背景:已知分子的遗传多态性会导致抗癌药物治疗效果的个体差异。然而,到目前为止,抗癌药物的种系突变(但不是体细胞突变)尚未得到充分研究。这项研究的目的是研究吉西他滨代谢和转运蛋白基因的种系多态性与碳水化合物抗原19-9(CA19-9)反应(在8周时比治疗水平降低≥50%)和总生存期(OS)之间的关系接受吉西他滨为基础的化疗的转移性胰腺癌患者。
方法:这个多中心,prospective,观察性研究纳入接受吉西他滨单药治疗或吉西他滨联合纳米粒白蛋白结合型紫杉醇联合化疗的转移性胰腺癌患者.对可能与吉西他滨反应性有关的13种多态性进行了基因分型,单变量和多变量逻辑回归分析用于确定这些基因型与CA19-9应答和OS的关联。显著性水平设定为5%。
结果:总计,来自日本11家医院的180名患者进行了登记,最终分析中纳入了可评估CA19-9应答的159例患者.具有CA19-9反应的患者的OS明显更长(372与241天;p=.007)。RRM12464A>G和RRM2175T>G多态性提示与CA19-9应答和OS弱相关,但没有统计学意义。COX-2-765G>C多态性与CA19-9反应没有显着相关,但与OS显着相关(风险比,2.031;p=.019)。
结论:来自吉西他滨药代动力学的遗传多态性表明与疗效没有显着关联,但参与肿瘤细胞增殖的COX-2多态性可能影响OS。
BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy.
METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%.
RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019).
CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.