ACTR-53. MGMT PROMOTER METHYLATION ANALYSIS FOR ALLOCATING COMBINED CCNU/TMZ CHEMOTHERAPY: LESSONS LEARNED FROM THE CeTeG/NOA-09 TRIAL

Abstract BACKGROUND The CeTeG/NOA-09 trial recently showed a survival benefit for combination chemotherapy with CCNU/TMZ in glioblastoma patients with a methylated MGMT promoter as determined by quantitative Methylation-Specific PCR (qMSP). Identifying patient subgroups with a pronounced benefit from this novel treatment is crucial. Here, we report on the prognostic and predictive value of MGMT promoter methylation ratio determined by qMSP and investigate the concordance of pyrosequencing (PSQ) and qMSP for patients in this trial. METHODS qMSP and PSQ were used for MGMT promoter methylation analysis. The mITT population of the CeTeG/NOA-09 trial was used for multivariate analysis including the parameters MGMT promoter methylation ratio, RPA class and study center. RESULTS Patients of the mITT population of the CeTeG/NOA-09 trial (n=129) with MGMT promoter methylation ratio greater than 4 (qMSP) showed a superior overall survival compared to patients with borderline methylation ratio of 2–4 (p=0.0251). In the latter patients, treatment with CCNU/TMZ did not show a survival benefit (p=0.924). Multivariate analysis with treatment arm, RPA class and study center as covariates did not confirm a prognostic or predictive value of MGMT promoter methylation ratio (qMSP) for patients of the mITT population (n=129, HR=0.88; 95% CI: 0.72 – 1.08) or patients with a ratio greater than 4 (n=117, HR =0.86; 95% CI: 0.69 – 1.07). In a subset of 49 trial patients, qMSP and PSQ showed not only a high qualitative (45/49; 91.8%), but also a high quantitative concordance rate (Spearman correlation, r=0.83, p< 0.0001). CONCLUSION Glioblastoma patients with borderline MGMT promoter methylation (qMSP ratio 2–4) do not seem to benefit from combination treatment with CCNU/TMZ. Thus, we propose a qMSP cut-off of 4 as a novel decision tool for clinicians. qMSP and PSQ show a high concordance rate indicating that a decision for combination therapy can also be based on PSQ results.

Download Full-text

Faculty Opinions recommendation of Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718120909.793486641 ◽

2013 ◽

Author(s):

Marc Chamberlain

Keyword(s):

Promoter Methylation ◽

Predictive Value ◽

Idh1 Mutation ◽

Mgmt Promoter Methylation ◽

Mgmt Promoter

Download Full-text

RESULTS OF THE INTERNATIONAL INTERLABORATORY COMPARISON OF MGMT PROMOTER METHYLATION ANALYSIS INVOLVING TWENTY-THREE ACADEMIC CENTERS IN GERMANY, AUSTRIA AND THE NETHERLANDS

Neuro-Oncology ◽

10.1093/neuonc/nou209.30 ◽

2014 ◽

Vol 16 (suppl 3) ◽

pp. iii49-iii50 ◽

Cited By ~ 3

Author(s):

G. Reifenberger ◽

B. Malzkorn ◽

T. Acker ◽

M. Bettstetter ◽

R. Buslei ◽

...

Keyword(s):

The Netherlands ◽

Promoter Methylation ◽

Interlaboratory Comparison ◽

Mgmt Promoter Methylation ◽

Methylation Analysis ◽

Mgmt Promoter

Download Full-text

Determination of O-6-methylguanine-DNA methyltransferase by immunochemistry and pyrosequencing as a predictive factor of response to temozolomide in pancreatic neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.195 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 195-195

Author(s):

Roberto Escala ◽

L Miguel Navarro ◽

Sofía Del Carmen Martínez ◽

Sandra I Malmierca Gonzalez ◽

Julia Ayuso Martín-Romo ◽

...

Keyword(s):

Positive Predictive Value ◽

Predictive Factor ◽

Promoter Methylation ◽

Predictive Value ◽

Dna Methyltransferase ◽

Predictive Power ◽

Mgmt Promoter Methylation ◽

Pancreatic Neuroendocrine Tumors ◽

Methylguanine Dna Methyltransferase ◽

Mgmt Promoter

195 Background: Temozolomide (TMZ) is an alkylating agent that has shown good results in the treatment of neuroendocrine and central nervous system (CNS) tumors. The loss of O-6-methylguanine-DNA methyltransferase (MGMT) expression by pyrosequencing (PSQ) is a predictive factor of response to treatment with TMZ in high-grade gliomas. However, its predictive value in pancreatic neuroendocrine tumors (pNET) is controversial, and there is no consensus on how to best assess MGMT. The aim was to evaluate the objective response rate in pNET according to the state of MGMT, assessed by PSQ for evaluation of promoter methylation and immunohistochemistry (IHC). Methods: Patients with pNET who were treated with TMZ at the center between 2008 and 2017 were studied retrospectively. Ten patients were included in the study. A deficiency of MGMT was determined by IHC and MGMT promoter methylation by PSQ. For IHC, the cut-off was 10%, defined as negative < 10% of tumor cells positive in the tumor tissue. For the PSQ, the cut-off was 8%, defined as methylated who presented > 8%. Results: A deficiency of MGMT was detected in five patients (50%) by IHC. An MGMT promoter methylation by PSQ was observed in three patients (30%). The IHC results were consistent with PSQ results in only six patients (60%); one patient with methylated MGMT had positive IHC, and three patients had unmethylated MGMT by PSQ unmethylated, IHC negative. PSQ had a high positive predictive value of response because the three patients with MGMT promoter methylation by PSQ presented objective responses (OR). Nevertheless, a low negative predictive power (57%) was observed because three of seven patients with unmethylated MGMT presented OR. Of the five patients with MGMT deficiency by IHC, four (80%) presented OR, suggesting positive predictive value of 80%; however, it also presented a low negative predictive power of 60%. Conclusions: Despite having 100% of the patients with MGMT promoter methylation showing OR in this series, the low negative predictive power suggests that the absence of MGMT deficiency by IHC or MGMT unmethylated by PSQ does not contraindicate the use of TMZ in pNET treatment.

Download Full-text