Predictive Biomarkers and Personalized Medicine Promoter CpG Island Hypermethylation of the DNA Repair EnzymeMGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer

Purpose:O-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O-guanine in DNA. Approximately 40% of colorectal cancers (CRC) displayMGMTdeficiency due to the promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O-guanine site, inducing base pair mismatch; therefore, activity of dacarbazine could be enhanced in CRCs lackingMGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild-type). Experimental Design: All patients had tumor tissue assessed forMGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m intravenously every day for four consecutive days, every 21 days, until progressive disease or intolerable toxicity. We used a Simon two-stage design to determine whether the overall response rate would be 10% or more. Secondary endpoints included association of response, progression-free survival, and disease control rate withMGMT