Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design

Abstract

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %, C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size.

Impact of Including Peritumoral Edema in Radiotherapy Target Volume on Patterns of Failure in Glioblastoma following Temozolomide-based Chemoradiotherapy

“…In the era of concurrent chemoradiotherapy with TMZ, many studies have reported that local recurrence is still a major failure pattern in limited-margin radiotherapy. Recently, several studies reported improved local control but higher rates of distant failures in patients with favorable prognostic factors including O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation or extensive surgical resection 14 15 16 17 18 . However, there is no report so far concerning the relationship between radiotherapy volume and these prognostic factors.…”

<p>High dose vs low dose irradiation of the subventricular zone in patients with glioblastoma—a systematic review and meta-analysis</p>

“…The location of the tumor is also to be taken into account. Studies conducted on patients whose tumors come into contact with the SVZ have indicated decreased OS and PFS 15,32. This could be explained by the fact that the NSC located in the SVZ can increase the aggressiveness of the tumor 24,31.…”

“…The importance of the interaction between GBM and the SVZ has been highlighted, as the tumors coming into contact with the area that contains NSC have a worse prognosis than those located at a distance 2,3,11,17,25,36. The subject needs more research because there are also studies that could not confirm the prognostic role of SVZ invasion by GBM 15,16…”

Glioblastoma radiomics: can genomic and molecular characteristics correlate with imaging response patterns?

“…At WFBMC, genomic techniques for data processing and evaluation were previously described by Holmes et al [14]. In brief, Affymetrix Human Exon 1.0 ST GeneChips (Affymetrix, Santa Clara, CA) and Infinium HumanMethylation (HM) 450 BeadChip from Illumina (Illumina, San Diego, CA) were used for genomic analysis offresh frozen tissue from the Brain Tumor Center of Excellence Tumor Bank at WFBMC [15]. Of note, tissue banking was performed predominantly on patients with tumor resection as opposed to stereotactic biopsy as the latter tended to yield an insufficient quantity of tissue.…”