LCD L35974: MolDX: MGMT Promoter Methylation Analysis

Indications and Limitations of Coverage

This policy provides limited coverage for methylation analysis for hypermethylation of the O-6-methylguanine DNA methyltransferase (MGMT) gene promoter. MGMT methylation analysis testing is considered to be reasonable and necessary for adult patients when the following criteria are met:

• Tumor type is high-­grade malignant glioma (e.g. glioblastoma multiforme (GBM), anaplastic astrocytoma) and

• Patients are able to tolerate temozolomide therapy or radiation therapy, and

• The physician will use the MGMT testing results to decide between radiation therapy and chemotherapy alone as 1st line adjuvant treatment, or between temozolomide and other chemotherapy for 1st line adjuvant treatment

Note: This assessment is predicated on the assumption that therapy is considered beneficial for the specific patient.

Cancer is the consequence of genetic alterations that result in a deregulation of important cellular pathways responsible for various essential functions, including cell growth, cell cycle progression, and apoptosis (programmed cell death). One result of these genetic alterations is gliomas. The treatment of high-grade gliomas, especially GBM, remains difficult as no contemporary treatments are curative. For the past several years, the standard treatment for GBM consists of maximal surgical resection, radiotherapy (RT), and concomitant and adjuvant chemotherapy with temozolomide.

Although surgical resection, RT, and chemotherapy with temozolomide are considered standard of care for most patients with high-grade glioma (including GBM and anaplastic astrocytoma), not all patients tolerate these treatments. For patients older than 70 years with a low performance rating, radiation or temozolomide alone is sometimes employed. Temozolomide treatment is not considered inferior to radiation therapy and may be tolerated better than RT by “frail” patients with low performance scores.

In patients for whom temozolomide is not the current standard of care, it has been proposed that MGMT methylation analysis can be used to predict the efficacy of temozolomide treatment. Epigenetic silencing of the MGMT DNA repair gene, by promoter methylation, leads to a lack of MGMT protein expression. Lack of MGMT protein expression immunohistochemically is related to drug responses in patients with malignant glioma treated with alkylating agents. In particular, MGMT hypermethylation is a known predictive biomarker of response to temozolomide treatment with favorable outcomes in terms of overall survival (OS) and progression free survival (PFS) in GBM patients.

MGMT promoter methylation status is a strong and independent prognostic factor in patients with newly diagnosed GBM and a clinically relevant predictive marker in the subpopulation of elderly GBM patients. MGMT promoter methylation analysis can aid in treatment decisions for patients over 70. For patients older than 70 with a good performance rating, there is evidence of the benefit of temozolomide in addition to RT. In patients with lower performance, temozolomide can be used alone as it was found to be equally as effective as RT alone and it has lower toxicity for the frail population. In the temozolomide arm of both the Nordic and German trials, patients with MGMT promoter methylation had longer survival than those without. (9.7 vs 6.8 months; HR, 0.56; 95% CI, 0.34­0.93)