Stool DNA and Occult Blood Testing for Screen Detection of Colorectal Neoplasia

Colorectal cancer remains the second most common cause of death among the types of cancer (1). Although screening reduces colorectal cancer mortality (2–6), observed reductions have been modest (6, 7) and more than one half of adults in the United States have not received screening (8). More accurate, user-friendly, and widely distributable tools have the potential to improve screening effectiveness, acceptability, and access. Several molecular approaches to screening stool for colorectal cancer have been studied and reviewed (9, 10), and stool DNA testing has been jointly endorsed by the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (11). The advantages of stool DNA testing include noninvasiveness, absence of bowel preparation or dietary restrictions, and ease of access via mail courier. However, the reported accuracy of stool DNA tests for the detection of colorectal neoplasia varies. In clinical studies that used different assays and selected groups (12–20), sensitivities ranged from 62% to 100% for colorectal cancer and 27% to 82% for advanced adenomas, with specificities ranging from 82% to 100%. In the only reported multi-center study on asymptomatic average-risk patients (21), a precommercial multitarget DNA assay (SDT-1, a prototype of PreGenPlus, EXACT Sciences, Marlborough, Massachusetts) detected 52% of cases of colorectal cancer, compared with 13% by Hemoccult (P = 0.003), at specificities of 94.4% and 95.2%, respectively. The accuracy of stool DNA testing is influenced by both biological and technical factors. A panel of markers must be used to accommodate the molecular heterogeneity of colorectal neoplasia, and marker selection critically affects discrimination (9). Unlike occult bleeding, which is intermittent (22), DNA markers seem to be shed continuously by exfoliation (23). Thus, the multiple stool sampling practiced with fecal occult blood tests may not be necessary with stool DNA tests. However, recovery of the minute quantities of human DNA and assay of tumor-specific DNA alterations from stool present technical challenges and require exquisite laboratory sensitivity to achieve optimal detection rates. Our primary aim was to compare the precommercial stool DNA test (SDT-1), which was studied by Imperiale and colleagues (21), with widely used fecal occult blood tests for the detection of screen-relevant neoplasia, defined as curable-stage colorectal cancer (no distant metastases), high-grade dysplasia, or adenomas larger than 1 cm. A secondary aim was to explore neoplasm detection by another stool DNA test 2 (SDT-2), which uses a more broadly informative marker panel.