MolDX: MGMT Promoter Methylation Analysis

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 Changes

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 of 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 forGBM 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)

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 anexperienced 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.

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.

Documentation Requirements

The patient's medical record must contain documentation that fully supports the medical necessity for services included within this LCD. (See “Coverage Indications, Limitations, and/or Medical Necessity") This documentation includes, but is not limited to, relevant medical history, physical examination, and results of pertinent diagnostic tests or procedures.

Documentation supporting the medical necessity should be legible, maintained in the patient's medical record, and must be made available to the J15 MAC upon request.

References

1. Berghoff AS, Hainfellner JA, Marosi C, Preusser M. Assessing MGMT methylation status and its current impact on treatment in glioblastoma. CNS Oncol. 2015;4(1):47­-52.
2. Chang IW, Hsu CT, Lin JW, Hung CH. The prognostic impact of MGMT expression on low­grade gangliogliomas: a clinicopathological and immunohistochemical study. Folia Neuropathol. 2013;51(4):275-2­82.
3. Furnari FB, Fenton T, Bachoo RM, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 2007;21(21):2683­-2710.
4. Hasina R, Surati M, Kawada I, et al. O-­6-­methylguanine ­deoxyribonucleic acid methyltransferase methylation enhances response to temozolomide treatment in esophageal cancer. J Carcinog. 2013;12:20.
5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
6. Keime­-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007; 356(15):1527­-1535.
7. Krex D, Klink B, Hartmann C, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130(10):2596-2606.
8. Larijani L, Madjd Z, Samadikuchaksaraei A, et al. Methylation of O6-­methyl guanine methyltransferase gene promoter in meningiomas­­comparison between tumor grades I, II, and III. Asian Pac J Cancer Prev. 2014;15(1):33-3­8.
9. Lattanzio L, Borgognone M, Mocellini C, et al. MGMT promoter methylation and glioblastoma: a comparison of analytical methods and of tumor specimens. Int J Biol Markers. 2015;30(2):208-216.
10. Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomid versus standard 6-­week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised phase 3 trial. Lancet Oncol. 2012;13(9):916-926.
11. Martinez R, Schackert G, Yaya-Tur R, et al. Frequent hypermethylation of the DNA repair gene MGMT in long-term survivors of glioblastoma multiforme. J Neurooncol. 2007;83(1):91-93.
12. Mollemann M, Wolter M, Felsberg J, et al. Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer. 2005;113(3):379-­385.
13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Central Nervous System Cancers. Version 1.2021. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed August 25, 2021.
14. Ogino S, Kawasaki T, Brahmandam M, et al. Precision and performance characteristics of bisulfite conversion and real-time PCR (MethyLight) for quantitative DNA methylation analysis. J Mol Diagn. 2006;8(2):209-217.
15. Oliver JA, Ortiz R, Melguizo C, Alvarez PJ, Gomez-Millan J, Prados J. Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. BMC Cancer. 2014;14:511. doi: 10.1186/1471­2407­14­511
16. Preusser M, de Ribaupierre S, Wohrer A, et al. Current concepts and management of glioblastoma. Ann Neurol. Jul 2011;70(1):9­21. doi:10.1002/ana.22425
17. Rizzo D, Scalzone M, Ruggiero A, et al. Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise? J Chemother. 2014;27(2):106-110.
18. Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22(9):1583-158­8.
19. Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JM. Molecularly targeted therapy for malignant glioma. Cancer. 2007;110(1):13­-24.
20. Wang K, Wang YY, Ma J, et al. Prognostic value of MGMT promoter methylation and TP53 mutation in glioblastomas depends on IDH1 mutation. Asian Pac J Cancer Prev. 2014;15(24):10893­-10898.
21. Zhang W, Lin Y, Chen B, Song SW, Jiang T. Recurrent glioblastoma of childhood treated with bevacizumab: case report and molecular features. Childs Nerv Syst. 2010;26(1):137-1­43.