Genetic analyses for predictors of radiation response in glioblastoma

Purpose: Radiotherapy (RT) for patients with glioblastoma improves survival and is recommended for nearly all patients with this diagnosis. However, the response to RT is variable in this patient population. Prior studies have suggested that underlying genetic alterations in the tumor may account for some of this treatment-related heterogeneity. It has been previously reported that epidermal growth factor receptor (EGFR) gene amplification and TP53 mutation correlate with the response to RT in patients with glioblastoma.

Methods and Materials: We sought to identify molecular markers that could predict the response to RT, progression-free survival after RT, and overall survival among 75 glioblastoma patients treated with RT at a single institution. Genetic analyses assessed EGFR amplification, TP53 mutations, CDKN2A/p16 deletion, and losses of chromosomes 1p, 10q, and 19q.

Results: Unlike previous reports, no association of EGFR amplification with response to RT, progression-free survival, or overall survival was found. Moreover, no association was found between these endpoints and the other genetic alterations assayed (TP53 mutation, CDKN2A/p16 deletion, loss of heterozygosity 1p, loss of heterozygosity 10q, and loss of heterozygosity 19q). However, in accordance with recent observations that the prognostic effects of genetic alterations in glioblastoma may depend on patient age, we observed age-dependent prognostic effects of TP53 and CDKN2A/p16 alterations in our patient population. For patients ≥57 years old, those harboring TP53 mutations had a decreased overall survival compared with patients without TP53 mutations. Similarly, deletion of CDKN2A/p16 in patients ≥57 years was associated with decreased progression-free survival after RT and a trend toward a shorter time to progression after RT compared with similar patients without the deletion.

Conclusion: These data contrast with previous studies regarding the significant prognostic effect of EGFR with respect to RT response. Although our observations regarding the age-dependent prognostic effects of TP53 and CDKN2A/p16 are consistent with a prior report regarding these alterations, the present results should be considered preliminary, given the small sample size.

Introduction

Glioblastoma remains a poorly understood tumor despite being the most common primary brain malignancy. Recent advancements in understanding the genetics of this disease have not yet translated into improved clinical outcomes. Most patients survive for approximately 1 year from the time of diagnosis despite surgery, radiotherapy (RT), and chemotherapy. However, many patients experience disease progression earlier, with survival of only a few months, or, conversely, show relatively stable disease for a few years before inevitable progression. Accurate prediction of the treatment response remains elusive.

Current treatment of glioblastoma involves a multidisciplinary approach. Most glioblastoma patients undergo surgical resection, RT, and chemotherapy. Recently, the addition of an oral alkylating drug, temozolomide, to RT has been shown to improve progression-free survival (PFS) and overall survival (OS) compared with RT alone (1). Some studies have suggested a correlation of genetic features with patient prognosis. Genetic determinants of response to treatment are not well-defined; however, Barker et al. (2) found that epidermal growth factor receptor (EGFR) overexpression correlated with poor RT response and, ultimately, a worse OS. In an attempt to identify genetic markers predictive of RT response, PFS, and OS, we evaluated a panel of genetic alterations in a cohort of glioblastoma patients who received RT at a single institution. Such predictive markers would be useful in decision-making regarding the optimal therapy for patients with glioblastoma.