Next-Generation Multitarget Stool DNA Screening Results

Colorectal

Douglas K. Rex, MD, MASGE reviewing Imperiale TF, et al. N Eng J Med 2024 Mar 14.

In this study of 20,176 persons aged 40 years or older and eligible for colorectal cancer (CRC) screening, participants completed a next-generation multitarget stool DNA test (mt-sDNA). Like the current commercially available Cologuard, this new test was developed by Exact Sciences (Madison, Wisc). The new test also utilizes a fecal immunochemical test (FIT), but the DNA markers are modified, primarily to enhance specificity.

In addition to completing the new mt-sDNA test, participants completed a FIT with a hemoglobin cutoff of 20 μg/g of feces and a colonoscopy at one of 186 U.S. sites. Key findings were:

Among 98 cancers, overall mt-sDNA sensitivity was 93.9%, including 92.7% for stage I to III cancers, and the positive predictive value (PPV) for CRC was 3.4%.
Among 2144 subjects with advanced precancerous lesions (adenoma or sessile serrated lesion [SSL] ≥1 cm, villous elements, or high-grade dysplasia), sensitivity was 43.4% overall, 39.6% in subjects younger than 65 years, and 47.0% in subjects 65 years or older. PPV for advanced neoplasia was 37.7%.
Among subjects without CRC or advanced precancerous lesions, specificity was 90.6%. Among those with a negative colonoscopy or only nonneoplastic findings, specificity was 92.7%. Among those with a negative colonoscopy, specificity was 93.4%. The issue of decreased specificity with increasing age persists in the new test. Specificity was 97.3% in 45- to 49-year-olds, which dropped progressively to 84.6% in subjects 76 years or older.
FIT alone had a sensitivity of 67.3% for CRC and 23.3% for advanced precancerous lesions, which were both lower than with mt-sDNA (P < .001). The sensitivity appeared higher with mt-sDNA than with FIT for all types and sizes of advanced precancerous lesions, but the separation was, again, greatest for SSLs, with FIT again appearing essentially ineffective for SSL detection. FIT specificity was 94.8% for advanced neoplasia, which was higher than specificity with mt-sDNA (P < .001). FIT specificity was high across age groups. Of course, in a program of annual FIT, the sensitivity of FIT would rise relative to mt-sDNA, and specificity would fall.

Comment:

To many gastroenterologists, this study will seem like an enormous effort to demonstrate incremental improvements. Although this study does not directly compare the new mt-sDNA with the currently available test, comparisons are inevitable. In a previous study that established the currently available test, sensitivity was 92.3% for CRC and 42.4% for advanced precancerous lesions. Thus, the new test has no loss of sensitivity. The specificity for advanced neoplasia was 86.6% for the currently available test. Since the new test has a specificity of 90.6%, the new test drops the false positive rate from 13.3% to 9.4%. Since specificity or a false-positive result is a key driver of colonoscopy use, the new test appears to have achieved the goal of improving specificity without losing sensitivity. The new test has not yet received approval from the U.S. Food and Drug Administration.

Douglas K. Rex, MD, MASGE

Bio and Disclosures

Citation(s):

Imperiale TF, Porter K, Zella J, et al. Next-generation multitarget stool DNA test for colorectal cancer screening. N Eng J Med 2024;390:984-993. (https://doi.org/10.1056/NEJMoa2310336)