternative for saving lives by detecting precancerous polyps and colorectal cancer.

Jamie Oliver is a 3rd year student NY NYU Langone Health

Peer reviewed by Michael Poles, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


[1]. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.

[2]. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;315(23):2564-2575.

[3]. Centers for Disease Control and Prevention. National Health Interview Survey. Available at: Published March 1, 2014. Accessed June 21, 2018.

[4].National Cancer Institute. SEER Cancer Statistics Fact sheets: Colon and Rectum Cancer. Available at: September, 2014. Accessed June 21, 2018.

[5]. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multi target stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297.

[6]. RedwoodDG, Asay ED, Blake ID, et al. Stool DNA testing for screening detection of colorectal neoplasia in Alaska Native people. Mayo Clin Proc. 2016;91(1):61-70.

[7]. Knudsen AB, Zauber AG, Rutter CM, et al. Estimation of benefits, burden, and harms of colorectal cancer screening strategies: modeling study for the US Preventive Services Task Force. JAMA. 2016;315(23):2595-2609.

[8]. Berger BM, Schroy PC 3rd, Dinh TA. Screening for colorectal cancer using a multi target stool DNA test: modeling the effect of the intertest interval on clinical effectiveness. Clin Colorectal Cancer. 2016;15(3):e65-74.

[9]. BarziA, Lenz HJ, Quinn DI, Sandeghi S. Comparative effectiveness of screening strategies for colorectal cancer. Cancer.2017;123(9):1516-1527.

[10]. Johnson DH, Kisiel JB, Burger KN, et al. Multitarget stool DNA test: clinical performance and impact on yield and quality of colonoscopy for colorectal cancer screening. Gastrointest Endosc. 2017;85(3):657-665.e1.

[11]. A longitudinal study of Cologuard in an average risk population assessing a three year test interval. NCT02419716. Accessed June 19, 2018.

[12].Pickhardt PJ. Emerging stool-based and blood-based non-invasive DNA tests for colorectal cancer screening: the importance of cancer prevention in addition to cancer detection. Abdom Radiol (NY). 2016;41(8):1441-1444.

[13]. Gupta S, Halm EA, Rockey DC, et al. Comparative effectiveness of fecal immuno chemical test outreach, colonoscopy outreach, and usual care for boosting colorectal cancer screening among the underserved: a randomized clinical trial. JAMA Intern Med. 2013;173(18):1725-1732.