Progressive low-grade oligodendrogliomas: response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression.
BACKGROUND
Loss of heterozygosity (LOH) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with oligodendrogliomas. The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) may induce resistance to DNA-alkylating agents. Recent studies demonstrated that temozolomide (TMZ), an oral alkylating agent, has efficacy in the treatment of patients with progressive, low-grade oligodendroglioma (LGO). However, to the authors' knowledge, limited data are available regarding the 1p/19q profile and its correlation with MGMT protein expression and response to treatment with DNA-alkylating drugs.


METHODS
Adult patients with magnetic resonance imaging (MRI) findings and/or clinical deterioration compatible with progressive LGO were eligible for the study if they were radiotherapy-naive. TMZ cycles were repeated every 28 days at a dose of 200 mg/m2 daily for 5 consecutive days. Clinical and MRI data were used to evaluate outcomes, and Kaplan-Meier estimates were used to assess the median time to tumor progression (TTP). The 1p/19q status was analyzed from paired tumor-blood DNA samples using polymerase chain reaction-based microsatellite analysis. MGMT protein expression was estimated semiquantitatively by immunohistochemistry using paraffin embedded tumor sections.


RESULTS
There were 28 patients who received treatment, and the median time from diagnosis to tumor progression was 33.5 months. The median number of TMZ cycles per patient was 12.5. Marked clinical improvements were recorded in 15 patients (54%), and objective responses were recorded in 17 patients (61%). The median TTP was 31 months, and the progression-free survival rate was 70% at 24 months. Loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively).


CONCLUSIONS
TMZ was active in patients with progressive LGO, and their response to treatment was associated with 1p deletion and low MGMT protein expression. The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting tumor chemosensitivity.
Levin
Netta
N
Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah Hebrew University Hospital, Jerusalem, Israel. imbar l@netvision.net.il
Lavon
Iris
I
Zelikovitsh
Bracha
B
Fuchs
Dana
D
Bokstein
Felix
F
Fellig
Yakov
Y
Siegal
Tali
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis*; D009837:Oligodendroglioma / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide