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

Erica H. Bell, Peixin Zhang, Edward G. Shaw, Jan Craig Buckner, Geoffrey R. Barger, Dennis E. Bullard, Minesh P. Mehta, Mark R. Gilbert, Paul D. Brown, Keith J. Stelzer, Joseph P. McElroy, Jessica l. Fleming, Cynthia D. Timmers, Aline P. Becker, Andrea L. Salavaggione, Ziyan Liu, Kenneth Aldape, David G. Brachman, Stanley Z. Gertler, Albert D. MurthaChristopher J. Schultz, David Johnson, Nadia N. Laack, Grant K. Hunter, Ian R. Crocker, Minhee Won, Arnab Chakravarti

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8 Scopus citations

Abstract

PURPOSE NRG 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. METHODS IDH1/2 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. RESULTS Of 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. CONCLUSION This 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.

Original languageEnglish (US)
Pages (from-to)3407-3417
Number of pages11
JournalJournal of Clinical Oncology
Volume38
Issue number29
DOIs
StatePublished - Oct 10 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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