Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma

被引：138

作者：

Bell, Erica H. ^{[1
]}

Zhang, Peixin ^{[2
]}

Shaw, Edward G. ^{[3
]}

Buckner, Jan C. ^{[4
]}

Barger, Geoffrey R. ^{[5
]}

Bullard, Dennis E. ^{[6
]}

Mehta, Minesh P. ^{[7
]}

Gilbert, Mark R. ^{[8
]}

Brown, Paul D. ^{[4
]}

Stelzer, Keith J. ^{[9
]}

McElroy, Joseph P. ^{[1
]}

Fleming, Jessica I. ^{[1
]}

Timmers, Cynthia D. ^{[1
]}

Becker, Aline P. ^{[1
]}

Salavaggione, Andrea L. ^{[1
]}

Liu, Ziyan ^{[1
]}

Aldape, Kenneth ^{[10
]}

Brachman, David G. ^{[11
]}

Gertler, Stanley Z. ^{[12
]}

Murtha, Albert D. ^{[13
]}

Schultz, Christopher J. ^{[14
]}

Johnson, David ^{[15
]}

Laack, Nadia N. ^{[16
]}

Hunter, Grant K. ^{[17
]}

Crocker, Ian R. ^{[18
]}

Won, Minhee ^{[2
]}

Chakravarti, Arnab ^{[1
]}

机构：

[1] Ohio State Univ, Columbus, OH 43210 USA

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

[3] Wake Forest Sch Med, Winston Salem, NC 27101 USA

[4] Mayo Clin, Rochester, MN USA

[5] Wayne State Univ, Detroit, MI USA

[6] Triangle Neurosurg, Raleigh, NC USA

[7] Baptist Hosp Miami, Miami, FL USA

[8] NIH, Bldg 10, Bethesda, MD 20892 USA

[9] Mid Columbia Med Ctr, The Dalles, OR USA

[10] Princess Margaret Canc Ctr, Toronto, ON, Canada

[11] Arizona Oncol Serv Fdn, Phoenix, AZ USA

[12] Ottawa Hosp, Reg Canc Ctr, Ottawa, ON, Canada

[13] Cross Canc Inst, Edmonton, AB, Canada

[14] Froedtert & Med Coll Wisconsin, Milwaukee, WI USA

[15] Wichita NCORP, Wichita, KS USA

[16] Rochester Methodist Hosp, Rochester, MN USA

[17] Intermt Med Ctr, Murray, UT USA

[18] Emory Univ, Atlanta, GA 30322 USA

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2020年 / 38卷 / 29期

关键词：

MOLECULAR CLASSIFICATION; OLIGODENDROGLIOMA; CHEMOTHERAPY; MUTATIONS; TUMORS; ATRX; IDH;

D O I：

10.1200/JCO.19.02983

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSENRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.METHODSIDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.RESULTSOf the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.CONCLUSIONThis study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

引用

页码：3407 / 3417

页数：12

共 26 条

[1] MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status (vol 124, pg 547, 2012) [J].

Bady, Pierre ;

Sciuscio, Davide ;

Diserens, Annie-Claire ;

Bloch, Jocelyne ;

van den Bent, Martin J. ;

Marosi, Christine ;

Dietrich, Pierre-Yves ;

Weller, Michael ;

Mariani, Luigi ;

Heppner, Frank L. ;

Macdonald, David R. ;

Lacombe, Denis ;

Stupp, Roger ;

Delorenzi, Mauro ;

Hegi, Monika E. .

ACTA NEUROPATHOLOGICA, 2013, 126 (01) :159-159

[2] MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status [J].

Bady, Pierre ;

Sciuscio, Davide ;

Diserens, Annie-Claire ;

Bloch, Jocelyne ;

van den Bent, Martin J. ;

Marosi, Christine ;

Dietrich, Pierre-Yves ;

Weller, Michael ;

Mariani, Luigi ;

Heppner, Frank L. ;

Mcdonald, David R. ;

Lacombe, Denis ;

Stupp, Roger ;

Delorenzi, Mauro ;

Hegi, Monika E. .

ACTA NEUROPATHOLOGICA, 2012, 124 (04) :547-560

[3] Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study [J].

Baumert, Brigitta G. ;

Hegi, Monika E. ;

van den Bent, Martin J. ;

von Deimling, Andreas ;

Gorlia, Thierry ;

Hoang-Xuan, Khe ;

Brandes, Alba A. ;

Kantor, Guy ;

Taphoorn, Martin J. B. ;

Ben Hassel, Mohamed ;

Hartmann, Christian ;

Ryan, Gail ;

Capper, David ;

Kros, Johan M. ;

Kurscheid, Sebastian ;

Wick, Wolfgang ;

Enting, Roelien ;

Reni, Michele ;

Thiessen, Brian ;

Dhermain, Frederic ;

Bromberg, Jacoline E. ;

Feuvret, Loic ;

Reijneveld, Jaap C. ;

Chinot, Olivier ;

Gijtenbeek, Johanna M. M. ;

Rossiter, John P. ;

Dif, Nicolas ;

Balana, Carmen ;

Bravo-Marques, Jose ;

Clement, Paul M. ;

Marosi, Christine ;

Tzuk-Shina, Tzahala ;

Nordal, Robert A. ;

Rees, Jeremy ;

Lacombe, Denis ;

Mason, Warren P. ;

Stupp, Roger .

LANCET ONCOLOGY, 2016, 17 (11) :1521-1532

[4] 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 [J].

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 .

JAMA ONCOLOGY, 2018, 4 (10) :1405-1409

[5] Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas [J].

Brat, Daniel J. ;

Verhaak, Roel G. W. ;

Al-dape, Kenneth D. ;

Yung, W. K. Alfred ;

Salama, Sofie R. ;

Cooper, Lee A. D. ;

Rheinbay, Esther ;

Miller, C. Ryan ;

Vitucci, Mark ;

Morozova, Olena ;

Robertson, A. Gordon ;

Noushmehr, Houtan ;

Laird, Peter W. ;

Cherniack, Andrew D. ;

Akbani, Rehan ;

Huse, Jason T. ;

Ciriello, Giovanni ;

Poisson, Laila M. ;

Barnholtz-Sloan, Jill S. ;

Berger, Mitchel S. ;

Brennan, Cameron ;

Colen, Rivka R. ;

Colman, Howard ;

Flanders, Adam E. ;

Giannini, Caterina ;

Grifford, Mia ;

Iavarone, Antonio ;

Jain, Rajan ;

Joseph, Isaac ;

Kim, Jaegil ;

Kasaian, Katayoon ;

Mikkelsen, Tom ;

Murray, Bradley A. ;

O'Neill, Brian Patrick ;

Pachter, Lior ;

Parsons, Donald W. ;

Sougnez, Carrie ;

Sulman, Erik P. ;

Vandenberg, Scott R. ;

Van Meir, Erwin G. ;

von Deimling, Andreas ;

Zhang, Hailei ;

Crain, Daniel ;

Lau, Kevin ;

Mallery, David ;

Morris, Scott ;

Paulauskis, Joseph ;

Penny, Robert ;

Shelton, Troy ;

Sherman, Mark .

NEW ENGLAND JOURNAL OF MEDICINE, 2015, 372 (26) :2481-2498

[6] Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma [J].

Buckner, Jan C. ;

Shaw, Edward G. ;

Pugh, Stephanie L. ;

Chakravarti, Arnab ;

Gilbert, Mark R. ;

Barger, Geoffrey R. ;

Coons, Stephen ;

Ricci, Peter ;

Bullard, Dennis ;

Brown, Paul D. ;

Stelzer, Keith ;

Brachman, David ;

Suh, John H. ;

Schultz, Christopher J. ;

Bahary, Jean-Paul ;

Fisher, Barbara J. ;

Kim, Harold ;

Murtha, Albert D. ;

Bell, Erica H. ;

Won, Minhee ;

Mehta, Minesh P. ;

Curran, Walter J., Jr. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 374 (14) :1344-1355

[7] Phase III Trial of Chemoradiotherapy for Anaplastic Oligodendroglioma: Long-Term Results of RTOG 9402 [J].

Cairncross, Gregory ;

Wang, Meihua ;

Shaw, Edward ;

Jenkins, Robert ;

Brachman, David ;

Buckner, Jan ;

Fink, Karen ;

Souhami, Luis ;

Laperriere, Normand ;

Curran, Walter ;

Mehta, Minesh .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (03) :337-343

[8] Benefit From Procarbazine, Lomustine, and Vincristine in Oligodendroglial Tumors Is Associated With Mutation of IDH [J].

Cairncross, J. Gregory ;

Wang, Meihua ;

Jenkins, Robert B. ;

Shaw, Edward G. ;

Giannini, Caterina ;

Brachman, David G. ;

Buckner, Jan C. ;

Fink, Karen L. ;

Souhami, Luis ;

Laperriere, Normand J. ;

Huse, Jason T. ;

Mehta, Minesh P. ;

Curran, Walter J., Jr. .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (08) :783-+

[9] Monoclonal antibody specific for IDH1 R132H mutation [J].

Capper, David ;

Zentgraf, Hanswalter ;

Balss, Joerg ;

Hartmann, Christian ;

von Deimling, Andreas .

ACTA NEUROPATHOLOGICA, 2009, 118 (05) :599-601

[10]

COX DR, 1972, J R STAT SOC B, V34, P187

← 1 2 3 →