Multitarget Stool DNA for Average Risk Colorectal Cancer Screening: Major Achievements and Future Directions

Abstract

After 2 screen-setting studies showing high sensitivity for colorectal cancer and advanced precancerous lesions, multitarget stool DNA testing was endorsed by the US Preventative Services Task Force as a first-line colorectal cancer screening test. Uptake has increased exponentially since approval by the US Food and Drug Administration and Centers for Medicare and Medicaid Services. Adherence to testing is approximately 70%. Patients with positive results have high diagnostic colonoscopy completion rates in single-center studies. The positive predictive value for colorectal neoplasia in postapproval studies is high. Next-generation test prototypes show promise to extend specificity gains while maintaining high sensitivity.

Keywords: Colonoscopy/trends; Colorectal neoplasms/diagnosis; Colorectal neoplasms/prevention and control; DNA; Early detection of cancer/methods; Neoplasm/analysis; Precancerous conditions/diagnosis; Proximal colorectal neoplasia.

Fig. 1.

Preclinical observations supporting the rationale to develop stool DNA testing. (A) Bleeding into stool from asymptomatic CRCs can be intermittent. (B, C, cytokeratin immunostain) Neoplastic cells and debris are continuously shed into the luminal mucocellular layer above (B) colon cancers and polyps, but not in (C) healthy control mucosae. HQT, HemoQuant. (Adapted from Ahlquist DA, McGill DB, Fleming JL, et al. Patterns of occult bleeding in asymptomatic colorectal cancer. Cancer 1989;63(9):1826-1830; and Ahlquist DA, Harrington JJ, Burgart LJ, et al. Morphometric analysis of the “mucocellular layer” overlying colorectal cancer and normal mucosa: relevance to exfoliation and stool screening. Human pathology 2000;31(1):51-57; with permission.)

Fig. 2.

Detection of CRN by mt-sDNA test in clinical studies. (A) mt-sDNA colorectal neoplasm detection rates by in the United States general and Alaska Native populations. (B) Comparison between mt-sDNA and FIT for sessile serrated polyp detection in Alaska Native people. (Adapted from Redwood DG, Asay ED, Blake ID, et al. Stool DNA Testing for Screening Detection of Colorectal Neoplasia in Alaska Native People. Mayo Clin Proc 2016;91(1):61-70; with permission.)

Fig. 3.

Use of mt-sDNA testing in clinical practice. (A) Cumulative mt-sDNA tests completed over time and (B) providers who have enrolled to prescribe mt-sDNA. (Courtesy of Exact Sciences Corporation, Madison, WI.)

Fig. 4.

Timeline of major milestones in mt-sDNA testing for CRC screening. FOBT, fecal occult blood test; HEDIS, Healthcare Effectiveness Data and Information Set; MSTF, US Multi-Society Task Force; NCCN, National Comprehensive Cancer Network; NEJM, New England Journal of Medicine.