IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma

Abstract

Recent studies have shown that isocitrate dehydrogenase1 ⁄ 2 (IDH1 ⁄ 2) mutations occur frequently in secondary glioblastoma. This study aimed to investigate their impact on temozolomide chemosensitivity and relationship with O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation in secondary glioblastoma. Searches for IDH1 and IDH2 mutations, 1p19q codeletion, MGMT promoter methylation, and p53 expression were carried out in a series of 86 secondary glioblastomas and correlated with progression-free survival and overall survival. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, then correlated with molecular alterations. IDH (IDH1 or IDH2) mutations were found in 58 ⁄ 79 patients (73.4%). IDH mutation, MGMT promoter methylation, and 1p19q codeletion were associated with prolonged progression-free survival in univariate (P < 0.001, P < 0.001, P = 0.003, respectively) and multivariate analysis (P < 0.001, P < 0.001, P = 0.035, respectively). IDH mutation (P = 0.001) and MGMT promoter methylation (P = 0.011) were correlated with a higher rate of objective response to temozolomide. Further analysis of response to temozolomide showed that patients with both IDH mutation and MGMT promoter methylation had the best response rate to temozolomide. IDH mutation appears to be a significant marker of positive chemosensitivity in secondary glioblastoma. Use of IDH status combined with MGMT promoter status as a stratification factor seems appropriate in future clinical trials involving temozolomide for the treatment of patients with secondary glioblastoma. (Cancer Sci 2012; 103: 269-273) G lioblastomas (GBMs), the most common and malignant primary brain tumors in adults, may develop rapidly after a short history and without evidence of less malignant precursor lesions (primary GBM, pGBM), or through progression from low-grade or anaplastic gliomas (secondary GBM, sGBM).(1-3)In GBM, the clinical value of O(6)-methylguanine DNA methyltransferase (MGMT) promotor methylation status in predicting benefit from alkylating agents has been validated by several clinical trials, both in patients treated with nitrosourea and in those with temozolomide (TMZ). (4,5) In the European Organization for Research and Treatment of Cancer (EORTC) ⁄ National Cancer Institute of Canada (NCIC) 26981 ⁄ 22981 trial evaluating the effect of radiotherapy plus concomitant and adjuvant TMZ versus radiotherapy alone in GBM, methylation of MGMT promotor emerged as the strongest predictor for outcome and benefit from chemotherapy.(6,7) However, all of these studies were based on newly diagnosed GBMs, most of which were pGBMs. So far, there is no clear evidence that MGMT promotor methylation plays the same role in sGBMs, as these two subtypes constitute distinct disease entities and develop through different genetic pathways. (2,3,8) In 2008, a genome-wide sequencing study identified somatic mutations on codon 132 in a gene encoding isocitrate dehydrogenase-1 (IDH1) in 12% s...

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

“…3). IDH1/2 mutations have been associated with overall better prognosis across all diffusely infiltrating malignant astrocytic entities (9,10,12,15,16) and their absence in elderly glioblastoma patients may explain in part why age is a negative prognostic factor in this disease (17). However, it has never been explored whether tumors with IDH1/2 mutations are enriched in long-term survivors of glioblastomas.…”

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

“…The robustness of IDH1 mutation and MGMT methylation may drive other genetic changes in tumor cells, tumors accompanied by IDH1 mutation and methylated MGMT may consequently have different genetic characteristics compared to tumors unaccompanied by the alternations, which may lead to their varied biological features and patients' survival. As previous reported that the survival time of glioblastoma patients with only IDH1 mutation is shorter than that for patients with both IDH1 mutation and MGMT methylation (Hartmann et al, 2010;Juratli et al, 2012;SongTao et al, 2012). It is suggested that the IDH1-mutated patients is not homogeneous and that the prognosis is not only depend on IDH1 mutation but also on MGMT methylation, so there may be a underlying mechanistic link between IDH1 mutations and MGMT methylation and needs to be further explored (Wick et al, 2013).…”

Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma

“…29 Similarly, the presence of an IDH mutation predicts response to temozolomide in low-grade gliomas and secondary glioblastomas. 11,26 In contrast, little reliable information is available to demonstrate any difference in the impact of the extent of resection in glioma with a mutated and wild-type IDH1/IDH2 gene. If any difference between glioma with mutated or wild-type IDH genes can be demonstrated in the future, an intraoperative molecular diagnosis will provide useful information for designing the surgical strategy.…”

“…3 Additionally, the mutations have been shown to be prognostic 1,20,25 in high-grade gliomas and we can expect them to be present after radiation therapy and chemotherapy. 11,26,29 Based on these findings, we considered that the intraoperative detection of these mutations has potential for clinical application.…”