**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 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 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 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 al1, 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.

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.