BackgroundGenetic 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.MethodsThis 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%.ResultsIn 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).ConclusionsGenetic 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.

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吉西他滨对转移性胰腺癌患者疗效的药物基因组学研究：一项多中心、前瞻性、观察性队列研究（GENESECT 研究）

背景已知分子的基因多态性会导致抗癌药物治疗功效的个体差异。然而，迄今为止，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。本研究的目的是调查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 (CA 19-9) 反应（8 周时较治疗前水平降低 ≥50%）和总生存期 (OS) 之间的关联) 接受吉西他滨化疗的转移性胰腺癌患者。方法这项多中心、前瞻性、观察性研究纳入了接受吉西他滨单药治疗或吉西他滨加纳米颗粒白蛋白结合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，并使用单变量和多变量逻辑回归分析来确定这些基因型与 CA 19-9 反应和 OS 的关联。显着性水平设定为5%。结果总共登记了来自日本11家医院的180名患者，其中159名可评估CA 19‐9反应的患者纳入最终分析。具有 CA 19‐9 缓解的患者的 OS 显着延长（372 天 vs. 241 天；p=.007)。无线资源管理12464A>G 和无线资源管理2175T>G 多态性表明与 CA 19-9 反应和 OS 存在微弱关联，但不具有统计学意义。环氧化酶-2−765G>C 多态性与 CA 19-9 反应不显着相关，但与 OS 显着相关（风险比，2.031；p= .019)。结论吉西他滨药代动力学的基因多态性并未表明与疗效存在显着相关性，但环氧化酶-2参与肿瘤细胞增殖的多态性可能会影响 OS。