| Coverage Policy Manual | |
| Policy #: | 2014001 |
| Category: | Laboratory |
| Initiated: | January 2014 |
| Last Review: | January 2024 |
|
|
|
|||||||||||
| Genetic Test: Analysis of MGMT Promoter Methylation in Malignant Gliomas | |
|
|
|
| Description: |
Testing for MGMT gene promoter methylation has been proposed as a method to predict which patients with malignant gliomas may benefit from the use of alkylating agent chemotherapy, such as temozolomide. Malignant gliomas are often treated with combined therapy, including resection, chemotherapy, and radiation. However, combined therapy may be too intensive in the elderly population, in whom these tumors are most commonly seen. A better understanding of the genetic diversity of these tumors has led to an effort to incorporate molecular findings into clinical practice to provide personalized treatment for individual patients, including possible single-agent therapy.
Malignant Gliomas
Malignant gliomas are the most common primary brain cancer in adults, with approximately 17,000 new cases diagnosed annually in the United States (Holdhoff, 2012). Until 2016, brain tumors were graded using histologic criteria corresponding to the degree of malignancy, ranging from World Health Organization (WHO) grade I (least aggressive) to grade IV (most aggressive). For malignant gliomas, anaplastic astrocytomas are considered to be grade III and glioblastoma multiforme (GBM) grade IV. Of these, GBM is the most common and most studied subtype (Holdhoff, 2012). Despite treatment advances, prognosis for GBM remains poor, with only one-third of patients surviving 1 year and less than 5% surviving beyond 5 years.
In 2016, WHO revised its classification of tumors of the central nervous system (CNS) so that diffusely infiltrating gliomas are grouped based on genetic driver mutations (Louis, 2016). Diffuse gliomas in the new classification include the former WHO grade II and III astrocytic tumors, grade II and III oligodendrogliomas, grade IV glioblastomas, and diffuse gliomas of childhood. Tumors with glioblastoma histology are grouped based on the presence of IDH mutations.
The 2016 National Comprehensive Cancer Network (NCCN) guidelines and most published studies continue to report the older WHO grades.
Treatment
For high-grade malignant gliomas (anaplastic astrocytomas and GBM), standard treatment combines maximal possible surgical resection, postoperative radiotherapy (RT), and chemotherapy (NCCN, 2016). Chemotherapy may include intraoperative placement of an implantable carmustine wafer. Temozolomide (TMZ) is an oral alkylating agent. Response to TMZ has been associated with decreased O6-methylguanine-DNA methyltransferase (MGMT) activity in tumor tissue (see MGMT and Promoter Methylation section below) because a methylated MGMT promoter leads to decreased MGMT levels, which enhances the effect of the alkylating agent.
TMZ is considered standard systemic chemotherapy for malignant gliomas in patients ages 70 or younger with good performance status and a methylated MGMT promoter (NCCN, 2016). This is based primarily on the results of a large, randomized multicenter trial (2005) that compared RT with or without TMZ in patients with GBM, which showed statistically significant better overall survival in the combination therapy group (Stupp, 2005). Adjuvant options mainly depend on the performance status of the patient.
Options for patients with good performance status and age older than 70 years with methylated MGMT promoter may involve hypofractionated RT alone or TMZ alone. For patients with poor performance status, options include RT alone, chemotherapy alone, or palliative or best supportive care.
MGMT and promoter methylation
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 for by the gene.
O6-methylguanine-methyltransferase (MGMT) is a DNA repair protein that causes resistance to the effect of alkylating chemotherapy by removing the alkylation of the O6 position of guanine, the most cytotoxic lesion induced by an alkylating chemotherapy agent (Weller, 2012). 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 making the tumor more susceptible to alkylating agent-based therapy. Approximately 40%-50% of GBMs have MGMT gene promoter methylation. Mutations in IDH1, which occur with varying frequency across glioma tumor types, appear to mediate the effect of MGMT methylation status on glioma prognosis and treatment response (Chamberlain, 2014; Kalkan, 2014; Minniti, 2014; Molenaar, 2014; Myung, 2014; Takahashi, 2013; Wick, 2014; Wick, 2013 Woester. 2014).
Commercially available testing for MGMT promoter methylation.
MGMT promoter methylation testing is available from several commercial laboratories and academic centers, and typically involves methylation-specific polymerase chain reaction (PCR) technology. Laboratories that offer this test include Mayo Clinic, Cleveland Clinic, Henry Ford Health System, OHSU Knight Diagnostic Laboratories, University of Wisconsin, University of Pittsburgh, Stanford University, University of North Carolina, LabCorp and Caris Life Sciences.
Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA).
|
|
|
|
|
Policy/ Coverage: |
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Effective January 2018
Methylation analysis of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter from glioma tumor tissue meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals who meet the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
MGMT promoter methylation analysis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in situations that do not meet the above criteria.
For members with contracts without primary coverage criteria, MGMT promoter methylation analysis is considered investigational in situations that do not meet the above criteria. Investigational services are specific contract exclusions in most member benefit certificates of coverage.ct exclusions in most member benefit certificates of coverage.
Effective Prior to January 2018
MGMT promoter methylation testing for prognostic value or as a predictive biomarker for response to
treatment with alkylating agents does not meet member benefit certificate primary coverage criteria
that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, MGMT promoter methylation testing
for prognostic value or as a predictive biomarker for response to treatment with alkylating agents is
considered investigational. Investigational services are specific contract exclusions in most member
benefit certificates of coverage.
|
|
|
|
| Rationale: |
This policy was created in 2013 and is based on a search of the MEDLINE database through October 8, 2013. Literature that describes the analytic validity, clinical validity, and clinical utility of testing for MGMT promoter methylation was sought.
Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
A biomarker test should be standardized, reproducible in independent laboratories, suitable for high-throughput analyses and have prospectively validated cut-off values for prognostic and predictive effects (Weller, 2010).
Published data on the analytic validity of commercially available tests for MGMT promoter methylation are lacking.
Assessing MGMT promoter methylation in gliomas
In 1998, reports first indicated that high activity of MGMT protein in gliomas was associated with limited benefit from alkylating-agent chemotherapy. Subsequently, it has been suggested that MGMT promoter methylation may lead to improved outcomes in patients receiving alkylating-type chemotherapy. Although MGMT transcription can be silenced by promoter methylation, and it is widely assumed that MGMT promoter methylation in tumors causes decreased MGMT protein expression, the relationship between MGMT protein expression and promoter methylation in tumor remains controversial.
Various methods have been developed to assess MGMT status in tumor tissue, and include measuring enzyme activity, assessing at the level of mRNA or protein expression, or by assessing for gene promoter methylation (Weller, 2010).
Immunohistochemistry can be used to measure MGMT protein levels. However, MGMT protein level assessment by immunohistochemistry has failed to correlate consistently with outcomes and has been associated with high interobserver variability in interpretation, even among expert neuropathologists. In addition, many authors have failed to identify a correlation between MGMT promoter methylation assessed by PCR and protein levels in glioma tissue measured by immunohistochemistry (Weller, 2010). Other protein based assays such as Western Blot or MGMT enzyme activity assays require unfixed (fresh or frozen) material, which may not be available in the clinical setting (Berghoff, 2012). DNA-based methods include multiplex-ligation assay (MLPA) and methylation specific polymerase-chain reaction (MSP). MSP is currently the most commonly used technique and is the only test that has been shown to be of predictive and prognostic value in phase 2 and 3 clinical trials (Weller, 2010; Malmstrom, 2012; Wick, 2012). However, MSP has been reported to be limited by the adverse influence of formalin fixation and paraffin embedding on bisulfite modification, an essential step of the assay (Berghoff, 2012; Preusser). Additional papers have reported modifications of the MSP technique to overcome this problem, but no consensus on a specific protocol reliably yielding high quality test results has been reached (Berghoff, 2012). Few centers have implemented routine clinical MGMT testing in part because of technical issues with the test itself.
A 2013 multidisciplinary neuro-oncology taskforce of the Vienna Comprehensive Cancer Center Central Nervous System Unit (CCC-CNS) assessed the analytical and clinical performance of a number of potential tissue biomarkers for brain tumors, including MGMT, using criteria from a four-tiered level-of-evidence system (A-D, with A being the highest level), reviewing published data and reaching consensual agreement within the taskforce (Berghoff, 2013). Analytic performance was defined as the reliability of the results yielded by a test, and was established by the taskforce by evaluating published data with regard to repeatability of test results (intra-laboratory and intra-observer agreement) and reproducibility of testing (inter-laboratory and inter-observer agreement). For clinical performance, they defined the prognostic value of a marker (association with patient outcome) and the predictive value (association with response to a given therapy). Only those biomarkers reaching an A or B level for both analytical and clinical performance were considered to be adequate for recommendation in routine clinical use as a prognostic or predictive biomarker. For MGMT methylation analytical performance, only DNA based methods were reviewed, for which the level of evidence was determined to be C, and the conclusion was that none of the methods have been sufficiently analyzed for intra- and interlaboratory reproducibility. The taskforce concluded that the high prognostic value of MGMT methylation in GBM had been confirmed by studies, including prospective trial data (Hegi, 2005; Gilbert, 2013) and that the predictive value of MGMT promoter methylation status for response to temozolomide-based chemotherapy in elderly GBM patients was supported by two independent prospective randomized controlled trials (RCTs) (Malmstrom, 2012; Wick, 2012). Despite the high predictive and prognostic clinical performance of MGMT promoter methylation status, the taskforce concluded that recommendation of MGMT testing for routine clinical use was impeded by the insufficient evidence for a high analytical test performance.
Section summary. Sufficient analytic performance of MGMT testing has not been demonstrated in the published literature. Laboratories that offer commercially available tests do not identify how cut-off levels for determining a positive versus a negative test were established, nor has it been established which test method has the best repeatability and reproducibility.
Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
There are two ways that MGMT methylation analysis may have clinical validity. The first is as a prognostic marker for survival from GBM. The second is as predictive measure for response to chemotherapy, specifically TMZ. This second measure of clinical validity is more clinically relevant, since it might lead to alterations in treatment decisions based on expected response.
MGMT promoter methylation as a prognostic test
Systematic Reviews
Chen and colleagues conducted a systematic review and meta-analysis of MGMT promoter methylation and prognosis in GBM (Chen, 2013). A PubMed search from January 2003 to November 2011 identified 24 studies that met their inclusion criteria. Twenty two studies reported on the relationship between MGMT methylation status and overall survival (OS) and 12 on progression free survival (PFS). Patients with a methylated status of MGMT had significant OS and PFS advantage (HR=0.48, 95% CI, 0.35-0.65 for OS; HR=0.43, 95% CI, 0.32-0.56 for PFS). However, there was moderate to high heterogeneity in the studies included in the review for PFS and OS, respectively. Heterogeneity existed according to when studies were published, because of the inclusion in some studies of tumors with histology other than GBM (e.g., anaplastic gliomas), from one country to another and in the chemotherapeutic agents used.
MGMT promoter methylation as a predictive test
Randomized Controlled Trials
Evidence on this question comes from analyses of at least three RCTs in which a subset of participants had MGMT analysis and MGMT status was correlated with treatment response ot TMZ.
The phase 3 NOA-08 trial enrolled patients between May 2005 and November 2009 who had de novo glioblastoma (n=331) or anaplastic astrocytoma (n=40) that was histologically confirmed after biopsy or resection (Wick, 2012). Patients were from 23 university centers across Germany or Switzerland, and had to be older than 65 years of age with a Karnofsky performance score of 60 or higher. Randomization was done centrally and generated electronically. Patients were randomized to radiotherapy (RT) alone of 60.0 Gy, administered over 6-7 weeks in 30 fractions, or 100 mg/m2 temozolomide (TMZ) alone given one week on, one week off, schedule. Crossover from one treatment group to the other was allowed if disease progressed. The primary end point was OS. Non-inferiority of TMZ compared with RT, with a 25% margin, was assessed for all patients who received at least one dose of assigned treatment. Tumor response was defined as complete response, partial response, stable disease or progressive disease by MRI. MGMT promoter methylation analysis was assessed with two different PCR assays. Minimum follow-up was 12 months (median follow-up from the start of the study was 25.2 months, range 20.0 months to not reached). Seventy-six percent of patients in the TMZ group completed at least 4 cycles (8 weeks; median 5, range 0-20) of chemotherapy, and 84% of patients completed RT. Among patients in the TMZ group and in the RT group in whom disease progression was seen, (62% and 70%, respectively), salvage therapy was received, which mainly consisted of RT in the TMZ group and vice versa. At 6 months, OS was 66.7% (95% CI, 60.0%-73.0%) in the TMZ group, and 71.7% (95% CI, 65.0%-78.4%) in the RT group. At one year, OS was 34.4% (27.6-41.4%) in the TMZ group and 37.4% (30.1-44.7%) in the RT group. Median OS was 8.6 months (95% CI, 7.3-10.2) in the TMZ group and 9.6 months (95% CI, 8.2-10.8) in the RT group (hazard ratio HR=1.09, 95% CI, 0.84-1.42. pnoninferiority=0.033), indicating that TMZ was noninferior to RT. No grade 5 events were reported in either group. Grade 2-4 adverse events were more frequent in the TMZ group than in the RT group in all categories except cutaneous events.
Data on MGMT promoter methylation status was available in 56% of patients. In the TMZ group (n=195), 16% of patients had methylated MGMT promoter, 39% were unmethylated, and 45% were missing/inconclusive. Of the RT group (n=178), 24% had methylation, 33% unmethylated, and in 43%, the status was missing or inconclusive. MGMT promoter methylation was associated with prolonged OS (median 11.9 months [95% CI, 9.0 to not reached] vs. 8.2 months [7.0-10.0]; HR=0.62, 95% CI, 0.42-0.91, p=0.014). Event-free survival (EFS) was longer in patients with MGMT promoter methylation when treated with TMZ versus RT (8.4 months [95% CI, 5.5-11.7 months] versus 4.6 months [3.7-6.3]). The opposite was observed in patients without MGMT promoter methylation (3.3 months [3.0-3.5 months] versus 4.6 months [3.7-6.3 months]).
This trial demonstrates that MGMT status is a predictor of response to TMZ, while there is little difference in response to RT by MGMT status. It is limited by the lack of comparisons of TMZ to a control group, or a comparison of RT plus TMZ to RT alone.
In the Nordic phase 3 trial, glioblastoma patients were randomized to single-agent TMZ, hypofractionated RT or standard RT, to compare survival, quality of life and safety (Malmstrom, 2012). Patients were recruited from 28 European centers between February 2000 and June 2009, and were eligible if they were age 60 years or older and had newly diagnosed GBM. Randomization was to TMZ (200 mg/m2 days 1–5 every 28 days for 6 cycles), hypofractionated RT (34 Gy over 2 weeks) or standard RT (60 Gy over 6 weeks). Randomization lists were computer-generated and only available to oncology staff. The primary end point was OS. Baseline assessments consisted of physical and neurologic examinations, blood counts and administration of the EORTC quality of life questionnaire 30 (EORTC QLQ-30). Patients were assessed 6 weeks, 3 months and 6 months after the start of therapy. Overall, 342 patients were enrolled; 291 were randomized across 3 treatment groups: TMZ (n=93), hypofractionated RT (n=98) and standard RT (n=100). Fifty-one additional patients from 4 centers that did not offer standard RT were randomized across TMZ (n=26) or hypofractionated RT (n=25) groups. In the 3-group randomization, of the standard RT group, 72% of patients completed irradiation according to protocol, versus 95% in the hypofractionated RT group. TMZ was started in 97% of patients assessed as part of the 3-group randomization; 86% received at least 2 cycles of chemotherapy and 34% completed all cycles. Second-line RT was given to 37% of TMZ patients and 26% of RT groups received second-line chemotherapy.
MGMT promoter methylation could be assessed in tumor tissue from 75% of the 342 patients enrolled.
In the 3-group randomization. As compared to standard RT, median OS was significantly longer with temozolomide (83 months [95% CI, 7·1–9·5] vs. 60 months [95% CI, 5·1–6·8], HR=0·70; 95% CI, 0·52–0·93, p=0·01), but not with hypofractionated RT (75 months [6·5–8·6], HR=0·85 [0·64–1·12], p=0·24). For all patients who received TMZ or hypofractionated RT (n=242), OS was similar (84 months [7·3–9·4] vs 74 months [6·4–8·4]; HR=0·82, 95% CI, 0·63–1·06; p=0·12). Patients treated with TMZ who had tumor MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (97 months [95% CI, 8·0–11·4] vs. 68 months [5·9–7·7]; HR=0·56 [95% CI, 0·34–0·93], p=0·02), but there was no difference between those with methylated and unmethylated MGMT promoter treated with RT (HR=0·97 [95% CI, 0·69–1·38]; p=0·81).
The European Organization for Research and Treatment of Cancer (EORTC) Brain Tumor and Radiotherapy Groups for the National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a randomized, multicenter, phase 3 trial to compare RT alone versus RT plus concomitant and adjuvant TMZ in patients with newly diagnosed GBM (Stupp, 2055). A total of 573 patients from 85 centers were randomized. At a median follow-up of 28 months, 84% of patients had died. Median survival was 14.6 months (95% CI, 13.2-16.8) for RT plus TMZ and 12.1 months (95% CI, 11.2-13.0) with RT alone. The 2-year survival rate was 26.5% (95% CI, 21.2-31.7) with RT plus TMZ and 10.4% (95% CI, 6.8-14.1) with RT alone.
Five-year follow-up data of the original study showed that survival was improved even in patients without MGMT promoter methylation when TMZ was added to RT (Stupp, 2009).
This observation has led some to suggest that current practice in the treatment of newly diagnosed GBM patients who are candidates for combination therapy should include RT and TMZ regardless of MGMT promoter status (Holdhoff, 2012).
Section summary. As a prognostic marker, MGMT promoter methylation has been shown to be correlated with improved survival from GBM. As a predictive marker for response to alkylating chemotherapy, randomized trials have suggested a positive effect of MGMT promoter methylation and improved survival in patients with GBM treated with TMZ (Malmstrom, 2012; Wick, 2012). However, these studies had high rates of crossover between treatment arms, heterogeneity of treatment completion rates and, in one study, only approximately half of the patients had their tumors tested for promoter methylation and correlated with survival.
One other RCT (Stupp, 2009) showed a greater survival benefit in the patients with MGMT promoter methylation treated with TMZ and RT, however, the patients without MGMT methylation showed a slight improvement in survival with the addition of TMZ to RT, suggesting a gradation of benefit to the use of TMZ in patients with or without MGMT promoter methylation. Therefore, it is uncertain whether testing for MGMT promoter methylation can identify patients in whom the risk of treatment with TMZ outweighs the benefit. Given this uncertainty, it is not clear how the test would be used in clinical care to improve outcomes.
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
Published data on the clinical utility of testing for MGMT promoter methylation are lacking. The results of methylation testing might be used as part of the decision-making process in deciding whether to give TMZ therapy. If the test can identify patients in whom the risk of treatment with TMZ exceeds the benefit, then health outcomes may be improved by withholding TMZ. However, it is not certain that this would always be the case. MGMT analysis will identify patients who are expected to have less benefit from TMZ, but it is still possible that TMZ treatment has some benefit, and that withholding TMZ may lead to a net harm by reducing a potential survival benefit. It is not possible to determine from the available evidence whether a net benefit or a net harm occurs as a result of using MGMT analysis to select patients for TMZ treatment.
A study published in 2012 assessed current use and impact of available molecular predictive and prognostic biomarkers, including MGMT promoter methylation, on clinical care in patients with GBM (Holdhoff, 2012). An online questionnaire with 15 questions about frequency of use and clinical utility of tumor tissue-based molecular tests was sent by email to 1,053 members of the Neuro-Oncology Community in the U.S. A total of 320 responses were received (~30%), of which 73 were excluded because the respondents did not see GBM patients in clinic were excluded. Of the biomarkers included on the questionnaire, MGMT promoter methylation testing was the most commonly requested of all of the available biomarkers potentially used in the care of patients with GBM (37.2 % of questionnaire participants stated that they order this marker; 95% CI, 31-44%). In response as to whether the decision to give temozolomide was based on MGMT promoter status, only 3.6% of the respondents stated “all the time”, 20.6% stated that it “depended on the clinical situation”, 12.1% stated “only rarely” and 19.8% stated that they “never” based this decision on MGMT promoter methylation status. Reasons given for not ordering the test included: 20.6% of respondents stated that it would not affect their choice of treatment, 11.7% that the test was difficult to order and 6.5% because of the cost of the test. The authors concluded that the results of their questionnaire showed that while molecular markers are not infrequently ordered for patients with GBM, only a minority of clinicians who ordered the tests report that the results influence clinical decision-making.
Section summary. Data on the clinical utility of testing for MGMT promoter methylation status are lacking. It is not possible to conclude that use of MGMT testing to withhold TMZ treatment will improve outcomes because there is still a potential treatment benefit even for patients who are negative on MGMT analysis. One study assessed the use of this type of testing among the neuro-oncology community, and showed that although MGMT status is not infrequently ordered by clinicians, it did not influence clinical decision-making in the majority of the cases. Therefore, the clinical utility of testing for MGMT promoter methylation status is unclear.
Ongoing Clinical Trials
The CENTRIC trial is a multicenter, randomized controlled open-label Phase III trial in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter status. The study assessed the efficacy and safety of adding cilengitide to chemoradiotherapy (CRT; temozolomide [TMZ] and radiotherapy followed by TMZ), versus CRT alone. OS is the primary outcome measure. Estimated enrollment is 545, with a study completion date of August 2013. (NCT00689221)
The CORE trial is a multicenter, randomized controlled open-label phase II trial in patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter status. The study is assessing the safety and tolerability of two cilengitide dosing schedules added to CRT, versus that of CRT alone. (NCT00813943)
Summary
The analytic validity of testing for MGMT promoter methylation status has not been established, nor is it clear which testing method is optimal in terms of reproducibility. There is some evidence of clinical validity for the test. Several studies have suggested that MGMT gene promoter methylation in glioblastoma multiforme (GBM) tumor cells is associated with an improved prognosis. However, the utility of the prognostic information from MGMT promoter methylation status in clinical decision-making is unclear.
Data from RCTs supports that MGMT promoter methylation also serves as a predictive marker for response to alkylating chemotherapeutic agents like temozolomide (TMZ). RCTs have shown a greater response rate to and overall survival with the use of TMZ in patients with GBMs that have MGMT promoter methylation. However, it has also been demonstrated that, in patients without MGMT promoter methylation, TMZ may offer some survival benefit. It has not been established that the determination of MGMT promoter methylation status will alter clinical decision-making, and as a result it is not possible to determine the impact of MGMT testing on health outcomes.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) guidelines for central nervous system tumors (v.2.2013) recommend chemotherapy using temozolomide as one adjuvant treatment option for patients >70 years old with glioblastoma or anaplastic gliomas and good performance status if MGMT promoter methylation is positive (category 2A)
2015 Update
This policy is being updated with a literature search using the MEDLINE database through December 2014. There was no information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
Assessing MGMT Promoter Methylation in Gliomas
Researchers continue to develop biochemical methods for querying the MGMT promoter region. Techniques under investigation in 2014 include targeted pyrosequencing (a bioluminescence “sequencing by synthesis” assay) (Preusser, 2014; Quillien, 2014) and full sequencing (Kanemoto, 2014). Unresolved issues pertaining to these and all techniques include which methylation sites (ie, CpG [cytosine-phosphate-guanine] islands) and how many need to be assayed to provide greatest accuracy; (Wick, 2014; Fietkau, 2013) optimal assay-specific cutoff levels; biopsy technique; (Weise, 2014) and specimen fixation method (eg, formalin-fixed paraffin embedded vs RCL2 [a non-crosslinking alternative to formalin]-fixed paraffin-embedded) (Pulverer, 2014).
MGMT Promoter Methylation as a Prognostic Test
Meta-analyses published in 2014 and 2014 have examined the association between MGMT promoter methylation status and survival outcomes (Dong, 2014; Yang, 2014).
Dong et al (2014) conducted a systematic literature search through 2012 and included 8 moderate-to-good quality prognostic cohort studies (total N=573) (Dong, 2014). All studies used methylation-specific PCR (MSP) assay. Treatment effects were not considered. Publication bias was not detected for either outcome assessed (disease-free survival [DFS] and overall survival [OS]). OS was improved in patients with methylated MGMT compared with unmethylated MGMT, but not DFS.
Yang et al (2014) systematically searched the literature through 2013 and included 50 studies (total N=6309; Caucasian: 5663, Asian: 646) (Yang, 2014). Quality of included studies was not assessed. Assay type was not reported, and treatments varied across studies, although most patients received TMZ plus radiotherapy (RT). Both progression-free survival (PFS) and OS were improved in patients with methylated MGMT compared with unmethylated MGMT; however, statistical heterogeneity was substantial for both outcomes (I2>50%), suggesting inappropriateness of pooling. Similarly, observed differences across race (OS improved in both Asians and Caucasians with methylated MGMT, but PFS improved in Caucasians only) may be unreliable due to substantial statistical heterogeneity in the pooled results.
MGMT Promoter Methylation as a Predictive Test
Yin et al (2014) published a systematic review and meta-analysis of patients 65 years of age or older with newly-diagnosed glioblastoma (Yin, 2014). Five clinical trials and 8 observational studies were included (total N=1105). Risk of bias, primarily selection bias, was low in trials and moderate-to-high in observational studies. Assay methods and treatments varied across studies. Publication bias was not detected. PFS and OS were improved (1) in patients with methylated MGMT compared with unmethylated MGMT only in patients who received TMZ-containing chemotherapy regimens; and (2) in patients who received TMZ-containing chemotherapy regimens compared with RT only in patients with methylated MGMT but not in patients with unmethylated MGMT. Statistical tests for interaction of treatment and MGMT methylation status were not done.
In 2 randomized trials that compared different alkylating chemotherapy regimens, MGMT methylation status was not predictive of treatment response (Gilbert, 2013; Collins, 2014). Gilbert et al (2013) conducted a phase 3 RCT to compare 2 maintenance TMZ regimens after completion of RT (standard TMZ treatment: 150-200 mg/m2 days 1-5 of a 28-day cycle vs dose-dense TMZ: 75-100 mg/m2 days 1-21 of a 28-day cycle) (Gilbert, 2013). Patents with newly-diagnosed GBM were randomized 1:1 to standard (n=411) or dose-dense TMZ (n=422), stratified by MGMT methylation status, as determined by MSP. Median number of cycles received was 3 in the standard TMZ group (37% received at least 6 cycles) and 4 in the dose-dense TMZ group (43% received at least 6 cycles). At median follow-up of 31.9 months, no statistical between-group difference in PFS or OS was observed. MGMT methylation status was available for 762 patients (91%). Tests of interaction between MGMT methylation status and treatment were not statistically significant.
Similarly, Collins et al (2014) used 354 tumor samples from the MRC BR12 RCT and found no evidence that MGMT methylation status was predictive of benefit with TMZ versus PCV (procarbazine, lomustine, vincristine) or with 21-day TMZ versus 5-day TMZ (Collins, 2014). MRC BR12 enrolled patients with high-grade glioma who experienced first relapse after RT. MGMT methylation, assessed by pyrosequencing, was analyzed successfully in tumor samples from 63% of patients enrolled in the original trial.
Ongoing and Unpublished Clinical Trials
Investigators in Spain are conducting a multicenter, phase 2 RCT in patients with GBM who have completed 6 cycles of first-line TMZ. Patients will be randomized according to MGMT methylation status and presence of residual disease to receive an additional 6 cycles of TMZ or no additional treatment. Six-month PFS is the primary outcome measure. Estimated enrollment is 160, with a trial completion date of July 2017 (NCT02209948).
The National Cancer Institute (NCI) is sponsoring a phase 2/3 RCT in patients with newly diagnosed GBM with MGMT promoter hypermethylation to evaluate TMZ with or without veliparib chemotherapy. Veliparib is an investigational PARP (poly ADP-ribose polymerase)-inhibitor. OS is the primary outcome. Additionally, concordance between site-determined MGMT methylation status and central laboratory determination of MGMT status will be assessed. Estimated enrollment is 440, with a trial completion date of June 2022 (NCT02152982).
The NCIC (National Cancer Institute of Canada) Trials Group is sponsoring an international phase 3 RCT in older patients (≥65 years) newly diagnosed with GBM to compare treatment with TMZ plus hypofractionated RT versus hypofractionated RT alone. OS is the primary outcome measure. MGMT methylation status is a secondary outcome; results will be adjusted for MGMT methylation status. Estimated enrollment is 562, with a trial completion date of July 2015 (NCT00482677).
2016 Update
A literature search conducted through December 2015 did not reveal any new information that would prompt a change in the coverage statement. Three new studies identified are summarized below.
MGMT Promoter Methylation as a Selection Criterion for Study Entry
As a consequence of the differential treatment response to TMZ based on methylation status, recent studies of novel treatments have used methylation status as a critical entry criterion. In 1 study, only patients with methylated MGMT were enrolled, due to a hypothesized mechanism of action that would be effective in these patients. In other studies, only patients with unmethylated MGMT were enrolled. In these studies, the rationale for selecting patients with unmethylated MGMT was to investigate a treatment that might be better than the relatively poor response these patients have to standard treatment with TMZ. TMZ-based treatment is still the standard treatment despite the known poorer response. In these clinical trials, if the novel agent is effective, testing for MGMT methylation might be considered necessary to define the appropriate patients to treat. However, the effect of treatment in the unselected patients would be unknown.
Stupp et al investigated combination cilengitide plus TMZ compared with TMZ alone in subjects with methylated MGMT in an open-label randomized phase 3 study (Stupp, 2014). Median survival did not differ between treatment groups (26.3 months vs 26.3 months). No predefined subgroups showed a benefit from cilengitide.
Elinzano et al investigated paclitaxel poliglumex (PPX) plus RT versus TMZ plus RT in patients with unmethylated MGMT in a phase 2 randomized trial (Elinzano, 2015). Median survival was 16 months versus 14.8 months for PPX plus RT and TMZ plus RT (p=0.27), respectively. In the PPX and TMZ groups, 44% versus 22% of patients, respectively, experienced 1 or more grade 3 or higher toxicities during chemoradiation.
Raizer et al investigated bevacizumab and erlotinib after RT and TMZ in a single-arm study of unmethylated MGMT patients (Raizer, 2015). Median survival of 46 patients was 13.2 months, which did not meet the prespecified end point to be considered consistent with survival benefit.
In sum, these studies, selected patients based of MGMT methylation status for treatment with novel agents, have not shown definitive or suggestive evidence of benefit.
2017 Update
A literature search conducted through January 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wick and colleagues compared TMZ plus RT to temsirolimus plus RT in patients with unmethylated MGMT in a phase 2 randomized trial (Wick, 2016). Actuarial 1-year survival was 72.2% in the TMZ arm and 69.6% in the temsirolimus arm. Temsirolimus did not show evidence of efficacy in patients selected to have poor response to TMZ.
Nabors and colleagues investigated cilengitide with TMZ and RT compared to standard TMZ and RT in patients with unmethylated MGMT in a phase 2 randomized trial (Nabors, 2015). OS and PFS favored the 2 cilengitide arms, but the results were not statistically significant, making it difficult to drawn firm conclusions.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2017. Policy coverage statement changed to allow Methylation analysis of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter from glioma tumor tissue.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
MGMT Promoter Methylation as a Predictive Test for TMZ Response
Perry et al published the results of a trial designed to assess the benefit of adding TMZ to hypofractionated RT in patients 65 years of age and older (Perry, 2017). The addition of TMZ resulted in longer median OS and PFS. There were no significant differences in global quality-of-life measure, and there was a low rate of high-grade adverse events in both arms. An exploratory analysis of outcomes based on MGMT status demonstrated the greatest benefit in patients with methylated MGMT receiving RT plus TMZ.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2020. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2021. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement.
|
|
|
|
| CPT/HCPCS: | |
|
|
|
| References: |
Berghoff AS, Preusser M.(2012) Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients--yes, but how? Clin Neuropathol 2012; 31(6):405-8. Berghoff AS, Stefanits H, Woehrer A et al.(2013) Clinical neuropathology practice guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers. Clin Neuropathol 2013; 32(3):148-58. Chamberlain MC.(2014) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. Jun 10 2014;82(23):2147-2148. PMID 24912510 Chen Y, Hu F, Zhou Y et al.(2013) MGMT promoter methylation and glioblastoma prognosis: a systematic review and meta-analysis. Arch Med Res 2013; 44(4):281-90. Collins VP, Ichimura K, Di Y, et al.(2014) Prognostic and predictive markers in recurrent high grade glioma; results from the BR12 randomised trial. Acta Neuropathol Commun. 2014;2:68. PMID 24952577 Dong X, Liu RY, Chen WD.(2014) Correlation of Promoter Methylation in the MGMT Gene with Glioma Risk and Prognosis: a Meta-Analysis. Mol Neurobiol. Jun 10 2014. PMID 24913835 Elinzano H, Glantz M, Mrugala M, et al.(2015) PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244. Am J Clin Oncol. Dec 9 2015. PMID 26658237 Fietkau R, Putz F, Lahmer G, et al.(2013) Can MGMT promoter methylation status be used as a prognostic and predictive marker for glioblastoma multiforme at the present time? A word of caution. Strahlenther Onkol. Dec 2013;189(12):993-995. PMID 24177536 Gilbert MR, Wang M, Aldape KD et al.(2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013; 31(32):4085-91. Hegi ME, Diserens AC, Gorlia T et al.(2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10):997-1003. Holdhoff M, Ye X, Blakeley JO et al.(2012) Use of personalized molecular biomarkers in the clinical care of adults with glioblastomas. J Neurooncol 2012; 110(2):279-85. Kalkan R, Atli EI, Ozdemir M, et al.(2014) IDH1 mutations is prognostic marker for primary glioblastoma multiforme but MGMT hypermethylation is not prognostic for primary glioblastoma multiforme. Gene. Oct 14 2014;554(1):81-86. PMID 25455102 Kanemoto M, Shirahata M, Nakauma A, et al.(2014) Prognostic prediction of glioblastoma by quantitative assessment of the methylation status of the entire MGMT promoter region. BMC Cancer. 2014;14:641. PMID 25175833 Louis DN, Perry A, Reifenberger G, et al.(2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary. Acta Neuropathol. Jun 2016;131(6):803-820. PMID 27157931. Malmstrom A, Gronberg BH, Marosi C et al.(2012) Temozolomide 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):916-26. Minniti G, Scaringi C, Arcella A, et al.(2014) IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy. J Neurooncol. Jun 2014;118(2):377-383. PMID 24748470 Molenaar RJ, Verbaan D, Lamba S, et al.(2014) The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone. Neuro Oncol. Sep 2014;16(9):1263-1273. PMID 24510240 Myung JK, Cho HJ, Kim H, et al.(2014) Prognosis of glioblastoma with oligodendroglioma component is associated with the IDH1 mutation and MGMT methylation status. Transl Oncol. Dec 2014;7(6):712-719. PMID 25500080 Nabors LB, Fink KL, Mikkelsen T, et al.(2015) Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study Neuro Oncol. May 2015;17(5):708-717. PMID 25762461 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Central Nervous System Cancers. v.2.2013. 2013. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Last accessed December, 2013. NCCN(2016) NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2016. 2016; https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed April, 2017. Accessed April, 2017. Perry JR, Laperriere N, O'Callaghan CJ, et al.(2017) Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. Mar 16 2017;376(11):1027-1037. PMID 28296618 Preusser M, Berghoff AS, Manzl C, et al.(2014) Clinical Neuropathology practice news 1-2014: pyrosequencing meets clinical and analytical performance criteria for routine testing of MGMT promoter methylation status in glioblastoma. Clin Neuropathol. Jan-Feb 2014;33(1):6-14. PMID 24359605 Preusser M, Elezi L, Hainfellner JA.(2008) Reliability and reproducibility of PCR-based testing of O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation status in formalin-fixed and paraffin-embedded neurosurgical biopsy specimens. Clin Neuropathol 2008; 27(6):388-90. Pulverer W, Hofner M, Preusser M, et al.(2014) A simple quantitative diagnostic alternative for MGMT DNA-methylation testing on RCL2 fixed paraffin embedded tumors using restriction coupled qPCR. Clin Neuropathol. Jan-Feb 2014;33(1):50-60. PMID 23993306 Quillien V, Lavenu A, Ducray F, et al.(2016) Validation of the high-performance of pyrosequencing for clinical MGMT testing on a cohort of glioblastoma patients from a prospective dedicated multicentric trial. Oncotarget. Sep 20,2016;7(38):61916-61929. PMID 27542245 Quillien V, Lavenu A, Sanson M, et al.(2014) Outcome-based determination of optimal pyrosequencing assay for MGMT methylation detection in glioblastoma patients. J Neurooncol. Feb 2014;116(3):487-496. PMID 24420923 Raizer JJ, Giglio P, Hu J, et al.(2015) A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. J Neurooncol. Oct 17 2015. PMID 26476729 Stupp R, Hegi ME, Gorlia T, et al.(2014) Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. Sep 2014;15(10):1100-1108. PMID 25163906 Stupp R, Hegi ME, Mason WP et al.(2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10(5):459-66. Stupp R, Mason WP, van den Bent MJ et al.(2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10):987-96. Takahashi Y, Nakamura H, Makino K, et al.(2013) Prognostic value of isocitrate dehydrogenase 1, O6-methylguanine-DNA methyltransferase promoter methylation, and 1p19q co-deletion in Japanese malignant glioma patients. World J Surg Oncol. 2013;11:284. PMID 24160898 Weise LM, Harter PN, Eibach S, et al.(2014) Confounding factors in diagnostics of MGMT promoter methylation status in glioblastomas in stereotactic biopsies. Stereotact Funct Neurosurg. 2014;92(3):129-139. PMID 24776650 Weller M, Stupp R, Hegi ME et al.(2012) Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol 2012; 14 Suppl 4:iv100-8. Weller M, Stupp R, Reifenberger G et al.(2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 2010; 6(1):39-51. Wick W, Gorlia T, Bady P, et al.(2016) Phase II study of radiotherapy and temsirolimus versus radiochemotherapy with temozolomide in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (EORTC 26082). Clin Cancer Res. Oct 01 2016;22(19):4797-4806. PMID 27143690 Wick W, Meisner C, Hentschel B, et al.(2013) Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation. Neurology. Oct 22 2013;81(17):1515-1522. PMID 24068788 Wick W, Platten M, Meisner C et al.(2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 2012; 13(7):707-15. Wick W, Weller M, van den Bent M, et al.(2014) MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol. Jul 2014;10(7):372-385. PMID 24912512 Wiestler B, Capper D, Hovestadt V, et al.(2014) Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. Neuro Oncol. Dec 2014;16(12):1630-1638. PMID 25028501 Yang H, Wei D, Yang K, et al.(2014) The Prognosis of MGMT Promoter Methylation in Glioblastoma Patients of Different Race: A Meta-analysis. Neurochem Res. Dec 2014;39(12):2277-2287. PMID 25230908 Yin AA, Zhang LH, Cheng JX, et al.(2014) The predictive but not prognostic value of MGMT promoter methylation status in elderly glioblastoma patients: a meta-analysis. PLoS One. 2014;9(1):e85102. PMID 24454798 |
|
|
|
|
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association. |
|