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

被引：160

作者：

Bell, Erica H. ^{[1
]}

Zhang, Peixin ^{[2
]}

Fisher, Barbara J. ^{[3
]}

Macdonald, David R. ^{[4
]}

McElroy, Joseph P. ^{[5
]}

Lesser, Glenn J. ^{[6
]}

Fleming, Jessica ^{[1
]}

Chakraborty, Arup R. ^{[1
]}

Liu, Ziyan ^{[1
]}

Becker, Aline P. ^{[1
]}

Fabian, Denise ^{[1
]}

Aldape, Kenneth D. ^{[7
]}

Ashby, Lynn S. ^{[8
]}

Werner-Wasik, Maria ^{[9
]}

Walker, Eleanor M. ^{[10
]}

Bahary, Jean-Paul ^{[11
]}

Kwok, Young ^{[12
]}

Yu, H. Michael ^{[13
]}

Laack, Nadia N. ^{[14
]}

Schultz, Christopher J. ^{[15
]}

Gray, Heidi J. ^{[16
]}

Robins, H. Ian ^{[17
,18
,19
]}

Mehta, Minesh P. ^{[20
]}

Chakravarti, Arnab ^{[1
]}

机构：

[1] Ohio State Univ, Dept Radiat Oncol, Columbus, OH 43210 USA

[2] NRG Oncol, Stat & Data Management Ctr, Philadelphia, PA USA

[3] London Reg Canc Program, Dept Radiat Oncol, London, ON, Canada

[4] London Reg Canc Program, Dept Oncol, London, ON, Canada

[5] Ohio State Univ, Dept Biomed Informat, Ctr Biostat, Columbus, OH 43210 USA

[6] Wake Forest Univ, Bowman Gray Sch Med, Dept Hematol & Oncol, Winston Salem, NC USA

[7] Toronto Gen Hosp Princess Margaret, Dept Pathol, Toronto, ON, Canada

[8] Accruals Arizona Oncol Serv Fdn, St Josephs Hosp & Med Ctr, Dept Neurol, Phoenix, AZ USA

[9] Thomas Jefferson Univ Hosp, Dept Radiat Oncol, Philadelphia, PA 19107 USA

[10] Henry Ford Hosp, Dept Radiat Oncol, Detroit, MI 48202 USA

[11] Ctr Hosp Univ Montreal Notre Dame, Dept Radiat Oncol, Montreal, PQ, Canada

[12] Univ Maryland Med Syst, Dept Radiat Oncol, Baltimore, MD USA

[13] H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, Tampa, FL USA

[14] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA

[15] Med Coll Wisconsin, Dept Radiat Oncol, Milwaukee, WI 53226 USA

[16] Univ Washington, Med Ctr, Accruals Univ Calif San Francisco, Dept Obstet & Gynecol, Seattle, WA 98195 USA

[17] Univ Wisconsin Hosp, Dept Med, Madison, WI USA

[18] Univ Wisconsin Hosp, Dept Human Oncol, Madison, WI USA

[19] Univ Wisconsin Hosp, Dept Neurol, Madison, WI USA

[20] Baptist Hosp Miami, Dept Radiat Oncol, Miami, FL USA

来源：

JAMA ONCOLOGY | 2018年 / 4卷 / 10期

关键词：

LOW-GRADE GLIOMA; GLIOBLASTOMA; GENE;

D O I：

10.1001/jamaoncol.2018.1977

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 O-6-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.

引用

页码：1405 / 1409

页数：5

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