Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide: An Analysis from the NRG Oncology/RTOG 0424 Trial

Erica H. Bell, Peixin Zhang, Barbara J. Fisher, David R. Macdonald, Joseph P. McElroy, Glenn J. Lesser, Jessica Fleming, Arup R. Chakraborty, Ziyan Liu, Aline P. Becker, Denise Fabian, Kenneth D. Aldape, Lynn S. Ashby, Maria Werner-Wasik, Eleanor M. Walker, Jean Paul Bahary, Young Kwok, H. Michael Yu, Nadia N Laack, Christopher J. SchultzHeidi J. Gray, H. Ian Robins, Minesh P. Mehta, Arnab Chakravarti

Research output: Contribution to journalArticle

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Abstract

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial - evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes - was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P <.001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P <.001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P =.045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P =.02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

Original languageEnglish (US)
Pages (from-to)1405-1409
Number of pages5
JournalJAMA oncology
Volume4
Issue number10
DOIs
StatePublished - Oct 1 2018

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temozolomide
Radiation Oncology
Methyltransferases
Glioma
Methylation
Radiotherapy
Survival
DNA
Disease-Free Survival
Astrocytoma
Oligodendroglioma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide : An Analysis from the NRG Oncology/RTOG 0424 Trial. / Bell, Erica H.; Zhang, Peixin; Fisher, Barbara J.; Macdonald, David R.; McElroy, Joseph P.; Lesser, Glenn J.; Fleming, Jessica; Chakraborty, Arup R.; Liu, Ziyan; Becker, Aline P.; Fabian, Denise; Aldape, Kenneth D.; Ashby, Lynn S.; Werner-Wasik, Maria; Walker, Eleanor M.; Bahary, Jean Paul; Kwok, Young; Yu, H. Michael; Laack, Nadia N; Schultz, Christopher J.; Gray, Heidi J.; Robins, H. Ian; Mehta, Minesh P.; Chakravarti, Arnab.

In: JAMA oncology, Vol. 4, No. 10, 01.10.2018, p. 1405-1409.

Research output: Contribution to journalArticle

Bell, EH, Zhang, P, Fisher, BJ, Macdonald, DR, McElroy, JP, Lesser, GJ, Fleming, J, Chakraborty, AR, Liu, Z, Becker, AP, Fabian, D, Aldape, KD, Ashby, LS, Werner-Wasik, M, Walker, EM, Bahary, JP, Kwok, Y, Yu, HM, Laack, NN, Schultz, CJ, Gray, HJ, Robins, HI, Mehta, MP & Chakravarti, A 2018, 'Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide: An Analysis from the NRG Oncology/RTOG 0424 Trial', JAMA oncology, vol. 4, no. 10, pp. 1405-1409. https://doi.org/10.1001/jamaoncol.2018.1977
Bell, Erica H. ; Zhang, Peixin ; Fisher, Barbara J. ; Macdonald, David R. ; McElroy, Joseph P. ; Lesser, Glenn J. ; Fleming, Jessica ; Chakraborty, Arup R. ; Liu, Ziyan ; Becker, Aline P. ; Fabian, Denise ; Aldape, Kenneth D. ; Ashby, Lynn S. ; Werner-Wasik, Maria ; Walker, Eleanor M. ; Bahary, Jean Paul ; Kwok, Young ; Yu, H. Michael ; Laack, Nadia N ; Schultz, Christopher J. ; Gray, Heidi J. ; Robins, H. Ian ; Mehta, Minesh P. ; Chakravarti, Arnab. / Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide : An Analysis from the NRG Oncology/RTOG 0424 Trial. In: JAMA oncology. 2018 ; Vol. 4, No. 10. pp. 1405-1409.
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title = "Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide: An Analysis from the NRG Oncology/RTOG 0424 Trial",
abstract = "Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial - evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes - was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1{\%}) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0{\%}] male): 57 (76.0{\%}) methylated and 18 (24.0{\%}) unmethylated. A total of 13 unmethylated patients (72.2{\%}) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4{\%}) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95{\%} CI, 1.64-7.56; P <.001) and PFS (HR, 3.06; 95{\%} CI, 1.55-6.04; P <.001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95{\%} CI, 1.02-7.14; P =.045) and PFS (HR, 2.74; 95{\%} CI, 1.19-6.33; P =.02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.",
author = "Bell, {Erica H.} and Peixin Zhang and Fisher, {Barbara J.} and Macdonald, {David R.} and McElroy, {Joseph P.} and Lesser, {Glenn J.} and Jessica Fleming and Chakraborty, {Arup R.} and Ziyan Liu and Becker, {Aline P.} and Denise Fabian and Aldape, {Kenneth D.} and Ashby, {Lynn S.} and Maria Werner-Wasik and Walker, {Eleanor M.} and Bahary, {Jean Paul} and Young Kwok and Yu, {H. Michael} and Laack, {Nadia N} and Schultz, {Christopher J.} and Gray, {Heidi J.} and Robins, {H. Ian} and Mehta, {Minesh P.} and Arnab Chakravarti",
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TY - JOUR

T1 - Association of MGMT Promoter Methylation Status with Survival Outcomes in Patients with High-Risk Glioma Treated with Radiotherapy and Temozolomide

T2 - An Analysis from the NRG Oncology/RTOG 0424 Trial

AU - Bell, Erica H.

AU - Zhang, Peixin

AU - Fisher, Barbara J.

AU - Macdonald, David R.

AU - McElroy, Joseph P.

AU - Lesser, Glenn J.

AU - Fleming, Jessica

AU - Chakraborty, Arup R.

AU - Liu, Ziyan

AU - Becker, Aline P.

AU - Fabian, Denise

AU - Aldape, Kenneth D.

AU - Ashby, Lynn S.

AU - Werner-Wasik, Maria

AU - Walker, Eleanor M.

AU - Bahary, Jean Paul

AU - Kwok, Young

AU - Yu, H. Michael

AU - Laack, Nadia N

AU - Schultz, Christopher J.

AU - Gray, Heidi J.

AU - Robins, H. Ian

AU - Mehta, Minesh P.

AU - Chakravarti, Arnab

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial - evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes - was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P <.001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P <.001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P =.045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P =.02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

AB - Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial - evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes - was not previously reported. Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures: Progression-free survival (PFS) and overall survival (OS). Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P <.001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P <.001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P =.045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P =.02). Conclusions and Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.

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