Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer
Promoter CpG Island Hypermethylation of the DNA Repair Enzyme MGMT Predicts Clinical Response to Dacarbazine in a Phase II Study for Metastatic Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-12-3518
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发表时间：
2013-04-15
影响因子：
11.5
通讯作者：
Siena, Salvatore
中科院分区：
文献类型：
--
作者：
Amatu, Alessio;Sartore-Bianchi, Andrea;Siena, Salvatore
目的：o -6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是一种DNA修复蛋白，可清除DNA中o -6-鸟嘌呤的致突变和细胞毒性加合物。大约40%的结直肠癌（CRC）由于启动子超甲基化导致基因沉默而表现出MGMT缺陷。烷基化剂，如达卡巴嗪，通过在o -6-鸟嘌呤位点上的DNA甲基化，诱导碱基对错配来发挥其抗肿瘤活性；因此，在缺乏MGMT的crc中，达卡巴嗪的活性可以增强。我们对标准治疗(奥沙利铂、伊立替康、氟嘧啶和西妥昔单抗或帕尼单抗（KRAS野生型）失败的crc患者进行了一项用达卡巴嗪治疗的II期研究。实验设计：所有患者的肿瘤组织在双盲中评估MGMT作为启动子超甲基化的治疗结果。患者每天静脉注射达卡巴嗪250 mg/m(2)，连续4天，每21天一次，直到疾病进展或无法忍受的毒性。我们使用Simon两阶段设计来确定总体反应率是否为10%或更高。次要终点包括反应、无进展生存期和疾病控制率与MGMT状态的关联。结果：2011年5月至2012年3月共入组68例患者。患者接受中位数为3个周期的达卡巴嗪治疗（范围1-12）。3级和4级毒性包括：疲劳（41%）、恶心/呕吐（29%）、便秘（25%）、血小板计数减少（19%）和贫血（18%）。总体而言，2例患者（3%）达到部分缓解，8例患者（12%）病情稳定。相应肿瘤的疾病控制率（部分缓解+病情稳定）与MGMT启动子高甲基化显著相关。结论：目的：达卡巴嗪对转移性结直肠癌患者的临床疗效仅限于那些DNA修复酶MGMT表观遗传失活的肿瘤。临床癌症研究；19日(8);2265 - 72。(c) 2013年aacr。
Purpose: 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.Results: 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.Conclusion: Objective clinical responses to dacarbazine in patients with metastatic CRC are confined to those tumors harboring epigenetic inactivation of the DNA repair enzyme MGMT. Clin Cancer Res; 19(8); 2265-72. (C) 2013 AACR.