Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

Abstract

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.