Malignant gliomas are the most common primary brain cancer in adults, with approximately 17,000 new cases diagnosed annually in the United States. Glioblastoma multiforme (GBM) is the most common type and despite treatment advances, prognosis for GBM remains poor, with less than 5% surviving beyond five years. For high-grade malignant gliomas, standard treatment combines surgical resection, postoperative radiation and chemotherapy using alkylating agents such as temozolomide (TMZ). Adjuvant options mainly depend on the performance status of the individual.
Testing for MGMT (O6-methylguanine-DNA methyltransferase) gene promoter methylation has been proposed as a method to predict which patients with malignant gliomas may benefit from the use of TMZ. 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 alkylation of the O6 position of guanine, the most cytoxic 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, potentially increasing tumor susceptibility to alkylating agent-based chemotherapy.
MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation testing is considered medically necessary if the medical appropriateness criteria are met. (See Medical Appropriateness below.)
MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation testing for all other indications is considered investigational.
MGMT (O6-methylguanine-DNA methyltransferase) promoter methylation testing is considered medically appropriate if ALL of the following criteria are met:
Tumor is consistent with high-grade malignant glioma (e.g., glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma)
Individual is able to tolerate temozolomide or radiation therapy
Results of test will influence treatment choice (i.e., adjuvant therapy with temozolomide)
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A high frequency of MGMT promoter methylation was noted in long-term survivors of glioblastoma who received repetitive alkylating chemotherapy during the course of the disease. Generally, carriers of the methylated form of the MGMT promoter respond substantially better to therapy with temozolomide. Despite its well-established role in carcinogenesis, studies have not demonstrated MGMT promoter methylation status as an effective prognostic tool or biomarker in cancers other than high-grade gliomas.
BlueCross BlueShield Association. Evidence Positioning System. (5:2018). Analysis of MGMT Promoter Methylation in Malignant Gliomas (2.04.113). Retrieved February 25, 2019 from http://www.evidencepositioningsystem.com. (27 articles and/or guidelines reviewed)
CMS.gov: Centers for Medicare & Medicaid Services. Palmetto GBA. (2018, February). LCD: MolDX: MGMT promoter methylation analysis (L35974). Retrieved February 25, 2019 from www.cms.gov.
Dullea, A., & Marignol, L. (2016). MGMT testing allows for personalized therapy in the temozolomide era. Tumour Biology, 37 (1), 87-96. Abstract retrieved July 27, 2016 from PubMed database.
National Comprehensive Cancer Network. (2018). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Central nervous system cancers V 2.2018. Retrieved February 25, 2019 from the National Comprehensive Cancer Network.
National Institute for Health and Clinical Excellence. (2016). Carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma. Retrieved February 25, 2019 from http://www.nice.org.uk.
Perry, J., Laperriere, N., O’Callaghan, C., Brandes, A., Menten, J., Phillips, C., et al. (2017). Short-course radiation plus temozolomide in elderly patients with glioblastoma. New England Journal of Medicine, 376, 1027-1037. (Level 2 evidence)
Yin, A., Zhang, L., Cheng, J., Dong, Y., Liu, B., Han, N., & Zhang, X. (2014). The predictive but not prognostic value of MGMT promoter methylation status in elderly glioblastoma patients: a meta-analysis. PLOS One, 9 (1), e85102. (Level 1 evidence)
Zarnett, O.J., Sahgal, A., Gosio, J., Perry, J., Berger, M.S., Chang, S., & Das, S. (2015). Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis. Journal of the American Medical Association - Neurology, 72 (5), 589-596. Abstract retrieved September 15, 2015 from PubMed database.
ORIGINAL EFFECTIVE DATE: 6/14/2014
MOST RECENT REVIEW DATE: 4/11/2019
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