2001 Publication

Dr. Quinn is correct when he points out that the value of the findings reported by Esteller et al. would be enhanced by comparison with data from a group of patients with gliomas who were not treated with carmustine (or other alkylating agents). If methylation of the MGMT promoter region in tumor samples from such patients were not correlated with improved overall and disease-free survival, that finding would strongly support the hypothesis of a causal relation between the activity of carmustine and the methylation. Going one step further, a survey of the methylation status of other promoter regions in the glioma samples analyzed by Esteller et al. would indicate whether the putative relation with methylation was specific to the MGMT promoter. Nonetheless, the authors' principal conclusion that "methylation of the MGMT promoter in gliomas is a useful predictor of the responsiveness of the tumors to alkylating agents" stands without such additional studies. One could argue that the term "alkylating agents" is too broad, since the data are only for the nitrosourea carmustine, but the data do identify a "useful predictor" if one assumes (on the basis of the clinical course and timing) that the observed responses were actually due to the treatment with carmustine. Dr. Quinn's critique illustrates the difficulty of establishing pharmacogenomic causality, especially in the clinical setting.