As the Centers for Medicare and Medicaid Services (CMS) sheds light on coverage changes for colorectal cancer (CRC) screening in 2025, clinical laboratory test developers have been busy rolling out their noninvasive CRC screening tests as potential alternatives to the gold standard colonoscopy.
Guardant Health announced on Monday (July 29) the U.S. regulatory approval of Shield, another in a line of its established molecular tests designed to detect CRC. A class III device per a May Molecular and Clinical Genetics Panel review document, Shield uses qualitative next-generation sequencing and a "multimodal approach, integrating genomics, epigenomics, and proteomics, to detect colorectal cancer signals in the bloodstream, including DNA that is shed by tumors, called circulating tumor DNA (ctDNA)," according to Guardant.
Shield test pivotal study
The pivotal study for the Shield test was Eclipse, a registrational study trial and evaluation of the ctDNA Lunar assay conducted at more than 200 clinical trial sites in rural and urban communities across 37 states, according to Guardant. Opposite lengthy exclusion criteria with the Eclipse study, the company in March highlighted certain results that included:
- 83% sensitivity in detecting individuals with CRC
- 88% sensitivity in detecting pathology-confirmed stages I-III
Results were on par with the performance of other guideline-recommended noninvasive screening modalities, where overall sensitivity in detecting CRC ranges from 74% to 92%, Guardant noted. The U.S. Food and Drug Administration (FDA) in its related announcement on July 30 said that the test is not a replacement for diagnostic colonoscopy or for surveillance colonoscopy in high-risk people.
Shield's approval for adults at average CRC risk comes more than a year after CMS lowered the minimum age for CRC screening from age 50 to 45 for certain tests. Annual updates to the Medicare Physician Fee Schedule (MPFS) and Hospital Outpatient Prospective Payment System reflect proposed changes for CRC screening coverage in 2025.
CMS has also expanded the regulatory definition of CRC screening tests for the purpose of early detection to include "other tests or procedures established by a national coverage determination, and modifications to tests ... with such frequency and payment limits as CMS determines appropriate, in consultation with appropriate organizations." For 2025, CMS also proposed replacing barium enema screening with computed tomography (CT)-based virtual colonoscopy (also called CT colonography), for example.
LDTs drive new options
Clinical laboratory leaders are among the first to know that the continuum of complete CRC testing has evolved as a result of advanced laboratory developed tests (LDTs). With its recent decisions, CMS primes the landscape for Medicare, Medicaid, and private payer coverage of new types of clinical lab testing in CRC screening.
First, CMS included noninvasive stool-based biochemical tests. It then acknowledged blood-based biomarker tests. The latest iteration of §410.37 CRC screening tests, conditions for, and limitations on coverage introduces the potential for additional tests. On the industry side, a urine analysis test may be on the horizon.
Among the factors driving alternative (and potentially more frequent) CRC screening methods is the statistic that more than 30% of Americans may not be up to date with their CRC screening, according to the U.S. Preventive Services Task Force (USPSTF) in 2021. Leading up to its July 31 investor call, Cologuard stool DNA test manufacturer Exact Sciences estimated that 60 million people have yet to be screened for CRC.
In practice, CRC screening may involve at-home CRC testing kits to send to a clinical lab for analysis, or tests and procedures in a healthcare facility. Noninvasive options range from blood tests, stool tests, and CT colonography, to invasive options such as flexible sigmoidoscopy and traditional colonoscopy.
USPSTF recommendations
However, as of this writing the USPSTF's 2021 recommendations are currently in place for asymptomatic adults 45 years or older at average risk of CRC (i.e., no prior diagnosis of CRC, adenomatous polyps, or inflammatory bowel disease; no personal diagnosis or family history of known genetic disorders that predispose them to a high lifetime risk of CRC [such as Lynch syndrome or familial adenomatous polyposis]). USPSTF recommends screening for CRC in all adults from ages 50 to 75 years (A recommendation), with a B recommendation for adults ages 45 to 49 years -- and certain methods as follows:
Stool-based tests:
- High-sensitivity guaiac fecal occult blood test (gFOBT)
- Fecal immunochemical test (FIT)
- Multitarget stool DNA test with fecal immunochemical test (sDNA-FIT); and
Direct visualization tests:
- Colonoscopy
- CT colonography
- Flexible sigmoidoscopy
- Flexible sigmoidoscopy with FIT
With additional FDA approvals, clinical trial results, and potentially aligning guidance, physicians and patients can expect more choices and more questions.
Traditional colonoscopy may be the gold standard, but completing the examination process is especially difficult for some people. Colonoscopy bowel prep involves drinking a strong medicinal brew. The procedure itself requires anesthesia and escorted transportation assistance. The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality from colorectal cancer (CONFIRM) study of over 50,000 patients is assessing the impact of patient preferences.
Knowing how best to achieve CRC screening for a particular individual is difficult, wrote retired Veterans Health Administration chief research and development officer Dr. Timothy O'Leary, PhD, for the Journal of Molecular Diagnostics in June. O'Leary, an anatomic and molecular and genetic pathologist and now an independent consultant, indicated uncertainty as to the best path forward. O'Leary noted that the ability to fully understand some test systems is limited.
Improving access
"The best screening test is the one that gets completed by the patient," O'Leary noted from a March 13 editorial in the New England Journal of Medicine (NEJM), written by Dr. John Carethers of the University of California, San Diego.
"We know that it is a struggle to bring patients in for colorectal cancer screening," added Dr. Judy Yee, a well-known CT colonography educator who also serves as professor and university chair of radiology at the Albert Einstein College of Medicine and Montefiore Medical Center in New York. In an interview with LabPulse's sister publication AuntMinnie.com, Yee said, "The needle has moved up a bit but it has stagnated and plateaued off."
However, it may not be easy to choose an alternative noninvasive CRC screening test such as Guardant's Shield, or others such as:
- Exact Sciences' multitarget stool DNA test Cologuard: This test gained more momentum with the pivotal Blue-C study. Next-generation Cologuard Plus is on the way in 2025, according to the company. In original research also published in NEJM, Dr. Thomas Imperiale of Indiana University and colleagues reported that in a study of 20,176 participants, the next-generation test showed higher sensitivity (93.9%) for CRC and advanced precancerous lesions (43.4%) than FIT but also showed lower specificity.
- Geneoscopy's ColoSense stool RNA biomarker test: With its FDA approval in May, Geneoscopy noted the pivotal CRC-Prevent study. The ColoSense test is intended for qualitative detection of colorectal neoplasia-associated RNA markers and for the presence of occult hemoglobin in human stool. The test evaluates eight stool-derived eukaryotic ribonucleic acid (seRNA) markers. Geneoscopy reported 93% sensitivity for CRC, identifying 100% in Stage I. Additionally, the test detected 45% of advanced adenomas. In November 2023, Geneoscopy announced a multiyear agreement with Labcorp. Labcorp will offer the test and Geneoscopy will perform the test.
- Grail's Galleri multicancer early detection screening cfDNA blood test and methylation platform: Grail announced earlier this year availability of the Galleri test through Curative Insurance Company and, in July, its Real-World Evidence to Advance Multi-Cancer Early Detection Health Equity (REACH) Galleri-Medicare study through Community Health Network in Indiana. REACH will assess reduction in diagnosed stage IV cancers and safety associated with Galleri use, and healthcare resource utilization associated with cancer diagnostic workup in the Medicare population.
- Others such as Metabolomic Technologies' PolypDx that analyzes a urine sample using liquid chromotography/mass spectrometry.
These tests also require specialized software for sample processing and special instrumentation.
Better than no CRC screening at all?
As more CRC screening choices come online, blood-based testing may be better than no screening at all, but it is unlikely to exceed performance of stool-based assessment unless a blood-based test is able to meaningfully detect precancerous growths, concluded a May 13 article published in the Journal of Medical Economics.
Blood-based CRC screening tests have the benefit of higher adherence and compliance, but depending on the blood-based screening test’s performance, there may be an increased risk that patients may fail to have CRC detected at earlier stage because they have chosen to forgo screening colonoscopies in favor of the convenience of the blood-based method, the FDA executive report further clarified. Moreover, a false-positive result will lead to a follow-up colonoscopy, and some may undergo unnecessary colonoscopy as a result.
In any event, experts say the probable benefits and risks of new clinical laboratory test medical devices for CRC screening for the average-risk population need to be carefully considered.
