Multitarget Stool DNA Test Performance in an Average-Risk Colorectal Cancer Screening Population

Abstract

Introduction: We set out to evaluate the performance of a multitarget stool DNA (MT-sDNA) in an average-risk colonoscopy-controlled colorectal cancer (CRC) screening population. MT-sDNA stool test results were evaluated against fecal immunochemical test (FIT) results for the detection of different lesions, including molecularly defined high-risk adenomas and several other tumor characteristics.

Methods: Whole stool samples (n = 1,047) were prospectively collected and subjected to an MT-sDNA test, which tests for KRAS mutations, NDRG4 and BMP3 promoter methylation, and hemoglobin. Results for detecting CRC (n = 7), advanced precancerous lesions (advanced adenoma [AA] and advanced serrated polyps; n = 119), and non-AAs (n = 191) were compared with those of FIT alone (thresholds of 50, 75, and 100 hemoglobin/mL). AAs with high risk of progression were defined by the presence of specific DNA copy number events as measured by low-pass whole genome sequencing.

Results: The MT-sDNA test was more sensitive than FIT alone in detecting advanced precancerous lesions (46% (55/119) vs 27% (32/119), respectively, P < 0.001). Specificities among individuals with nonadvanced or negative findings (controls) were 89% (791/888) and 93% (828/888) for MT-sDNA and FIT testing, respectively. A positive MT-sDNA test was associated with multiple lesions (P = 0.005), larger lesions (P = 0.03), and lesions with tubulovillous architecture (P = 0.04). The sensitivity of the MT-sDNA test or FIT in detecting individuals with high-risk AAs (n = 19) from individuals with low-risk AAs (n = 52) was not significantly different.

Discussion: In an average-risk screening population, the MT-sDNA test has an increased sensitivity for detecting advanced precancerous lesions compared with FIT alone. AAs with a high risk of progression were not detected with significantly higher sensitivity by MT-sDNA or FIT.

Figure 1.

Flowchart of the study design. The upper part indicates the stool collection derived from the colonoscopy arm of individuals who participated the COCOS trial. Only individuals who had a complete colonoscopy, who had a valid FIT result, and who provided a whole stool sample were included in the biomarker study population. Tissues were collected from participants with an advanced neoplasia, e.g., CRC, AA, and/or ASP, of which the numbers and performed analyses are indicated in the lower part. AA, advanced adenoma; ASP, advanced serrated polyp; COCOS, COlonoscopy or COlonography for Screening; CRC, colorectal cancer.

Figure 2.

Boxplots showing sDNA test values in the COCOS biomarker population. Boxplots show first quartile, median, third quartile, and range of sDNA test values. Dots represent individual data points. The horizontal dashed lines indicate the predefined threshold for a positive test results as reported before (*) [ref Imperiale et al., NEJM, 2014], and the adapter threshold as defined in the current study using a fixed specificity of 95%. COCOS, COlonoscopy or COlonography for Screening.

Figure 3.

Receiver operating characteristic (ROC) curves of the sDNA test vs FIT on advanced precancerous lesions (a) subdivided into advanced adenoma (b) and advanced serrated polyps (c). The continuous and dashed lines in the ROC curves show the performance of sDNA and FIT, respectively. AUC, area under the curve; FIT, fecal immunochemical test.