Expression of metabolic enzymes as predictors of prognosis in patients with aggressive primary brain cancers.

Abstract

e13529 Background: Aggressive primary brain cancers like glioblastoma multiforme (GBM) are metabolically active tumors. We hypothesis that abnormalexpression of metabolic enzymes may be useful in predicting survival. Methods: 60 patients (45 with GBM, 11 with anaplastic gliomas and 4 with gliosarcoma) were evaluated using Immunohistochemistry (IHC) to measure the relative expression of metabolic enzymes known to be predictors of prognosis including hexokinase-II (HK2) and mutated isocitrate dehydrogenase-1 (IDH1-R132H) as well as several ketolytic enzymes including cytosolic type 2 (R)-beta-hydroxybutyrate dehydrogenase (BDH2)..The tumors were graded based on the percentage of immunoreactive tumor cells: Positive (≥20%), Negative ( < 20%). Survival was calculated using Kaplan Meier (KM), and an age adjusted hazard ratio (aHR) for death was obtained using cox proportional analysis for enzyme expression. Significance p ≤0.05. Results: Demographics for 60 patients; 19 females and 41 males, median age 62 years, and median survival for all the patients 5.9 months. Univariate analysis showed positive HK2 and negative BDH2 expression had decreased survival with (HR of 1.8 p = 0.06 and 2.6 p = 0.01), respectively. In a multivariate analysis after adjusting to age, histology and other enzyme expression, positive HK2 and negative BDH2 expression were statistically associated with decreased survival (aHR of 11.3 p = 0.001 and 32.6, p = 0.0004), respectively. The group with favorable prognosis (negative HK2 and positive BDH2 expression) (n = 36) had a median survival of 9.7 months (95% CI 4.2 -13.5) whereas the group with non-favorable prognosis (neither a negative HK2 nor a positive BDH, n = 24) had a median survival of 3.1 months (95% CI 1.8 – 5.8). Because only 3 patients had GBM that were positive for the IDH1-R132H mutant protein, IDH1-R132H was not used as a statistically valid predictor in this study. Conclusions: Our current result confirms the poor prognosis associated with positive expression of HK2, and suggests that negative IHC expression of BDH2 may be a new indicator of poor prognosis for patients with aggressive primary brain cancers.