Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer

Department of Hematology and Oncology, Ospedale Niguarda Ca' Granda.
Clinical Cancer Research (Impact Factor: 8.72). 02/2013; 19(8). DOI: 10.1158/1078-0432.CCR-12-3518
Source: PubMed


O(6)-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O(6)-guanine in DNA. Approximately 40% of colorectal cancers (CRC) display MGMT deficiency 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(6)-guanine site, inducing base pair mismatch; therefore, activity of dacarbazine could be enhanced in CRCs lacking MGMT. 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 for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m(2) 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 with MGMT status.

Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of three cycles of dacarbazine (range 1-12). Grades 3 and 4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), and anemia (18%). Overall, two patients (3%) achieved partial response and eight patients (12%) had stable disease. Disease control rate (partial response + stable disease) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors.

Objective clinical responses to dacarbazine in patients with metastatic CRC are confined to those tumors harboring epigenetic inactivation of the DNA repair enzyme MGMT.

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    • "Also, DNA methylation status has been reported to correlate with clinicopathological features of many types of cancers (Brait et al. 2008; Kim et al. 2013; Sato et al. 2002; Yang and Park 2012). Taking these advantages, DNA methylation markers for the prediction of a response to a cancer therapy have been identified in other types of cancers (Amatu et al. 2013; Giovannetti et al. 2012; Hegi et al. 2005; Mikeska et al. 2012; Park et al. 2009; Toyota et al. 2009). However, in ESCC, few studies have demonstrated an association between DNA methylation status and response to dCRT (Brabender et al. 2009). "
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    • "However, given the effect of MGMT loss in sensitizing cancer cells to alkylating agents, recently several attempts were made to select suitable patients for these medications. In a phase II clinical trial study with dacarbazine in metastatic CRC patients who had failed standard therapies, objective clinical response was limited to those patients with MGMT methylation (47). Similar findings were seen in metastatic patients with MGMT methylation who were treated with single agent Temozolomide (48). "
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