FDA Approves First Non-invasive DNA Screening Test for Colorectal Cancer

Collaboration with USA Center for Medicare & Medicaid Services contributed to concurrently proposed Medicare coverage

The USA Food and Drug Administration (FDA) approved on 11 August 2014 Cologuard, the first stool-based colorectal screening test that detects the presence of haemoglobin and DNA mutations that may indicate the presence of colorectal cancer or its precursors. It is intended for patients who are typical candidates for colorectal cancer screening, adults 50 years or older who are at average risk for colorectal cancer.

Colorectal cancer primarily affects people age 50 and older. Colorectal cancer screening is effective at reducing illness and death related to colorectal cancer. The USA Center for Disease Control and Prevention (CDC) estimates that if everyone age 50 or older had regular screening tests as recommended, at least 60% of colorectal cancer deaths could be avoided.

Most colorectal cancers start as abnormal raised or flat tissue growths on the wall of the colon or rectum (polyps). Some very large polyps are called advanced adenomas and are more likely than smaller polyps to progress to cancer.

Using a stool sample, Cologuard detects haemoglobin. Cologuard also detects certain mutations associated with colorectal cancer in the DNA. Patients with positive test results are advised to undergo a diagnostic colonoscopy.

Cologuard is designed to analyse patients stool for the presence of 11 molecular markers

Because cellular exfoliation of DNA into stool occurs continuously, Cologuard can detect pre-malignant neoplasia at early onset of abnormality. This method is different from single marker faecal blood tests, which may not be reliable for detecting polyps or lesions that bleed intermittently.

Cologuard utilises a multi-target approach to detect DNA and haemoglobin markers associated with colorectal cancer, as well as pre-malignant colorectal neoplasia. Three independent categories of biomarkers are targeted.

The first category of biomarkers involves epigenetic DNA changes characterised by aberrant gene promoter region methylation. The specific methylated gene targets include N-Myc Downstream-Regulated Gene 4 (NDRG4) and the Bone Morphogenetic Protein 3 (BMP3). NDRG4 and BMP3 have been shown to be hypermethylated in colorectal cancer. The Cologuard procedure incorporates bisulfite conversion of non-methylated cytosine residues to uracil in the DNA sequence to enable sensitive detection of hypermethylated NDRG4 and BMP3.

The second category targets specific DNA point mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, which encodes a small GTPase that is activated transiently as a response to extracellular stimuli or signals. KRAS mutations have been detected in up to 35% of colorectal cancers and the 7 mutations in Exon 2 detected by Cologuard account for 98% of KRAS mutations. KRAS mutations, along with NDRG4 and BMP3 methylation markers, have been shown to be detected in the stool of subjects with colorectal neoplasia, including subjects with colorectal cancer and pre-malignant lesions.

The third category of biomarker is non-DNA based and detects haemoglobin, which can be associated with colon bleeding.

Results from the methylation, mutation, and haemoglobin assays are combined in the laboratory analysis to determine a positive or negative reportable result or no result.

Assay Technology

The patient stool samples are processed at the laboratory to isolate the DNA for testing. Amplification and detection of methylated target DNA (NDRG4, BMP3), KRAS point mutations, and ACTB (a reference gene for quantitative estimation of the total amount of human DNA in each sample) is performed using the Quantitative Allele-specific Real-time Target and Signal Amplification (QuARTS™) technology. Multi-plexed QuARTS reactions are processed using a real-time cycler with each marker monitored separately through independent fluorescent detection channels.

The haemoglobin assay stool sample is prepared and analysed in a quantitative Enzyme-Linked Immunosorbent Assay (ELISA) that determines the concentration of hemoglobin in the sample.

Safety and effectiveness

“This approval offers patients and physicians another option to screen for colorectal cancer,” said Alberto Gutierrez, PhD, director of the Office of In Vitro Diagnostics and Radiological Health at the FDA’s Center for Devices and Radiological Health. “Fecal blood testing is a well-established screening tool and the clinical data showed that the test detected more cancers than a commonly used fecal occult test.”

The approval of the Cologuard does not change current practice guidelines for colorectal cancer screening. Stool DNA testing (also called faecal DNA testing) is not currently recommended as a method to screen for colorectal cancer by the United States Preventive Services Task Force (USPSTF). Among other guidelines, the USPSTF recommends adults age 50 to 75, at average risk for colon cancer, be screened using foecal occult blood testing, sigmoidoscopy, or colonoscopy.

The safety and effectiveness of Cologuard was established in a clinical trial that screened 10,023 subjects. The trial compared the performance of Cologuard to the faecal immunochemical test (FIT), a commonly used non-invasive screening test that detects blood in the stool. Cologuard accurately detected cancers and advanced adenomas more often than the FIT test.

Cologuard detected 92% of colorectal cancers and 42% of advanced adenomas in the study population, while the FIT screening test detected 74% of cancers and 24% of advanced adenomas. Cologuard was less accurate than FIT at correctly identifying subjects negative for colorectal cancer or advanced adenomas. Cologuard correctly gave a negative screening result for 87% of the study subjects, while FIT provided accurate negative screening results for 95% of the study population.

Concurrent review reduced the time between the FDA’s approval of a medical device and Medicare coverage

On 11 August, the Centers for Medicare & Medicaid Services (CMS) issued a proposed USA national coverage determination for Cologuard. Cologuard is the first product reviewed through a joint FDA-CMS pilot programme known as parallel review where the agencies concurrently review medical devices to help reduce the time between the FDA’s approval of a device and Medicare coverage. This voluntary pilot programme is open to certain premarket approval applications for devices with new technologies and to medical devices that fall within the scope of a Part A or Part B Medicare benefit category and have not been subject to a national coverage determination.

“Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as six months from the time from study initiation to coverage,” said Nancy Stade, CDRH’s deputy director for policy. “The pilot program is ongoing, but we will apply what we have learned to improve the efficiency of the medical device approval pathway for devices that address an important public health need.”

“This is the first time in history that FDA has approved a technology and CMS has proposed national coverage on the same day,” said Patrick Conway, chief medical officer and deputy administrator for innovation and quality for CMS. “This parallel review represents unprecedented collaboration between the two agencies and industry and most importantly will provide timely access for Medicare beneficiaries to an innovative screening test to help in the early detection of colorectal cancer.”

Who should be tested?

CMS proposes to cover the Cologuard test once every three years for Medicare beneficiaries who meet all of the following criteria:

  • age 50 to 85 years,
  • asymptomatic (no signs or symptoms of colorectal disease including but not limited to lower gastrointestinal pain, blood in stool, positive guaiac faecal occult blood test or fecal immunochemical test), and
  • average risk of developing colorectal cancer who are typical candidates for colorectal cancer screening.

Cologuard was not clinically evaluated for the following types of patients:

  • Patients with a history of colorectal cancer, adenomas, or other related cancers.
  • Patients who have had a positive result from another colorectal cancer screening method within the last 6 months.
  • Patients who have been diagnosed with a condition that places them at high risk for colorectal cancer. These include but are not limited to inflammatory bowel disease, chronic ulcerative colitis, Crohn’s disease, familial adenomatous polyposis, family history of colorectal cancer.
  • Patients who have been diagnosed with a relevant hereditary cancer syndrome, such as hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome), Peutz-Jeghers syndrome, MYH-associated polyposis, Gardner’s syndrome, Turcot’s (or Crail’s) syndrome, Cowden’s syndrome, juvenile polyposis, Cronkhite-Canada syndrome, neurofibromatosis, familial hyperplastic polyposis.

Cologuard is manufactured by Exact Sciences in Madison, Wisconsin.