Association of O6-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer
Association of O6-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer
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O6-甲基鸟嘌呤-DNA甲基转移酶蛋白表达与II期或III期胃癌患者术后预后及辅助化疗获益的关系
DOI：
10.1001/jamasurg.2017.3120
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发表时间：
2017-11-01
期刊：
影响因子：
16.9
通讯作者：
Xu, Jiejie
中科院分区：
文献类型：
--
作者：
Cao, Yifan;Liu, Hao;Xu, Jiejie
O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)蛋白表达的重要性缺失在几种恶性肿瘤中已有报道，并可预测预后不良。目的探讨MGMT在可切除胃癌患者中的预后意义及其对以氟尿嘧啶为基础的辅助化疗的反应。设计、背景和对象2007年8月1日至2008年12月30日在上海复旦大学中山医院接受根治性胃切除术的445例可切除胃癌患者纳入本研究。患者被随机分为发现数据集(n=200)和验证数据集(n=245)，发现组的随访时间为2~76个月，验证组的随访时间为2~79个月。对临床病理资料视而不见的2位病理学家在光镜下观察了癌细胞中MGMT的免疫反应情况。分析MGMT的表达与临床病理特征、治疗措施及预后的关系。数据和标本收集自手术之日至2014年4月25日。数据分析从2016年5月9日到2016年7月15日。MAIN结果和测量基于MGMT表达和风险比(HR)的总体生存估计，以估计总体死亡风险。结果在纳入研究的445名患者中，315名(70.8%)为男性，所有患者的平均(SD)年龄为60(12)岁。MGMT的阳性表达表明，在发现数据集(HR，0.52；95%CI，0.32-0.84；P=.003)和验证数据集(HR，0.63；95%CI，0.43-0.93；P=.01)中，II或III期胃癌患者的总存活率较高。多因素分析表明，MGMT表达和TNM分期是影响总生存率的2个独立预后因素。在II期疾病中，与MGMT阴性患者相比，MGMT阳性患者接受氟尿嘧啶辅助化疗的益处更大(HR，0.35；95%CI，0.13~0.95；P=0.007)。结论MGMT阳性表达可作为独立的、有利的预后因素。在目前的TNM分期系统中结合MGMT的表达可能会导致更好的预后准确性。这些发现应该在与基因组DNA测序研究相关的随机临床试验的框架内得到证实。
IMPORTANCE Loss of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression has been reported in several malignant tumors and predicts dismal survival outcomes. In gastric cancer, existing studies on this topic are limited and the association between MGMT and fluorouracil-based adjuvant chemotherapy remains obscure.OBJECTIVE To investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy.DESIGN, SETTING, AND PARTICIPANTS This study recruited 445 consecutive patients with resectable gastric cancer who underwent radical gastrectomy between August 1, 2007, and December 30, 2008, at Zhongshan Hospital at Fudan University in Shanghai, China. Patients were randomly divided into a discovery data set (n = 200) and a validation data set (n = 245), and the range of follow-up time was from 2 to 76 months for the discovery group and 2 to 79 months for the validation group. The immunoreactivity for MGMT in cancer cells was reviewed under a light microscope by 2 pathologists who were blinded to the clinicopathological data. The association of MGMT expression with clinicopathological characteristics and measures and prognosis was inspected. Data and specimens were collected from patients from the date of surgery to April 25, 2014. Data analysis took place from May 9, 2016, to July 15, 2016.MAIN OUTCOMES AND MEASURES Estimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk.RESULTS Of the 445 patients included in the study, 315 (70.8%) were men, and the mean (SD) age of all patients was 60 (12) years. Positive expression of MGMT indicated better overall survival for patients with stage II or III gastric cancer in both the discovery data set (HR, 0.52; 95% CI, 0.32-0.84; P =.003) and the validation data set (HR, 0.63; 95% CI, 0.43-0.93; P =.01). Multivariate analysis identified MGMT expression and TNM stage as 2 independent prognostic factors for overall survival. In stage II disease, the benefit from fluorouracil-based adjuvant chemotherapy was superior among MGMT-positive patients (HR, 0.35; 95% CI, 0.13-0.95; P =.007 for interaction) compared with MGMT-negative patients.CONCLUSIONS AND RELEVANCE Positive expression of MGMT in gastric cancer was identified as an independent, favorable prognostic factor. Incorporating MGMT expression into the current TNM staging system could lead to better prognostic accuracy. These findings should be confirmed within the framework of randomized clinical trials associated with genomic DNA sequencing studies.