NantOmics, LLC, Rockville, MD, USA.
NantOmics, LLC, Santa Cruz, CA, USA.
Eur J Cancer. 2019 Jan;107:164-174. doi: 10.1016/j.ejca.2018.11.016. Epub 2018 Dec 19.
The repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT) is a validated predictor of benefit from temozolomide (TMZ) in glioblastoma. However, only 10% of patients with MGMT-methylated metastatic colorectal cancer (mCRC) respond to TMZ.
Archived tumour samples (N = 41) from three phase II TMZ trials carried out in MGMT-methylated mCRC (assessed by methylation-specific polymerase chain reaction [PCR]) were stratified by MGMT status as assessed by three different methods: mass spectrometry, PCR/methyl-BEAMing and RNA-seq. The performance of each method was assessed in relation to overall response rate, progression-free survival (PFS) and overall survival (OS).
Overall, 9 of 41 patients responded to TMZ. Overall response rates were 50% (9/18), 50% (6/12) and 35% (8/23) among patients determined likely to respond to TMZ by mass spectrometry, methyl-BEAMing and RNA-seq, respectively. Low/negative MGMT protein expressors by mass spectrometry had longer PFS than high MGMT expressors (3.7 vs 1.8 months; HR = 0.50, P = 0.014). Results for OS were similar but statistically non-significant (8.7 vs. 7.4 months; HR = 0.55, P = 0.077). No significant association between survival and MGMT status by methyl-BEAMing or RNA-seq could be demonstrated as comparable subgroups survival could not be confirmed/excluded. Specifically, the association of high versus low methyl-BEAMing MGMT hypermethylation with survival was HR = 0.783, P = 0.46 for PFS and 0.591, P = 0.126 for OS, while association of low versus high RNA-seq MGMT level with survival was HR = 0.697, P = 0.159 for PFS and HR = 0.697, P = 0.266 for OS.
Quantitative proteomic analysis of MGMT may be useful for refining the selection of patients eligible for salvage treatment with single-agent TMZ.
修复酶 O6-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）是替莫唑胺（TMZ）治疗胶质母细胞瘤获益的有效预测因子。然而，只有 10%的 MGMT 甲基化转移性结直肠癌（mCRC）患者对 TMZ 有反应。
对在 MGMT 甲基化 mCRC 中进行的三项 TMZ 试验的存档肿瘤样本（N=41）进行了研究，这些样本通过甲基化特异性聚合酶链反应（PCR）进行了评估，并根据三种不同的方法（质谱、PCR/甲基 BEAMing 和 RNA-seq）评估了 MGMT 状态。评估了每种方法与总缓解率、无进展生存期（PFS）和总生存期（OS）的关系。
总的来说，41 例患者中有 9 例对 TMZ 有反应。通过质谱、甲基 BEAMing 和 RNA-seq 分别确定为可能对 TMZ 有反应的患者中，总缓解率分别为 50%（9/18）、50%（6/12）和 35%（8/23）。质谱检测到的低/阴性 MGMT 蛋白表达者的 PFS 长于高 MGMT 表达者（3.7 与 1.8 个月；HR=0.50，P=0.014）。OS 结果相似，但无统计学意义（8.7 与 7.4 个月；HR=0.55，P=0.077）。由于无法确认/排除可比亚组的生存情况，因此无法证明通过甲基 BEAMing 或 RNA-seq 确定的生存与 MGMT 状态之间存在显著关联。具体而言，高甲基化与低甲基化的 MGMT 高甲基化与生存的关联 HR=0.783，P=0.46 用于 PFS，HR=0.591，P=0.126 用于 OS，而低 RNA-seq MGMT 水平与生存的关联 HR=0.697，P=0.159 用于 PFS 和 HR=0.697，P=0.266 用于 OS。
MGMT 的定量蛋白质组学分析可能有助于完善选择适合单药 TMZ 挽救治疗的患者。
