Correlations between O6-methylguanine DNA methyltransferase promoter methylation status, 1p and 19q deletions, and response to temozolomide in anaplastic and recurrent oligodendroglioma: a prospective GICNO study.

PURPOSE To date, no data are available on the relationship between 1p/19q deletions and the response to temozolomide (TMZ) in primary anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) recurrent after surgery and standard radiotherapy. The aim of this study was to evaluate correlations between 1p/19q deletions, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, and response rate to TMZ in this setting. PATIENTS AND METHODS From June 2000 to February 2005, 67 patients were enrolled; 39 patients (58%) had AO and 28 patients (42%) had AOA. All patients received 150 to 200 mg/m2 of TMZ every 28 days. Chromosome 1p and 19q deletions were detected by fluorescence in situ hybridization and MGMT promoter methylation was analyzed using methylation specific polymerase chain reaction. RESULTS The overall response rate was 46.3% (17 complete responses and 14 partial responses). The response rate was higher in patients with AO than in those with AOA (61.5% v 25%, P = .003). Combined 1p/19q allelic loss was found in 32 patients (47.8%), while MGMT methylation occurred in 37 (68.5%) of 54 assessable patients. 1p/19q loss was significantly correlated with response rate (P = .04), time-to-progression (P = .003), and overall survival (P = .0001). Despite the significant concordance found between MGMT promoter methylation and 1p/19q deletions (P = .02), MGMT promoter methylation showed only a borderline correlation with overall survival (P = .09). CONCLUSION TMZ is active in anaplastic oligodendroglial tumors treated at first recurrence. In this setting, 1p/19q allelic loss is an important predictive and prognostic factor. Further studies on MGMT promoter methylation should be performed in randomized trials to test its correlation with survival.

[1]  G. Pond,et al.  Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  I. Ferrer,et al.  Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Determined by Promoter Hypermethylation and Immunohistochemical Expression in Anaplastic Gliomas , 2005, Clinical Cancer Research.

[3]  M. Taphoorn,et al.  First analysis of EORTC trial 26951, a randomized phase III study of adjuvant PCV chemotherapy in patients with highly anaplastic oligodendroglioma , 2005 .

[4]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[5]  M. Wolter,et al.  Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors , 2005, International journal of cancer.

[6]  A. Brandes,et al.  Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy , 2004, Cancer.

[7]  M. Paz,et al.  CpG Island Hypermethylation of the DNA Repair Enzyme Methyltransferase Predicts Response to Temozolomide in Primary Gliomas , 2004, Clinical Cancer Research.

[8]  B. Scheithauer,et al.  An intergroup randomized controlled clinical trial (RCT) of chemotherapy plus radiation (RT) versus RT alone for pure and mixed anaplastic oligodendrogliomas: Initial report of RTOG 94–02 , 2004 .

[9]  M. Alonso,et al.  Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. , 2003, Cancer Genetics and Cytogenetics.

[10]  J. Menten,et al.  Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  R Alexandra Goldbohm,et al.  Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. , 2003, Cancer research.

[12]  Y. Roussos,et al.  O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolamide plus cisplatin in glioblastoma multiforme. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  M. J. van den Bent,et al.  Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features , 2003, Cancer.

[14]  G. Reifenberger,et al.  The WHO Classification of Tumors of the Nervous System , 2002, Journal of neuropathology and experimental neurology.

[15]  K. To,et al.  Concurrent Hypermethylation of Multiple Genes Is Associated with Grade of Oligodendroglial Tumors , 2001, Journal of neuropathology and experimental neurology.

[16]  J. Haaga,et al.  Temozolomide: the effect of once- and twice-a-day dosing on tumor tissue levels of the DNA repair protein O(6)-alkylguanine-DNA-alkyltransferase. , 2001, Clinical Cancer Research.

[17]  R A Betensky,et al.  Molecular subtypes of anaplastic oligodendroglioma: implications for patient management at diagnosis. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[19]  J. Herman,et al.  Predicting lung cancer by detecting aberrant promoter methylation in sputum. , 2000, Cancer research.

[20]  B. Scheithauer,et al.  Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[22]  A. Twijnstra,et al.  Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy , 1998, Neurology.

[23]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T. Cascino,et al.  Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  D. Ludlum.  DNA alkylation by the haloethylnitrosoureas: nature of modifications produced and their enzymatic repair or removal. , 1990, Mutation research.

[26]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.