Analysis of MGMT Promoter Methylation in Malignant Gliomas

POLICY NUMBER

L.2.04.450

DESCRIPTION

Testing for O⁶-methylguanine-DNA methyltransferase (MGMT)gene promoter methylation has been proposed as a method to predict which patients with malignant gliomas may benefit from the use of alkylating agent chemotherapy, such as temozolomide (TMZ). Malignant gliomas are often treated with combined therapy, including resection, chemotherapy, and radiotherapy. However, combined therapy may be too intensive in the elderly population, in whom these tumors are most commonly seen.

Malignant Gliomas

Malignant gliomas are the most common primary brain cancer in adults, with approximately 17,000 new cases diagnosed annually in the United States. Until 2016, brain tumors were graded using histologic criteria corresponding to the degree of malignancy, ranging from World Health Organization grade I (least aggressive) to grade IV (most aggressive). For malignant gliomas, anaplastic astrocytomas are considered to be grade III and glioblastoma multiforme (GBM) grade IV. Of these, GBM is the most common and most studied subtype. Despite treatment advances, the prognosis for GBM remains poor, with only one-third of patients surviving one year and less than 5% surviving beyond 5 years.

In 2016, World Health Organization revised its classification of tumors of the central nervous system so that diffusely infiltrating gliomas are grouped based on genetic driver mutations. Diffuse gliomas in the new classification include the former World Health Organization grade II and III astrocytic tumors, grade II and III oligodendrogliomas, grade IV glioblastomas, and diffuse gliomas of childhood. Tumors with glioblastoma histology are grouped based on the presence of IDH variants.

Treatment

For high-grade malignant gliomas (anaplastic astrocytomas and GBM), standard treatment combines maximal possible surgical resection, postoperative radiotherapy (RT), and chemotherapy. Chemotherapy may include intraoperative placement of an implantable carmustine wafer. Temozolomide (TMZ) is an oral alkylating agent. Response to TMZ has been associated with decreased O⁶-methylguanine-DNA methyltransferase (MGMT) activity in tumor tissue (see MGMT and Promoter Methylation section below) because a methylated MGMT promoter leads to decreased MGMT levels, which enhances the effect of the alkylating agent.

TMZ is considered standard systemic chemotherapy for malignant gliomas in patients ages 70 or younger with good performance status and a methylated MGMT promoter. This is based primarily on the results of a large, randomized multicenter trial that compared radiotherapy (RT) with or without TMZ in patients with GBM, which showed statistically significant better overall survival in the combination therapy group. Adjuvant options mainly depend on the performance status of the patient.

Survival with GBM declines with increasing age. Options for patients with good performance status and age older than 70 years with methylated MGMT promoter may involve hypofractionated RT alone or TMZ alone. For patients with poor performance status, options include RT alone, chemotherapy alone, or palliative or best supportive care.

MGMT and Promoter Methylation

Gene methylation is a control mechanism that regulates gene expression. In malignancies, gene promoter regions can have abnormal or increased levels of methylation, which can block gene function, leading to decreased or absent levels of the protein encoded by the gene. MGMT is a DNA repair protein that causes resistance to the effect of alkylating chemotherapy by removing the alkylation of the O⁶ position of guanine, the most cytotoxic lesion induced by alkylating chemotherapy agents. Aberrant methylation of the MGMT gene promoter region leads to loss of MGMT protein expression and reduced proficiency to repair DNA damage induced by alkylating chemotherapeutic agents, potentiallyincreasing tumor susceptibility to alkylating agent-based chemotherapy. Approximately 40% to 50% of GBMs have MGMT gene promoter methylation. Variants in IDH1 (isocitrate dehydrogenase 1), which occur at different frequencies across glioma tumor types, appear to mediate the effect of MGMT methylation status on glioma prognosis and treatment response.

Immunohistochemistry can be used to measure MGMT protein levels. However, MGMT protein level assessment by immunohistochemistry has failed to correlate consistently with outcomes and has been associated with high interobserver variability in interpretation, even among expert neuropathologists. Additionally, many have failed to identify a correlation between MGMT promoter methylation assessed by polymerase chain reaction and protein levels in glioma tissue measured by immunohistochemistry. Other protein-based assays such as Western blot or MGMT enzyme activity assays require unfixed (fresh or frozen) material, which may not be available in the clinical setting. DNA-based methods include multiplex ligation-dependent probe amplification and methylation-specific polymerase chain reaction (MSP). MSP is currently the most commonly used technique and is the only test shown to have predictive and prognostic value in phase 2 and 3 clinical trials. However, MSP has been reported to be limited by the adverse influence of formalin fixation and paraffin embedding on bisulfite modification, an essential step of the assay. Additional studies have reported modifications of the MSP technique to overcome this problem, but no consensus on a specific protocol reliably yielding high-quality test results has been reached.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service;laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA).MGMT promoter methylation testing is available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Methylation analysis of the O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter from glioma tumor tissue is medically necessary for individuals who meet the following criteria:

• They have a tumor type consistent with high-grade malignant glioma (eg, glioblastoma multiforme, anaplastic astrocytoma); and

• Candidate for temozolomide therapy or radiotherapy; and

• Methylation results will be used to direct their therapy choices.

MGMT promoter methylation analysis is investigational in situations that do not meet the above criteria.

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.

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

04/01/2014: Approved by Medical Policy Advisory Committee.

02/10/2015: Policy reviewed; description updated. Policy statement unchanged.

07/02/2015: Code Reference section updated for ICD-10.

03/08/2016: Policy description updated regarding MGMT and promoter methylation. Policy statement unchanged. Investigative definition updated in policy guidelines section.

06/07/2016: Policy number A.2.04.113 added.

02/15/2017: Policy description updated. Policy statement unchanged.

09/15/2017: Policy description updated regarding the 2016 NCCN guidelines for adjuvant treatment for anaplastic gliomas and glioblastomas. Policy section updated to state that methylation analysis of the MGMT gene promoter from glioma tumor tissue is medically necessary for individuals meeting certain criteria. Added statement that MGMT promoter methylation analysis is investigational in situations that do not meet the above criteria. Removed statement that MGMT promoter methylation testing for prognostic value or as a predictive biomarker for response to treatment with alkylating agents is considered investigational. Policy Guidelines updated to define medically necessary. Code Reference section updated to change Investigational Codes table to Medically Necessary Codes table. Added ICD-10 diagnosis codes C71.0 - C71.9.

06/13/2018: Policy description updated. Medically necessary policy statement updated to change "radiation therapy" to "radiotherapy."

12/21/2018: Code Reference section updated to revise code description for CPT code 81287, effective 01/01/2019.

06/07/2019: Policy reviewed; no changes.

11/01/2022: Policy number changed from "A.2.04.113" to "L.2.04.450." Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity." Sources updated.

08/07/2023: Policy reviewed; no changes.

08/20/2024: Policy reviewed; no changes.

SOURCE(S)

1. Blue Cross and Blue Shield Association Policy # 2.04.113

2. Perry JR, Laperriere N, O'Callaghan CJ, et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. Mar16 2017;376(11):1027-1037. PMID 28296618

3. National Comprehensive Cancer Network guidelines on central nervous system cancers (v.1.2022) https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf .

CODE REFERENCE

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

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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