Evaluation of Interactions of PI3K Pathway, IDH1(R132H), and OLIG2 Expression in Newly Diagnosed Glioblastoma Clinical Outcomes
Stefano Sioletic, Brian Alexander, Libero Lauriola, Mario Balducci, Keith Ligon. Dana Farber Cancer Institute, Boston, MA; Gemelli Hospital, Rome, Italy
Background: Clinical trial design for evaluation of emerging PI3K pathway inhibitors in glioblastoma (GBM) has generally focused on stratification of patients using biomarkers of PI3K pathway status but have not attempted to control for known heterogeneous survival in subtypes of glioblastoma which may significantly affect/distort correlation of outcomes with PI3K biomarkers. In particular, the IDH1(R132H) mutation and OLIG2 expression levels are proposed to help identify gliomas with prolonged survival and sensitivity to conventional treatment. We evaluated a well-defined cohort of GBM for PI3K pathway activation and status of IDH1(R132H) mutation and OLIG2 expression in primary GBM and correlate with the clinical outcome of the patients.
Design: A total of 82 patients (M/F 43/39; median age: 56; range: 21-78) who had undergone surgical resection for newly diagnosed glioblastoma were pathologically re-reviewed and used to construct a tissue microarray. All subjects had undergone a full course of conventional fractionated radiotherapy (RT) and temozolomide. Tissue microarray sections were IHC stained and scored manually for OLIG2, KI67, TP53, IDH1(R132H), PTEN, and pAKT-473.
Results: Clinical follow-up was available for all the patients (median: 27 months; range: 5-81 months). IDH1(R132H) was positive in 5 cases(6%) with a median survival of 49 months (3 patients alive).OLIG2 was positive in at least 60% of tumor cells in 32 patients (43%), no GBM with more than 90% of OLIG2 positive cells was found. 28 of the patients with OLIG2+/IDH1(R132H)- had a median survival of 22 months. pAKT staining was positive (>60% of the cells) in 59 patients (71%). Evidence for complete PTEN protein loss was found in 7 patients (8%). In our cohort only 6 patients (7%) showed a 2+ score similar to vessel staining. A positive correlation of high PTEN expression (2+) and pAKT (>80% of the cells) has been detected. PTEN loss (score 0) significantly correlated with progression following treatment (PD)(85% vs. 48% of all GBM). PTEN 2+, showed a significant response (all except one with PD), had a clinical responses (CR) (83% vs. 32% of all GBM) after RT and CT, however the overall survival did not change.
Conclusions: Of all the markers studied only IDH1(R132H) and Olig2 were found to be independent positive prognostic markers. PTEN, although doesn't have any predictive value in the conventional treatment of GBM, when is lost or overexpressed can be used to identify the patients that can have a clinical response to temozolomide.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 252, Tuesday Afternoon