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. 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.

SEPT9 Methylated DNA

ColoVantage (various manufacturers) blood tests for serum Septin9 (SEPT9) methylated DNA are offered by several laboratories (ARUP Laboratories, Quest Diagnostics, Clinical Genomics). Epi proColon (Epigenomics) received U.S. Food and Drug Administration (FDA) approval in April 2016. Epigenomics has licensed its Septin 9 DNA biomarker technology to Polymedco and LabCorp. ColoVantage and Epi proColon are both polymerase chain reaction (PCR) assays; however, performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes).

Gene Expression Profiling

ColonSentry (Stage Zero Life Sciences) is a PCR assay that uses a blood sample to detect the expression of 7 genes found to be differentially expressed in CRC patients compared with controls: ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, and IL2RB. The test is intended to stratify average-risk adults who are non-compliant with colonoscopy and/or fecal occult blood testing. "Because of its narrow focus, the test is not expected to alter clinical practice for patients who comply with recommended screening schedules. BeScreened-CRC (Beacon Biomedical) is a PCR assay that uses a blood sample to detect the expression of 3 protein biomarkers: teratocarcinoma derived growth factor-1 (TDGF-1, Cripto-1); carcinoembryonic antigen, a well-established biomarker associated with CRC; and an extracellular matrix protein involved in early stage tumor stroma changes.

The table below lists tests assessed in this medical policy.

Genetic and Molecular Diagnostic Tests Assessed in This Medical Policy

a. For example, ColoVantage and Epi proColon.b. ARUP, Quest, Clinical Genomics and Epigenomics.

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.

POLICY

SEPT9 methylated DNA testing (eg, ColoVantage®, Epi proColon®) is considered investigational for colorectal cancer screening.

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

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.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

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:

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

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

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

4. 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.

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

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.