Association of O<sup>6</sup>-Methylguanine-DNA Methyltransferase Protein Expression With Postoperative Prognosis and Adjuvant Chemotherapeutic Benefits Among Patients With Stage II or III Gastric Cancer
Authors: Yifan Cao, Hao Liu, He Li, Chao Lin, Ruochen Li, Songyang Wu, Heng Zhang, Hongyong He, Weijuan Zhang, Jiejie Xu
Journal: JAMA Surgery (2017)

<h3>Importance</h3> Loss of O<sup>6</sup>-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. <h3>Objective</h3> To investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy. <h3>Design, Setting, and Participants</h3> This study recruited 496 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. However, 468 of 496 patients had comprehensive information about chemotherapy, clinicopathological data, and survival outcomes for complete analysis. In this study, we used tissue microarrays (Shanghai Outdo Biotech Co, Ltd), and 15 dots of the 468 patients were lost after immunohistochemistry. Additionally, 8 patients of TMN stage IV were excluded. Consequently, 445 patients were included in this study. 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. <h3>Main Outcomes and Measures</h3> Estimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk. <h3>Results</h3> 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;<i>P</i> = .003) and the validation data set (HR, 0.63; 95% CI, 0.43-0.93;<i>P</i> = .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;<i>P</i> = .007 for interaction) compared with MGMT-negative patients. <h3>Conclusions and Relevance</h3> 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.