Scheu, Bradley

Abstract High-specificity colorectal cancer screening is desirable to triage patients <50 years for colonoscopy; however, most endorsed colorectal cancer screening tests have not been rigorously evaluated in younger populations. This prospective cross-sectional study determined the specificity of the multitarget stool DNA (mt-sDNA) test in an average-risk screening population of 45 to 49 year-olds. Specificity was the primary outcome and was measured in participants without colorectal cancer or advanced precancerous lesions [APL– advanced adenomas (AA), and sessile serrated lesions ≥10 mm], and in the subgroup of participants with negative colonoscopic findings. APL sensitivity was a secondary outcome. The evaluable cohort included those who completed the study without protocol deviations and had a usable mt-sDNA test. Of 983 enrolled participants, 816 formed the evaluable cohort, with a mean age of 47.8 (SD, 1.5) years; 47.7% were women. No participants had colorectal cancer, 49 had APL, 253 had nonadvanced adenomas (NAA), and 514 had negative colonoscopic findings. mt-sDNA test specificity was 95.2% (95% CI, 93.4–96.6) in participants with NAA or negative findings [96.3% (confidence interval (CI), 94.3%–97.8%)] in those with negative findings, and did not differ by sex (P = 0.75) or race (P = 0.36) in participants with NAA or negative findings. Sensitivity for APL was 32.7% (CI, 19.9–47.5%), with most APL (83.7%) measuring 10–19 mm and none having high-grade dysplasia. The area under the ROC curve for discriminating between APL and lesser findings was 0.72 (CI, 0.64–0.81). mt-sDNA's high specificity would help minimize risk from unnecessary diagnostic procedures in this age group. This study shows that mt-sDNA has high specificity among average-risk 45 to 49-year olds, supporting its use as a noninvasive option for colorectal cancer screening. Prevention Relevance: This study shows that mt-sDNA has high specificity among average-risk 45–49 year olds, supporting its use as a non-invasive option for colorectal cancer screening.

INTRODUCTION: Due to the rising incidence and mortality of colorectal cancer (CRC) in individuals < 55 years (Siegel R, et al, JNCI, 2017), American Cancer Society (ACS) guidelines now recommend average-risk CRC screening beginning at age 45 years. The multi-target stool DNA (mt-sDNA) test, an FDA-approved screening test for average-risk individuals ≥50 years, is one ACS-recommended option for this age group. To minimize invasive testing in the younger age group, a screening test with high specificity is necessary to triage patients for diagnostic colonoscopy. To date, most endorsed CRC screening tests have not been rigorously studied in younger age groups. The objective of this study (the Act Now study [NCT03728348]) is to quantify the specificity of the mt-sDNA test in average risk individuals ages 45-49. METHODS: Act Now is an ongoing prospective, cross-sectional, multi-center study in subjects ages 45-49 at average risk for CRC. 942 subjects are targeted for enrollment and will complete a mt-sDNA test prior to undergoing a screening colonoscopy (blinded to mt-sDNA test results). Specificity for advanced colorectal neoplasia will be determined by comparing mt-sDNA test results to the most advanced finding on colonoscopy, based on procedure report and histopathological findings. Due to the low prevalence of CRC in this age group, mt-sDNA test sensitivity will be a secondary measure. RESULTS: To date, 480 subjects have completed a mt-sDNA test and screening colonoscopy. A total of 468 subjects (97.5%) have no first-degree relative (FDR) with CRC and 12 subjects (2.5%) have an FDR diagnosed at age ≥60 years. No subject has had a previous screening colonoscopy. The study population has a mean age of 47.4 years and is 48.8% female. Self-reported race includes 84.2% white, 11.5% black/African American, 3.3% Asian, and 1.0% other. Self-reported ethnicity includes 95.2% not Hispanic or Latino, 4.6% Hispanic or Latino, and 0.2% other. The mean BMI of subjects is 29.6 kg/m 2 . Most subjects (67.1%) have never smoked cigarettes, while 21.9% are former smokers and 11.0% are current smokers. CONCLUSION: The ongoing Act Now study will quantify the specificity of the mt-sDNA test in average risk individuals ages 45-49. Given concerns regarding the resources required to screen this age group for CRC, a noninvasive screening test with high specificity and sensitivity will help to optimize use of colonoscopy resources.