Abstract
INTRODUCTION
The EORTC22033-26033 clinical trial investigated whether initial temozolomide (TMZ) chemotherapy confers a survival advantage compared to radiotherapy (RT) in high-risk low-grade glioma patients. The aim of this study was to identify markers associated with survival and treatment response in the tumors’ transcriptome.
METHODS
Gene expression profiling (n=195/477) was used to assign tumors to one of six intrinsic glioma subtypes (IGS; molecularly similar tumors predefined by unsupervised gene expression analysis) and to extract in silico the cellular composition of immune infiltrates. DNA copy number changes were determined on samples assigned to IGS-16.
RESULTS
We confirm that IGS-subtypes are prognostic in EORTC22033-26033 clinical trial samples. Specific genetic changes segregate in distinct IGS subtypes: most samples assigned to IGS-9 have IDH-mutations combined with 1p19q codeletion, while samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion (non-codeleted) and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards longer PFS in the RT arm as compared to TMZ was observed for samples assigned to IGS-9 (HR for TMZ is 1.90, 95% CI [0.95, 3.80], P=0.065), but not for samples assigned to IGS-17 (HR for TMZ vs RT is 0.87, 95% CI[0.50, 1.51], P=0.62). We did not identify genes significantly associated with progression free survival within intrinsic subtypes. Follow-up time is however limited. We also show that LGGs and GBMs differ in their immune-infiltrate with LGGs having higher suppressor (TREG, MDSC) and lower effector cell (CD4, CD8) populations compared to GBMs. This suggests that LGGs are less amenable to checkpoint inhibitor type immune therapies than GBMs. Copy number analysis of samples assigned to IGS-16 (a subtype to which pilocytic astrocytomas (PAs) are assigned) confirmed the typical genomic hallmark of PAs, a tandem duplication on 7q34, in one patient.
CONCLUSION
Intrinsic glioma expression subtypes are prognostic for PFS in EORTC22033-26033 clinical trial samples.