CORRELATION OF TUMOR O-6 METHYLGUANINE-DNA METHYLTRANSFERASE LEVELS WITH SURVIVAL OF MALIGNANT ASTROCYTOMA PATIENTS TREATED WITH BIS-CHLOROETHYLNITROSOUREA - A SOUTHWEST-ONCOLOGY-GROUP STUDY

Purpose: Prior studies show that increased levels of the DNA repair pr otein O-6 methylguanine-DNA methyltransferase (MGMT), also referred to as O-6-alkylguanine-DNA alkyltransferase (AGT) correlate with the res istance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-I) and those repair-proficient lines pretreated with MGMT-specifi c inhibitors leg, O-6 benzylguanine) has raised the possibility that t umor MGMT levels may be an important predictor of survival in patients with gliomas. Patients and Methods: We correlated the MGMT level in m alignant astrocytoma tissues, obtained from patients treated with radi otherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure -free survival, Results: Of 64 assessable patients with malignant astr ocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high ( > 60,000 molecules/nucleus) MGMT levels, The overall median survival f or patients with high versus low MGMT levels was 8 and 29 months, resp ectively (P =.0002), and median failure-free survival 3 and 6 months, respectively (P =.008). Subset analysis by histology thigh v low MGMT levels) for anaplastic astrocytoma wets 14 versus 62 months (n = 24) a nd for glioblastoma was 7 versus 12 months (n = 40). The overall hazar ds ratio [risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.1 9; age 41 to 60 years, 3.08) but became equal by MGMT level at age old er than 60 years (1.11), Multivariate analysis showed that MGMT was in dependent of other known prognostic factors (age, performance status, histology). Conclusion: The MGMT level in tumor tissue specimens may b e a predictive marker of survival in patients with malignant astrocyto ma that is independent of other previously described prognostic variab les, (C) 1998 by American Society of Clinical Oncology.