mt-sDNA test shows high specificity for colorectal cancer screening in average-risk 45- to 49-year-olds

March 05, 2021

Between 2005 and 2013, the incidence of colorectal cancer in adults ages 40 to 49 years increased 1.3% a year. Rectal cancer rates increased 2.3% a year in adults in that age group. Consequently, current American Cancer Society guidelines recommend average-risk colorectal cancer screening beginning at age 45.

"Although it's increasing, colorectal cancer in patients under age 50 remains less common than in older patients," says John B. Kisiel, M.D., Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minnesota. "Its low population prevalence requires a screening test with high specificity and good sensitivity to minimize false-positive results, which can generate unnecessary invasive diagnostic colonoscopies."

Because most currently endorsed colorectal cancer screening tests have not been studied in adults younger than 50, Dr. Kisiel and fellow researchers conducted a cross-sectional study of the specificity and sensitivity of the multitarget stool DNA (mt-sDNA) test for colorectal cancer screening in average-risk 45- to 49-year-olds. Results were published in Cancer Prevention Research in 2021.

mt-sDNA test

The mt-sDNA test detects biomarkers associated with advanced colorectal neoplasia; a positive test requires a colonoscopy. In a study of participants age 50 and older at average risk of colorectal cancer — published in The New England Journal of Medicine in 2014 — the mt-sDNA test was 92% sensitive for colorectal cancer and 87% specific among participants with nonadvanced adenomas or negative findings on colonoscopy. The sensitivity for advanced precancerous lesions was 42%. The specificity was even higher — 94% — in patients ages 50 to 64 years.

"In this study, we evaluated the performance of the mt-sDNA test in average-risk participants ages 45 to 49 years," says Dr. Kisiel. "Our primary aim was to quantify the specificity of the mt-sDNA test. A secondary aim was to determine the sensitivity of the mt-sDNA test for colorectal cancer and advanced precancerous lesions."

Study participants were enrolled at 31 sites from November 2018 through June 2019. To target participants at average risk, researchers excluded people with conditions such as overt rectal bleeding; positive fecal occult blood test or fecal immunochemical test within the six months prior to enrollment; or previous colonoscopy, double-contrast barium enema, CT colonography, or flexible sigmoidoscopy within five years of enrollment.

Participants completed the mt-sDNA test followed by a screening colonoscopy within 60 days of enrollment. Bowel preparation and colonoscopy were performed according to each site's usual practice. All colonoscopies were performed blinded to mt-sDNA results.

Performance and outcomes

The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. From 983 nonconsecutive study participants enrolled after providing informed consent, 876 underwent colonoscopy and submitted a stool sample. Of those participants, 816 were included in the evaluable cohort. The mean age was 47.8 years, and 47.7% were women. None had colorectal cancer, 49 had advanced precancerous lesions, 253 had nonadvanced adenomas and 514 had negative colonoscopic findings.

The researchers measured specificity in participants without colorectal cancer or advanced precancerous lesions and in a subgroup of participants with negative colonoscopic findings. In participants with nonadvanced adenomas or negative findings, mt-sDNA test specificity was 95.2%. In patients with negative findings, specificity was 96.3%. Specificity did not differ by sex (P = 0.75) or race (P = 0.36) in participants with nonadvanced adenomas or negative findings.

Sensitivity for advanced precancerous lesions was 32.7%, detecting 16 of 49 advanced precancerous lesions with most (83.7%) measuring 10 to 19 mm and none having high-grade dysplasia. This sensitivity estimate was not significantly different from the 42% value seen in the 2014 study of older patients.

Test specificity, rather than sensitivity, was the primary outcome of this study for two reasons, notes Dr. Kisiel. "First, the expected prevalence of colorectal cancer and advanced precancerous lesions is lower in the 45- to 49-year-old age group. For a screening test to be viable in a low-prevalence setting, it requires high specificity to minimize costs and burdens resulting from false-positive test results. Second, there is no reason to expect colorectal cancer sensitivity for adults ages 45 to 49 to differ from that in older persons, especially when most early-onset colorectal cancer is located in the distal colon and rectum."

Dr. Kisiel concludes: "With guidelines recommending initiation of average-risk colorectal cancer screening at age 45, a noninvasive test with high specificity is required to optimize resource use and minimize the risk from more-invasive procedures. Using noninvasive screening in this age group would identify individuals most likely to benefit from colonoscopy, mitigating the impact of potential diversion of colonoscopy resources from patients at higher risk to younger individuals with lower risks of colorectal cancer and advanced precancerous lesions."

For more information

Imperiale TF, et al. Specificity of the multi-target stool DNA test for colorectal cancer screening in average-risk 45-49 year-olds: A cross-sectional study. Cancer Prevention Research. In press.

Imperiale TF, et al. Multitarget stool DNA testing for colorectal-cancer screening. The New England Journal of Medicine. 2014;370:1287.