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Molecular Oncology, Markers, Clinical Correlates |
1 Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, Spain; 2 Medical Oncology and Radiotherapy Departments, Instituto Valenciano de Oncologia, Valencia, Spain; 3 Neurology Department, Hôpital Pitié-Salpetrière, INSERM U495, Paris, France; 4 Medical Oncology Department, Hospital Universitario La Fe, Valencia, Spain; 5 Cancer Epidemiology Unit, Spanish National Center for Epidemiology, Carlos III Institute of Health, Madrid, Spain; 6 National Institute of Neurology and Neurosurgery, Mexico DF, Mexico; 7 Medical Oncology and Pathology Departments, Hospital Ramón y Cajal, Madrid, Spain; 8 Neurosurgery and Medical Oncology Departments, Hospital de la Ribera, Alzira, Spain; 9 Medical Oncology Department, Hospital Germans Tries i Pujol, Badalona, Catalonia, Spain; and 10 Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
ABSTRACT
Purpose: The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide.
Experimental Design: Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses.
Results: Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P < 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729).
Conclusions: MGMT methylation predicts the clinical response of primary gliomas to first-line chemotherapy with the alkylating agent temozolomide. These results may open up possibilities for more customized treatments of human brain tumors.
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