UGT1A1*28 多态性与结直肠癌伊立替康为基础的化疗临床结局的关系：在高加索人群中的荟萃分析。

BACKGROUND

Whether UGT1A128 genotype is associated with clinical outcomes of irinotecan (IRI)-based chemotherapy in Colorectal cancer (CRC) is an important gap in existing knowledge to inform clinical utility. Published data on the association between UGT1A128 gene polymorphisms and clinical outcomes of IRI-based chemotherapy in CRC were inconsistent.

METHODOLOGY/PRINCIPAL FINDINGS: Literature retrieval, trials selection and assessment, data collection, and statistical analysis were performed according to the PRISMA guidelines. Primary outcomes included therapeutic response (TR), progression-free survival (PFS) and overall survival (OS). We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI). Twelve clinical trials were included. No statistical heterogeneity was detected in analyses of all studies and for each subgroup. Differences in TR, PFS and OS for any genotype comparison, UGT1A1*28/28 versus (vs) UGT1A11/1 (homozygous model), UGT1A11/28 vs UGT1A11/1 (heterozygous model), and UGT1A128/28 vs all others (recessive model, only for TR) were not statistically significant. IRI dose also did not impact upon TR and PFS differences between UGT1A1 genotype groups. A statistically significant increase in the hazard of death was found in Low IRI subgroup of the homozygous model (HR = 1.48, 95% CI = 1.06-2.07; P = 0.02). The UGT1A128 allele was associated with a trend of increase in the hazard of death in two models (homozygous model: HR = 1.22, 95% CI = 0.99-1.51; heterozygous model: HR = 1.13, 95% CI = 0.96-1.32). These latter findings were driven primarily by one single large study (Shulman et al. 2011).

CONCLUSIONS/SIGNIFICANCE: UGT1A128 polymorphism cannot be considered as a reliable predictor of TR and PFS in CRC patients treated with IRI-based chemotherapy. The OS relationship with UGT1A128 in the patients with lower-dose IRI chemotherapy requires further validation.

背景

UGT1A128 基因型是否与结直肠癌（CRC）中基于伊立替康（IRI）的化疗的临床结局相关，这是现有知识中的一个重要空白，需要告知临床应用。关于 UGT1A128 基因多态性与 CRC 中基于 IRI 化疗的临床结局之间的关联的已发表数据不一致。

方法/主要发现：根据 PRISMA 指南进行文献检索、试验选择和评估、数据收集和统计分析。主要结局包括治疗反应（TR）、无进展生存期（PFS）和总生存期（OS）。我们用 95%置信区间（CI）计算比值比（OR）和风险比（HR）。纳入了 12 项临床试验。在所有研究和每个亚组的分析中均未检测到统计学异质性。任何基因型比较（UGT1A1*28/28 与 UGT1A11/1[纯合子模型]、UGT1A11/28 与 UGT1A11/1[杂合子模型]和 UGT1A128/28 与所有其他基因型[隐性模型，仅用于 TR））的 TR、PFS 和 OS 差异均无统计学意义。IRI 剂量也没有影响 UGT1A1 基因型组之间的 TR 和 PFS 差异。在纯合子模型的低 IRI 亚组中，死亡风险的增加具有统计学意义（HR=1.48，95%CI=1.06-2.07；P=0.02）。UGT1A128 等位基因与两种模型（纯合子模型：HR=1.22，95%CI=0.99-1.51；杂合子模型：HR=1.13，95%CI=0.96-1.32）中死亡风险增加的趋势相关。这些发现主要是由一项大型研究（Shulman 等人，2011 年）驱动的。

结论/意义：UGT1A128 多态性不能被认为是接受基于 IRI 的化疗的 CRC 患者治疗反应和 PFS 的可靠预测因子。在接受低剂量 IRI 化疗的患者中，UGT1A128 与 OS 的关系需要进一步验证。