I have read with great interest the paper entitled “Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813” by Chang et al.1 The authors evaluated overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU), and secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. The Authors evidenced that out of 103 patients in which isocitrate dehydrogenase 1 (IDH1) status could be determined by immunohistochemistry, 54 patients were IDH negative and 49 were IDH positive, with a better OS in IDH-positive patients. Furthermore RT + TMZ did not appear to significantly improve OS or TTP for AA compared with RT + NU.
This study is very interesting; however, in my opinion the conclusions may be biased by a questionable assessment of IDH status. In this series, including about 70% of patients aged less than 50 years, only 47.5% (49/103) of enrolled cases resulted as AA IDH-mutated.
Several studies demonstrated IDH1 or IDH2 mutations in astrocytoma (A) and AA, and the percentages of IDH mutations given for AA ranged from 52% to 78%.2–6
Even if the p.R132H mutation is undoubtedly the most frequent alteration in IDH genes,5 other mutations have been observed in IDH1 or IDH2 genes at a lower frequency, such as p.R132S (c.394C>A), p.R132C (c.394C>T), and p.R132G (c.394C>G) in the IDH1 gene, and p.R172K (c.515G>A) and p.R172M (c.515G>T) in the IDH2 gene.7
For this reason, nowadays those cases that are negative for immunohistochemistry with IDH1-R132H–specific monoclonal antibody should be analyzed by sequencing of exon 4 in IDH1 and IDH2, in order to recognize all mutations.
According to 2016 World Health Organization (WHO) classification,8 assessment of IDH mutation status is crucial in diagnosis of gliomas, introducing IDH-mutant and IDH-wildtype entities for all astrocytic tumors (A, AA, and GBM). If IDH status had been determined only by immunohistochemistry with an IDH1-R132H–specific monoclonal antibody, as in the study by Chang et al,1 a significant proportion of AA would have been misclassified according to the current WHO criteria.8
In effect, such a dichotomous approach, distinguishing IDH-mutant and IDH-wildtype diffuse gliomas, evidences how essential is the accuracy of IDH status assessment, with significant and predictable implications also in evaluating primary and secondary endpoints.
Conflict of interest statement. The author has no conflict of interest to disclose.
References
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