Detection of Colorectal Serrated Polyps by Stool DNA Testing: Comparison with Fecal Immunochemical Testing for Occult Blood (FIT)

Abstract

ObjectivesPrecursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) ≥1 cm by sDNA and an occult blood fecal immunochemical test (FIT).MethodsIn a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP≥1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, β-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab ≤2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100).ResultsMedian ages: cases 61 (range 57–77), controls 62 (52–70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1–3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP≥1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP≥1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001).ConclusionsIn a screening and surveillance setting, SSP≥1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection.

Detection rate of serrated polyps and serrated polyposis syndrome in colorectal cancer screening cohorts: a European overview

“…No structural differences were found between the FOBT-based screening cohorts and the primary colonoscopy cohorts regarding the rate of SSP or clinically relevant SP, which suggests that for now, uniform standards in SP detection could be introduced. These data are supported by a recent report, which showed that faecal blood tests are not useful as pretest to increase the detection of SPs, possibly due to the fact that these lesions only seldom bleed 31. Furthermore, in the current study no uniform gender and/or age differences in NNS were found for SSP or clinically relevant SPs.…”

Molecular markers for colorectal cancer screening

“…74 Importantly, these markers in combination with DNA mutations, are also wellrepresented in stools from patients with sessile serrated polyps, which was shown in a blinded case-control analysis. 80 …”

Multi-Target Stool DNA Test: A New High Bar for Noninvasive Screening

“…The important subset of sessile serrated polyps C1 cm appears to be exclusively detected by assay of exfoliated DNA markers [43]. One of exfoliated DNA markers (methylated BMP3) from the MT-sDNA panel contributes nearly all of the diagnostic value, and the occult blood contribution is negligible (Fig.…”

“…Importantly, fecal blood tests fail entirely to detect the subset of sessile serrated polyps [4,43], lesions which are also often missed by colonoscopy and may help to explain its lesser effect on proximal disease [58].…”

“…Stool detection of sessile serrated polyps (SSP) from patients undergoing screening or surveillance: assay of methylated DNA marker (BMP3) versus a commercial fecal immunochemical blood test (FIT)[43] …”