MolDX: MGMT Promoter Methylation Analysis

LCD Information Document Information Source LCD ID N/A LCD ID L36188 Original ICD-9 LCD ID Not Applicable LCD Title MolDX: MGMT Promoter Methylation Analysis Proposed LCD in Comment Period N/A Source Proposed LCD DL36188 Opens in a new window Original Effective Date For services performed on or after 04/15/2016 Revision Effective Date For services performed on or after 01/22/2026 Revision Ending Date N/A Retirement Date N/A Notice Period Start Date 02/25/2016 Notice Period End Date 04/14/2016 CPT codes, descriptions, and other data only are copyright 2025 American Medical Association. All Rights Reserved. Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use. The AMA does not directly or indirectly practice medicine or dispense medical services. The AMA assumes no liability for data contained or not contained herein. 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Issue Issue Description This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity. Issue - Explanation of Change Between Proposed LCD and Final LCD CMS National Coverage Policy Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. 42 CFR §410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Change Coverage Indications, Limitations, and/or Medical Necessity Indications and Limitations of CoverageThis 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. Summary of Evidence 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 performances 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, 0.34-0.93) MGMT promoter methylation analysis also has prognostic utility. However, performing MGMT analysis is only recommended by NCCN guidelines for temozolomide guidance and not for overall prognosis prediction. Lattanzio et al9 confirmed that patients carrying methylation of the MGMT promoter reported a longer OS and PFS than patients with an unmethylated promoter. Wang et al20 also evaluated the prognostic value of MGMT promoter methylation and TP53 mutation status and found similar results.There is still a lack of consensus on the optimal assay for reliable MGMT promoter methylation testing and a variety of tests are being used in different laboratories. According to Berghoff et al,1 pyrosequencing is the only method for which an adequately high analytical performance (high intra and inter-laboratory repeatability and reproducibility) has been demonstrated in a fully published trial. MGMT promoter methylation testing should be performed by an experienced laboratory in which this testing has been validated.MGMT may also be useful for determining the prognosis of colorectal cancer patients and to identify those requiring more aggressive adjuvant therapies. Future studies will be necessary to determine its clinical utility in this area. Likewise, MGMT methylation may be an important biomarker in subsets of esophageal cancers where temozolomide may be utilized to successfully treat these patients, but where additional research on clinical utility is also needed. MGMT methylation analysis is also mentioned in the literature as a predictive marker for ovarian cancer and melanoma. However, evidence on the use of MGMT testing is unclear in these diagnoses and additional studies are needed on the clinical utility in these cancers. Analysis of Evidence (Rationale for Determination) Level of Evidence: Quality - Strong Strength - Strong Weight - Moderate In summary, the current literature and NCCN guidelines support the use of MGMT methylation analysis to predict the usefulness of temozolomide treatment in adult patients with high-grade gliomas.

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.