In persons at average risk, stool DNA tests had higher sensitivity than FIT for detecting colorectal cancer

Questions In persons at average risk, does a noninvasive, multitarget stool DNA test accurately detect colorectal cancer (CRC)? How does it compare with a fecal immunochemical test (FIT)? Methods Design Blinded comparison of stool DNA test and FIT with colonoscopy. ClinicalTrials.gov NCT01397747. Setting 90 sites in the USA and Canada. Patients 9989 asymptomatic persons 50 to 84 years of age (mean age 64 y, 54% women) who were at average risk for CRC and were scheduled for screening colonoscopy. Exclusion criteria were history of colorectal neoplasia, digestive cancer, or inflammatory bowel disease; colonoscopy within 9 years or barium enema, computed tomographic colonography, or sigmoidoscopy within 5 years; positive fecal blood test in the previous 6 months; colorectal resection; overt rectal bleeding in the previous 30 days; or personal or family history of CRC. Description of tests Stool samples were collected before bowel preparation. The multitarget stool DNA test included molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, mutant KRAS, and -actin and an immunochemical assay for human hemoglobin. A test was considered positive for values 183 based on a validated, prespecified logistic-regression algorithm. FIT (OC FIT-CHEK, Polymedco) was performed to manufacturer directions; the positive cutpoint was hemoglobin >100 ng/mL of buffer. Diagnostic standard Screening colonoscopy and histopathology. Outcomes Sensitivity, specificity, and number needed to screen for CRC and advanced precancerous lesions (advanced adenomas and sessile serrated polyps 1 cm in diameter). Main results 0.7% of participants had CRC, and 7.6% had advanced precancerous lesions. Stool DNA test had higher sensitivity than FIT for detecting CRC and lower specificity for nonadvanced or negative findings (Table). The number needed to screen with colonoscopy was 154 (95% CI 120 to 200) for CRC and 13 (CI 12 to 14) for advanced precancerous lesions. Conclusions In persons at average risk, a screening stool DNA test had 92% sensitivity for detecting colorectal cancer. The stool DNA test had higher sensitivity and lower specificity than a fecal immunochemical test. Diagnostic characteristics of stool DNA test and fecal immunochemical test (FIT) for detecting colorectal cancer* Lesion Stool DNA test FIT Sensitivity NNS Sensitivity NNS Colorectal cancer 92% (83 to 98) 166 (130 to 217) 74% (62 to 84) 208 (156 to 286) Advanced precancerous lesions 42% (39 to 46) 31 (28 to 35) 24% (21 to 27) 55 (48 to 65) Specificity Specificity All nonadvanced adenomas or negative findings 87% (86 to 87) 95% (94 to 95) Negative colonoscopy 90% (89 to 91) 96% (96 to 97) *NNS = number needed to screen; other diagnostic terms defined in Glossary. Advanced adenomas and sessile serrated polyps 1 cm. All nonadvanced adenomas, nonneoplastic findings, and negative results on colonoscopy. Commentary Randomized controlled trials of fecal occult blood test (FOBT) screening have shown reductions in CRC incidence and mortality (1). The US Preventive Services Task Force recommends screening with either FOBT (high-sensitivity FOBT or FIT) and/or lower endoscopy (1). Although Imperiale and colleagues evaluated the stool DNA test only for diagnostic accuracy, its high sensitivity for detecting advanced neoplasia suggests that it could be effective for cancer screening. Acceptance of a screening test depends on convenience and cost as well as accuracy. Collecting and shipping an entire bowel movement for a DNA test seems more burdensome than obtaining a stool sample for FIT. Additionally, transport and technical problems prevented DNA testing for about 6% of study samples. Neither the testing interval nor the costs of DNA tests have been determined. These factors could affect the uptake and actual effectiveness of DNA tests. The DNA tests had over twice as many abnormal results as FIT, with a higher rate of false-positive results. This means that more colonoscopies would need to be performed to detect an advanced neoplasm with DNA testing than with FIT testing. However, interpreting false-positive results is complicated because colonoscopy is an imperfect gold standard (2) and DNA testing can detect molecular abnormalities potentially arising from extracolonic neoplasia (3). Further diagnostic testing could increase the costs and risks of screening. Having unexplained positive DNA test results might also be stressful to patients. DNA testing is a marvelous example of translational research, but it does not seem ready for prime time.