gms | German Medical Science

The response of malignant gliomas to temozolomide varies from patient to patient. The present study investigates the potential significance of tumour-associated genetic aberrations in the TP53, MDM2, EGFR and CDK4 genes, as well as methylation of the MGMT promoter for the response to temozolomide and the survival of patients with malignant gliomas.

51 patients with 14 anaplastic gliomas of WHO grade III (AG) and 37 glioblastomas of WHO grade IV (GBM) were treated with temozolomide after tumour resection and radiation therapy. From each patient, clinical data were recorded, including age at diagnosis, gender, tumour location, Karnofsky performance score (KPS), extent of tumour resection, tumour volume (determined before and after resection, before chemotherapy and every 3 months during chemotherapy), overall survival (OS), and response to treatment. The tumour tissue was investigated for mutations in the TP53 gene, amplification of the EGFR, CDK4 and MDM2 genes, and hypermethylation of the MGMT promoter. Molecular genetic findings were correlated to OS and response to therapy.

59% of the patients were males and median age at operation was 54.3 years. The mean preoperative KPS was 80%. OS was 277.4 weeks (AG) and 87 weeks (GBM). A median number of 8 cycles of temozolomide was administered. Toxicity of grades 3 or 4 occurred in 6 patients. Chemotherapy was terminated due to tumour progression in 31 patients (4 AG, 29%; 27 GBM, 73%). A total of 33% of the investigated tumours demonstrated EGFR amplification (17% AG, 38% GBM), while MDM2 amplification was detected in 7% (8 % AG, 6% GBM), CDK4 amplification in 16 % (8 % AG, 18 % GBM), and TP53 mutation in 20% (12,5% AG, 22% GBM). MGMT hypermethylation could be demonstrated by methylation-sensitive PCR in 54% of the cases (82% AG, 46% GBM). Statistical analysis revealed that MGMT hypermethylation was significantly associated with longer OS (p=0.0013, log rank test) and better response to temozolomide (p=0.034, log rank test). Neither EGFR, MDM2 or CDK4 amplification nor TP53 mutation were significantly correlated to OS or response to temozolomide.

Our study clearly indicates that MGMT hypermethylation is a clinically important molecular marker that is significantly associated with longer overall survival and better response to temozolomide treatment in patients with malignant gliomas. In contrast, structural alterations in the TP53, MDM2, EGFR and CDK4 genes appear to be less important as prognostic factors.