Multitarget Stool DNA Testing for Colorectal-Cancer Screening

New England Journal of Medicine (Impact Factor: 55.87). 03/2014; 370(14). DOI: 10.1056/NEJMoa1311194
Source: PubMed


An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening.

We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings.

Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P=0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P=0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT.

In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; number, NCT01397747.).

49 Reads
  • Source
    • "They evaluated 21 mutations in APC, Kras, and P53 genes on asymptomatic subjects (n = 4404) tested already for FOBT (Imperiale et al., 2004), and they recently evaluated KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin on very large number of individuals (n = 9989) tested for FIT (Imperiale et al., 2014). Inclusion of a very large number of asymptomatic subjects shows the potential of sensitivity gain for molecular testing (Imperiale et al., 2004, 2014). With these inclusion criteria, the authors simulated a real situation of screening and applied powerful statistical tools to evaluate the true performance of the test used. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell-free nucleic acids (CFNA) have been reported by several authors in blood, stool, and urine of patients with colorectal cancer (CRC). These genetic biomarkers can be an indication of neoplastic colorectal epithelial cells, and can thus potentially be used as noninvasive tests for the detection of the disease in CRC patients and monitor their staging, without the need to use heavier and invasive tools. In a number of test-trials, these genetic tests have shown the advantage of non-invasiveness, making them well accepted by most of the patients, without major side effects. They have also shown a promising sensitivity and specificity in the detection of malignant and premalignant neoplasms. Moreover, costs for performing such tests are very low. Several studies reported and confirmed the proof of the principle for these genetic tests for screening, diagnosis, and prognosis; the main challenge of translating this approach from research to clinical laboratory is the validation from large and long-term randomized trials to prove sustainable high sensitivity and specificity. In this paper, we present a review on the noninvasive genetics biomarkers for CRC detection described in the literature and the challenges that can be encountered for validation processes.
    Frontiers in Genetics 08/2014; 5:182. DOI:10.3389/fgene.2014.00182
  • Source
    • "The benefit of using stool samples to identify colonic neoplasms has recently been demonstrated. Following promising results in the identification of neoplasms in patients with inflammatory bowel disease [71], methylation of BMP3 and NDRG4 were taken forward for use in conjunction with an immunochemical assay for haemoglobin and the detection of KRAS mutations, using bactin as a reference gene to establish DNA levels, for the detection of colorectal tumours [72]. Using an algorithm to calculate a score based upon these measurements, this stool-based approach offered superior sensitivity to the faecal immunochemical test in the detection of tumours (92% vs 74%) and advanced precancerous lesions (42% vs 24%), at the expense of a reduction in specificity (87% vs 95%). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic epidemiology includes the study of variation in epigenetic traits and the risk of disease in populations. Its application to the field of cancer has provided insight into how lifestyle and environmental factors influence the epigenome and how epigenetic events may be involved in carcinogenesis. Furthermore, it has the potential to bring benefit to patients through the identification of diagnostic markers that enable the early detection of disease and prognostic markers that can inform upon appropriate treatment strategies. However, there are a number of challenges associated with the conduct of such studies, and with the identification of biomarkers that can be applied to the clinical setting. In this review, we delineate the challenges faced in the design of epigenetic epidemiology studies in cancer, including the suitability of blood as a surrogate tissue and the capture of genome-wide DNA methylation. We describe how epigenetic epidemiology has brought insight into risk factors associated with lung, breast, colorectal and bladder cancer and review relevant research. We discuss recent findings on the identification of epigenetic diagnostic and prognostic biomarkers for these cancers.
    Biochemical and Biophysical Research Communications 08/2014; 455(1-2). DOI:10.1016/j.bbrc.2014.08.002 · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal-cancer screening in the United States is a success story. The American Cancer Society recently reported that rates of death from colorectal cancer are down by 46% from their peak.(1) There is good evidence that screening efforts have played an important role in the trend.(2) However, work remains to be done, since approximately one third of Americans report not being current with screening.(3) One approach to increase screening uptake is to broaden the available test options. On the basis of current U.S. Preventive Services Task Force guidelines, there are three recommended options: fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy. . . .
    New England Journal of Medicine 03/2014; 370(14). DOI:10.1056/NEJMe1400092 · 55.87 Impact Factor
Show more


49 Reads
Available from