The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia

Abstract

Background & aims: Several noninvasive tests have been developed for colorectal cancer (CRC) screening. We compared the sensitivities of a multimarker test for stool DNA (sDNA) and a plasma test for methylated septin 9 (SEPT9) in identifying patients with large adenomas or CRC.

Methods: We analyzed paired stool and plasma samples from 30 patients with CRC and 22 with large adenomas from Mayo Clinic archives. Stool (n = 46) and plasma (n = 49) samples from age- and sex-matched patients with normal colonoscopy results were used as controls. The sDNA test is an assay for methylated BMP3, NDRG4, vimentin, and TFPI2; mutant KRAS; the β-actin gene, and quantity of hemoglobin (by the porphyrin method). It was performed blindly at Exact Sciences (Madison, Wisconsin); the test for SEPT9 was performed at ARUP Laboratories (Salt Lake City, Utah). Results were considered positive based on the manufacturer's specificity cutoff values of 90% and 89%, respectively.

Results: The sDNA test detected adenomas (median, 2 cm; range, 1-5 cm) with 82% sensitivity (95% confidence interval [CI], 60%-95%); SEPT9 had 14% sensitivity (95% CI, 3%-35%; P = .0001). The sDNA test identified patients with CRC with 87% sensitivity (95% CI, 69%-96%); SEPT9 had 60% sensitivity (95% CI, 41%-77%; P = .046). The sDNA test identified patients with stage I-III CRC with 91% sensitivity (95% CI, 71%-99%); SEPT9 had 50% sensitivity (95% CI, 28%-72%; P = .013); for stage IV CRC, sensitivity values were 75% (95% CI, 35%-97%) and 88% (95% CI, 47%-100%), respectively (P = .56). False positive rates were 7% for the sDNA test and 27% for SEPT9.

Conclusions: Based on analyses of paired samples, the sDNA test detects nonmetastatic CRC and large adenomas with significantly greater levels of sensitivity than the SEPT9 test. These findings might be used to modify approaches for CRC prevention and early detection.

Figure 1

Detection rates of large colorectal adenomas by next generation stool DNA and plasma septin 9 tests (n = 22). Median adenoma size was 2.0 cm (range 1.0 – 5.4), and 55% were proximal to the splenic flexure.

Figure 2

Detection rates of colorectal cancer by stool DNA and plasma septin 9 testing. Rates are compared for the overall group, n = 30; the subset without distant metastases (stages I-III), n = 22; and the subset with distant metastases (stage IV), n = 8.

Figure 3

Comparison of colorectal cancer detection rates by stool DNA and plasma septin 9 testing according to tumor site. See footnote in Table 1 for definitions of proximal and distal.

Figure 4

Molecular marker release from colorectal neoplasms into target media. This conceptual model shows proportional differences (illustrated by arrow sizes) expected in rates of marker release into the bloodstream via the mechanism of vascular invasion and into the the stool via the mechanism of exfoliation during progressive phases of tumorigenesis. Marker release into the bloodstream from precursor lesions is negligible but increases progressively with advancing stages of cancer. In contrast, marker release by exfoliation into stool occurs at comparable rates from large precancers and all stages of cancer.