Intrinsic molecular subtypes of glioma are prognostic and predict benefit from adjuvant procarbazine, lomustine, and vincristine chemotherapy in combination with other prognostic factors in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951

Abstract

Purpose: Intrinsic glioma subtypes (IGSs) are molecularly similar tumors that can be identified based on unsupervised gene expression analysis. Here, we have evaluated the clinical relevance of these subtypes within European Organisation for Research and Treatment of Cancer (EORTC) 26951, a randomized phase III clinical trial investigating adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglial tumors. Our study includes gene expression profiles of formalin-fixed, paraffin-embedded (FFPE) clinical trial samples.

Patients and methods: Gene expression profiling was performed in 140 samples, 47 fresh frozen samples and 93 FFPE samples, on HU133_Plus_2.0 and HuEx_1.0_st arrays, respectively.

Results: All previously identified six IGSs are present in EORTC 26951. This confirms that different molecular subtypes are present within a well-defined histologic subtype. Intrinsic subtypes are highly prognostic for overall survival (OS) and progression-free survival (PFS). They are prognostic for PFS independent of clinical (age, performance status, and tumor location), molecular (1p/19q loss of heterozygosity [LOH], IDH1 mutation, and MGMT methylation), and histologic parameters. Combining known molecular (1p/19q LOH, IDH1) prognostic parameters with intrinsic subtypes improves outcome prediction (proportion of explained variation, 30% v 23% for each individual group of factors). Specific genetic changes (IDH1, 1p/19q LOH, and EGFR amplification) segregate into different subtypes. We identified one subtype, IGS-9 (characterized by a high percentage of 1p/19q LOH and IDH1 mutations), that especially benefits from PCV chemotherapy. Median OS in this subtype was 5.5 years after radiotherapy (RT) alone versus 12.8 years after RT/PCV (P = .0349; hazard ratio, 2.18; 95% CI, 1.06 to 4.50).

Conclusion: Intrinsic subtypes are highly prognostic in EORTC 26951 and improve outcome prediction when combined with other prognostic factors. Tumors assigned to IGS-9 benefit from adjuvant PCV.

Trial registration: ClinicalTrials.gov NCT00002840.

Fig 1.

CONSORT diagram. PCV, procarbazine, lomustine, and vincristine; PD, progressive disease; RT, radiotherapy.

Fig 2.

Kaplan-Meier survival curves of (A) overall survival (OS) and (B) progression-free survival (PFS) of the four major intrinsic glioma subtypes (IGSs) to which the patients from the European Organisation for Research and Treatment of Cancer (EORTC) 26951 trial were assigned. Survival is depicted as time (years) since random assignment. The four IGSs were highly prognostic for both OS and PFS because patient prognosis was different for each IGS. Only two and eight samples were assigned to IGS-16 and IGS-22, respectively (not shown).

Fig 3.

Genetic differences between intrinsic glioma subtypes (IGSs). Specific genetic changes segregate into distinct IGSs. 1p/19q loss of heterozygosity (LOH) was predominantly observed in tumors assigned to IGS-9 and, to a lesser extent, tumors assigned to IGS-17 but was not seen in tumors assigned to IGS-18 and IGS-23. IDH1 mutations (mut) were significantly more observed in samples assigned to IGS-9 and IGS-17 compared with IGS-18 and IGS-23. EGFR amplification (amp) was predominantly identified in IGS-18 and IGS-23 but rarely identified in samples assigned to IGS-9 and IGS-17. This segregation was highly similar to that reported by us previously using archival samples and demonstrates that each IGS has a different set of causal genetic changes.

Fig 4.

Kaplan-Meier survival curves of the four intrinsic glioma subtypes (IGSs) per treatment arm. (A and B) Adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy improved overall survival (OS) and progression-free survival (PFS) in samples assigned to IGS-9. (C and D) A trend toward an increase in both OS and PFS is seen between the two treatment arms in samples assigned to IGS-17. (E and F) Adjuvant PCV also improved PFS, but not OS, in samples assigned to IGS-18. (G and H) No difference between the two treatment arms was observed for both OS and PFS in samples assigned to IGS-23. Patients with one specific IGS (IGS-9) seem to benefit from adjuvant PCV chemotherapy, whereas patients with tumors assigned to IGS-23 do not. In this figure, survival is depicted as time (years) since random assignment. RT, radiotherapy.