New DNA Stool Test Offers Higher Sensitivity Screening

David Ransohoff, MD

A noninvasive stool DNA test may be a new option to increase rates of colorectal cancer screening, proving more sensitive in identifying colon cancer, advanced precancerous lesions, and polyps than currently available fecal immunochemical testing (FIT), according to findings of a large, multicenter study published online ahead of print March 19, 2014 in The New England Journal of Medicine.

Despite the known benefits of screening for colorectal cancer and modest increases in uptake in the last 15 years, 41% of Americans aged ≥50 years are not current with their recommended screening, according to the American Cancer Society; for certain populations, such as African Americans, screening rates are even lower.

For this study, researchers evaluated the performance of a new, multitarget DNA stool test and compared its cancer detection sensitivity with a commercially available FIT. The DNA screening tool involves quantitative molecular assays for KRAS mutations, abnormalities in methylated bone morphogenetic protein 3 (BMP3) and N-Myc downstream-regulated gene 4 (NDRG4), and β-actin. It also includes a hemoglobin immunoassay.

Specimens from 9989 individuals at average risk of colorectal cancer scheduled to undergo colonoscopy screening within 90 days of sample collection were obtained between June 2011 and November 2012 at 90 sites throughout the United States and Canada.

Of 65 study participants found to have cancer, the multitarget DNA test identified 60. Sensitivity of the DNA test was not significantly affected by cancer stage or location in the colon.

Both the DNA and the FIT test comparator were evaluated based on their detection sensitivity— defined as the true positive rate or the proportion of individuals with disease who have a positive test—in four areas: colorectal cancer (ie, adenocarcinoma); advanced precancerous lesions; polyps with high-grade dysplasia, and serrated sessile polyps measuring ≥1 cm.

The DNA test was found to be more sensitive across all four measures. For detecting colorectal cancer, sensitivity with the DNA testing was 92.3% versus 73.8% with FIT (P = .002). Sensitivity of the two tests for detecting advanced precancerous lesions was 42.4% with DNA testing versus 23.8% with FIT (P = .001); sensitivity was 69.2% and 46.2%, respectively, (P = .004) for detecting polyps with high-grade dysplasia, and 42.4% and 5.1%, respectively, (P < .001) for the detection of serrated sessile polyps.

The researchers noted, however, that although high sensitivity is the most important aspect of cancer screening, specificity (the proportion of individuals without disease who have a negative test result) also must be factored in, and here, results for FIT were better. Specificity with FIT was 94.9% to 96.4%, versus 86.6% to 89.8% for the multitarget DNA test. The majority of those with positive results, the researchers explained, will be false positives due to the low prevalence of cancer, and false-positive rates for FIT were 3.6% to 5.1% versus 10.2% to 13.4% with the DNA test. Among those with a negative colonoscopy result, the DNA test’s specificity was high—nearly 90%&mdash;though that result was still inferior to FIT specificity for this group (>96%).

Researchers also determined the number of persons who would need to be screened to detect one colorectal cancer using colonoscopy (154), multitarget DNA testing (166), and FIT (208). For the detection of one advanced precancerous lesion the numbers were 13, 31, and 55, respectively

“Detection of 92% of colon cancer is extremely high for a noninvasive test, so that a negative test result means that no further evaluation, like colonoscopy, is needed at that time,” said one of the study’s authors, David Ransohoff, MD, professor of medicine at the University of North Carolina School of Medicine and UNC Lineberger Comprehensive Cancer Center. “Having such a sensitive, noninvasive option could have an important effect on screening rates for colorectal cancer.”

On March 27, 2014, the FDA’s Molecular and Clinical Genetics advisory committee voted unanimously in support of the safety, efficacy, and positive risk-benefit profile of this noninvasive stool-based DNA test.

Nurse Perspective

Laura Metcalfe, MSN, RN, APN, C, AOCNS

John Theurer Cancer Center

Hackensack, NJ

Colorectal cancer is the third-most common type of cancer and the second leading cause of cancer death in the United States. Even so, about one in three adults aged 50 to 75 have not been tested for colorectal cancer as recommended by the US Preventive Services Task Force (USPSTF; http:// www.cdc.gov/vitalsigns).

The USPSTF recommends screening for colorectal cancer using fecal occult blood testing, sigmoidoscopy, or colonoscopy in adults beginning at age 50 years. The evidence is convincing that screening for colorectal cancer with any of these methods detects early-stage cancer and adenomatous, or precancerous, polyps. This is somewhat counter to what I have always believed— namely that colonoscopy is superior to the other methods, most notably as it can remove any polyps, thereby actually preventing a potential cancer from occurring. In March 2009, the American College of Gastroenterology (ACG) issued new colorectal cancer screening guidelines and stated, “Colonoscopy every 10 years, starting at age 50 years, is the preferred strategy.”

However, considering that one-third of the population who should be screened is not, we need to embrace any proven method that might improve this statistic. In a previous column for Oncology Nursing News (September 2011), I endorsed immunochemical fecal occult blood testing (iFOBT) as one way to increase screening with the understanding that any positive test could potentially lead to a colonoscopy. One drawback with iFOBT was the many false positives as well as false negatives.

The DNA test described here, if approved by the FDA, would represent an alternative or an adjunct screening method I would feel even better about recommending for those patients who either will not or cannot undergo a colonoscopy. It may be time to adopt a slogan from Australia’s 2014 bowel cancer awareness and screening campaign (testyourstool.org): “Don’t be a fool; test your stool.”