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

7 October 2008 | Volume 149 Issue 7 | Pages 441-450

Background: Stool DNA testing is a new approach to colorectal cancer detection. Few data are available from the screening setting.

Objective: To compare stool DNA and fecal blood testing for detection of screen-relevant neoplasia (curable-stage cancer, high-grade dysplasia, or adenomas >1 cm).

Design: Blinded, multicenter, cross-sectional study.

Setting: Communities surrounding 22 participating academic and regional health care systems in the United States.

Participants: 4482 average-risk adults.

Measurements: Fecal blood and DNA markers. Participants collected 3 stools, smeared fecal blood test cards and used same-day shipment to a central facility. Fecal blood cards (Hemoccult and HemoccultSensa, Beckman Coulter, Fullerton, California) were tested on 3 stools and DNA assays on 1 stool per patient. Stool DNA test 1 (SDT-1) was a precommercial 23-marker assay, and a novel test (SDT-2) targeted 3 broadly informative markers. The criterion standard was colonoscopy.

Results: Sensitivity for screen-relevant neoplasms was 20% by SDT-1, 11% by Hemoccult (P = 0.020), 21% by HemoccultSensa (P = 0.80); sensitivity for cancer plus high-grade dysplasia did not differ among tests. Specificity was 96% by SDT-1, compared with 98% by Hemoccult (P < 0.001) and 97% by HemoccultSensa (P = 0.20). Stool DNA test 2 detected 46% of screen-relevant neoplasms, compared with 16% by Hemoccult (P < 0.001) and 24% by HemoccultSensa (P < 0.001). Stool DNA test 2 detected 46% of adenomas 1 cm or larger, compared with 10% by Hemoccult (P < 0.001) and 17% by HemoccultSensa (P < 0.001). Among colonoscopically normal patients, the positivity rate was 16% with SDT-2, compared with 4% with Hemoccult (P = 0.010) and 5% with HemoccultSensa (P = 0.030).

Limitations: Stool DNA test 2 was not performed on all subsets of patients without screen-relevant neoplasms. Stools were collected without preservative, which reduced detection of some DNA markers.

Conclusion: Stool DNA test 1 provides no improvement over HemoccultSensa for detection of screen-relevant neoplasms. Stool DNA test 2 detects significantly more neoplasms than does Hemoccult or HemoccultSensa, but with more positive results in colonoscopically normal patients. Higher sensitivity of SDT-2 was particularly apparent for adenomas.

Editors' Notes Context Because the colonic mucosa constantly sheds cells, testing stool for cancer-related genes could be better for colorectal cancer screening than testing for occult bleeding, which is intermittent. Content A total of 3764 healthy adults had screening colonoscopy, fecal occult blood testing with Hemoccult and HemoccultSensa, and both a first- and a second-generation stool DNA test (SDT-1 and SDT-2, respectively) for a battery of cancer genes. The sensitivity of SDT-1 and HemoccultSensa was very similar for screen-relevant neoplasms (20% and 21%, respectively), whereas the sensitivity of SDT-2 was 40%. Caution The authors could not measure the specificity of SDT-2. Implication A second-generation stool test for cancer genes is substantially more sensitive than fecal occult blood testing. —The Editors

 

Author and Article Information

From the Mayo Clinic, Rochester, Minnesota; Kaiser Permanente, Oakland and Sacramento, California; University of Indiana, Indianapolis, Indiana; University of Colorado Health Sciences Center, Denver, Colorado; University of Portland, Portland, Oregon; University of Arizona Health Science Center, Tucson, Arizona; Abbott Northwestern Hospital, Minneapolis, Minnesota, and University of Texas, Houston, Texas.

Acknowledgment: The authors thank EXACT Sciences for performance of all genetic assays on tissue and stools and Beckman Coulter for provision of Hemoccult and HemoccultSensa cards at no cost; Sara Linker Nord for management at coordination center; Kelli Burger for statistical support; Jacalyn McCormick for secretarial support; H. Samuel Wieand, PhD (University of Pittsburgh), for statistical consulting; and Jane Milburn for assistance on protocol development. The authors also thank the physicians and study coordinators at the participating medical centers for their support (Appendix).

Grant Support: By grants UO1 CA 89389 and UO1 CA 37404 from the National Institutes of Health.

Potential Financial Conflicts of Interest: Consultancies: D.J. Ahnen (EXACT Sciences), J.E. Allison (Fujirebio, Quidel). Stock ownership or options (other than mutual funds): J.E. Allison (IntelligeneScan). Grants received: T.R. Levin (EXACT Sciences), M.P. Lance (National Institutes of Health), M.J. Lawson (EXACT Sciences). The Mayo Clinic is a minor equity investor in EXACT Sciences.

Reproducible Research Statement: Study protocol, statistical code, and data set: Available from Ms. Devens (devens{at}mayo.edu).

Requests for Single Reprints: David A. Ahlquist, MD, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905; e-mail, ahlquist.david{at}mayo.edu.

Current Author Addresses: Drs. Ahlquist, Sargent, and Loprinzi; Ms. Devens; Mr. Harrington; and Ms. Hillman: Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905.

Dr. Levin: Kaiser Permanente, 3505 Broadway, 12th Floor, Oakland, CA 94611-5714.

Dr. Rex: University of Indiana, Division of Gastroenterology/Hepatology, 550 North University Boulevard, UH 4100, Indianapolis, IN 46202.

Dr. Ahnen: University of Colorado Health Sciences Center, Denver VAMC 111E, 1055 Clermont Street, Denver, CO 80220.

Dr. Knigge: Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, PV-310, Division of Gastroenterology, Portland, OR 97239.

Dr. Lance: University of Arizona Health Science Center, 1515 North Campbell Avenue, Room 2964, PO Box 245028, Tucson, AZ 85724-5024.

Dr. Burgart: Hospital Pathology Associates, PA, Abbott Northwestern Hospital, 800 East 28th Street, Minneapolis, MN 55407.

Dr. Hamilton: University of Texas, Box 85, Room GI.3754, 1515 Holcombe Boulevard, Houston, TX 77030-4095.

Dr. Allison: Kaiser Permanente, 3505 Broadway, 7th Floor, Oakland, CA 94611-5714.

Dr. Lawson: Kaiser Permanente, 2025 Morse Avenue, 2nd Floor, Sacramento, CA 95825-2112.

Author Contributions: Conception and design: D.A. Ahlquist, D.J. Sargent, C.L. Loprinzi, T.R. Levin, K. Knigge, M.P. Lance, J.E. Allison, M.E. Devens, S.L. Hillman.

Analysis and interpretation of the data: D.A. Ahlquist, D.J. Sargent, D.K. Rex, D.J. Ahnen, K. Knigge, M.P. Lance, L.J. Burgart, S.R. Hamilton, J.E. Allison, J.J. Harrington, S.L. Hillman.

Drafting of the article: D.A. Ahlquist, D.J. Sargent.

Critical revision of the article for important intellectual content: D.A. Ahlquist, D.J. Sargent, C.L. Loprinzi, T.R. Levin, D.K. Rex, D.J. Ahnen, M.P. Lance, J.E. Allison, M.J. Lawson.

Final approval of the article: D.A. Ahlquist, D.J. Sargent, T.R. Levin, D.K. Rex, D.J. Ahnen, M.P. Lance, S.R. Hamilton, J.E. Allison, M.J. Lawson.

Provision of study materials or patients: D.A. Ahlquist, D.J. Sargent, T.R. Levin, D.K. Rex, D.J. Ahnen, M.P. Lance, M.E. Devens.

Statistical expertise: D.J. Sargent, S.L. Hillman.

Obtaining of funding: D.A. Ahlquist, D.J. Sargent, C.L. Loprinzi, M.P. Lance, M.E. Devens.

Administrative, technical, or logistic support: D.A. Ahlquist, D.J. Sargent, C.L. Loprinzi, D.K. Rex, D.J. Ahnen, K. Knigge, S.R. Hamilton, M.E. Devens, J.J. Harrington, S.L. Hillman.

Collection and assembly of data: D.J. Sargent, T.R. Levin, D.K. Rex, D.J. Ahnen, K. Knigge, M.P. Lance, L.J. Burgart, M.J. Lawson, M.E. Devens, J.J. Harrington, S.L. Hillman.