Serologic Genetic and Molecular Screening for Colorectal Cancer

POLICY NUMBER

A.2.04.150

DESCRIPTION

It is well established that early detection of colorectal cancer (CRC) reduces disease-related mortality. For patients at average risk for CRC, organizations such as the U.S. Preventive Services Task Force have recommended several options for colon cancer screening. Currently accepted screening options for CRC include colonoscopy or sigmoidoscopy, fecal occult blood testing, and fecal immunochemical testing. However, many individuals do not undergo recommended screening with fecal tests or colonoscopy. Approximately 75% of colorectal cancer deaths occur in people who are not up to date with cancer screening. A simpler screening blood test for genetic alterations associated with non-familial CRC may have the potential to encourage screening and decrease mortality if associated with increased screening compliance. Genetic testing is also being investigated to guide therapy.

Colorectal Cancer

For patients at average risk for colorectal cancer (CRC), organizations such as the U.S. Preventive Services Task Force have recommended several options for colon cancer screening. The diagnostic performance characteristics of the currently accepted screening options (ie, colonoscopy, sigmoidoscopy, fecal tests) have been established using colonoscopy as the criterion standard. Modeling studies and clinical trial evidence on some of the screening modalities have allowed some confidence in the effectiveness of several cancer screening modalities. The efficacy of these tests is supported by numerous studies evaluating the diagnostic characteristics of the test for detecting cancer and cancer precursors along with a well-developed body of knowledge on the natural history of the progression of cancer precursors to cancer. Early detection of CRC reduces disease-related mortality, yet many individuals do not undergo recommended screening with fecal occult blood test or colonoscopy. A simpler screening blood test may have the potential to encourage screening and decrease mortality if associated with increased screening compliance.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests evaluated in this medical policy are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. FDA has chosen not to require any regulatory review of these tests.

The Epi proColon test is the only SEPT9 DNA test that has received FDA approval. It was approved in 2016 for use in average-risk patients who decline other screening methods. In 2024, the Epi proColon test was purchased by New Day Diagnostics and renamed ColoHealth™.

Guardant Health’s Shield™ Blood Test was approved by the FDA in July 2024 for colorectal cancer (CRC) screening in adults aged 45 and older who are at average risk for the disease. The Molecular and Clinical Genetics Panel of the FDA’s Medical Devices Advisory Committee reviewed evidence for Shield and voted on three questions regarding the use of Shield. They voted 8 to 1 favorably that there is reasonable assurance Shield is safe, 6 to 3 favorably that there is reasonable assurance Shield is effective, and 7 to 2 favorably that the benefits of Shield outweigh its risks. The labeled indication is 'Shield is intended for colorectal cancer screening in individuals at average risk of the disease, age 45 years or older. Patients with a positive result should follow up with a colonoscopy. Shield is not a replacement for diagnostic colonoscopy or for surveillance colonoscopy in high-risk individuals.' A prospective, longitudinal Post-Approval Study (PAS) to evaluate the longitudinal performance of Shield in an average risk population was required (NCT04136002).

POLICY

SEPT9 methylated DNA testing (e.g., ColoVantage®, ColoHealth™) is considered investigational for colorectal cancer screening.

Gene expression profiling (e.g., ColonSentry®, BeScreened™ CRC) is considered investigational for colorectal cancer screening.

Epigenomic and genomic cell-free DNA (cfDNA) blood-based testing with Guardant Shield is considered investigational for all indications.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Guardant Shield

Cell-free DNA testing with Guardant Shield has not been directly compared with other colorectal cancer screening tests, but has sensitivity and specificity for the detection of CRC similar to stool-based tests and might be of higher uptake among individuals currently declining colorectal cancer screening. It is not known if higher uptake of a blood-based test will offset lower sensitivity for detection of advanced adenomas at a population level; yet, the right screening test is one that is utilized.

For the detection of precancerous adenomas or other polyps, technologies that allow visualization of the colorectal tract perform better than stool or blood-based tests. The performance of any liquid-based product is expected to be lower for the detection of precancerous lesions, as these early lesions generally do not release high amounts of DNA into the circulation. Other analytes outside of DNA-based markers may eventually prove to be useful for blood-based detection of precancerous lesions. Even for the stool-based tests, the majority of the test sensitivity comes from the fecal immunochemical component rather than the DNA contribution, indicating that other analytes outside of DNA may need to be assessed in future versions of tests.

The transformation of adenoma to carcinoma typically takes around 10 years, which is the basic screening interval for colonoscopy. However, other pathways of colorectal tumorigenesis have been described, such as the microsatellite instability pathway and the methylation pathway, and these do not have well-defined timeframes. A 3-year interval of the Guardant Shield test has been suggested in the publication of results of the pivotal study, but has not been tested.

Combination testing of blood-based cfDNA with other methods of colorectal cancer screening has not been studied.

Shield FDA labeling

The FDA-approved product label for the Shield test includes the following Precaution:

"Based on data from clinical studies, Shield has limited detection (55%-65%) of Stage I colorectal cancer and does not detect 87% of precancerous lesions. One out of 10 patients with a negative Shield result may have a precancer that would have been detected by a screening colonoscopy. Shield demonstrated high detection of Stages II, III, and IV colorectal cancer."

Other limitations listed in the label include, but are not limited to, the following:

• "The Shield test is not intended as a screening test for individuals who are at high risk for CRC."

• "Patients with a positive result should be followed by colonoscopy."

• "Patients with a negative result should continue participating in colorectal cancer screening programs, at the appropriate guideline recommended intervals."

• "The benefits and risks of programmatic colorectal screening (i.e., repeated testing over an established period of time) with Shield has not been studied.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

05/01/2022: New policy added. Approved by the Medical Policy Advisory Committee.

08/09/2022: Policy reviewed; no changes.

08/08/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

08/12/2024: Policy reviewed; no changes.

07/18/2025: Code Reference section updated to add new CPT code 0558U. Effective 07/01/2025.

07/01/2026: Policy description updated regarding colorectal cancer deaths and tests. Policy statement revised to replace "Epi proColon®" with "ColoHealth™." Added statement that epigenomic and genomic cell-free DNA (cfDNA) blood-based testing with Guardant Shield is considered investigational for all indications. Policy Guidelines updated regarding Guardant Shield and FDA labeling. Code Reference section updated to add CPT code 0537U.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.150

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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