Department of Clinical Pharmacy & Toxicology.
Department of Clinical Oncology, Leiden University Medical Center, Leiden.
Ann Oncol. 2011 May;22(5):1147-1153. doi: 10.1093/annonc/mdq572. Epub 2010 Nov 3.
Pharmacogenetic markers related to drug metabolism and mechanisms of action could help to better select patients with metastatic colorectal cancer (mCRC) for treatment. Genetic interaction analysis is used as a rational tool to study the contribution of polygenic variation in relation to drug response.
A selection of 17 polymorphisms in genes encoding drug targets, pathway molecules and detoxification enzymes was analyzed in 279 previously untreated mCRC patients treated with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Multifactor dimensionality reduction analysis was used to identify a genetic interaction profile for progression-free survival (PFS).
Median PFS was 10.9 [95% confidence interval (CI) 9.4-12.4] months. A genetic interaction profile consisting of the TYMS enhancer region and VEGF +405G>C polymorphisms was significantly associated with PFS. Median PFS was 13.3 (95% CI 11.4-15.3) and 9.7 (95% CI 7.6-11.8) months for the beneficial and unfavorable genetic profiles, respectively, corresponding to a hazards ratio for PFS of 1.58 (95% CI 1.14-2.19). None of the studied polymorphisms were individually associated with PFS.
Our results support a genetic interaction between the TYMS enhancer region and VEGF +405G>C polymorphisms as a predictor of the efficacy of CAPOX-B in mCRC patients.
与药物代谢和作用机制相关的药物遗传学标志物可以帮助更好地选择转移性结直肠癌（mCRC）患者进行治疗。遗传相互作用分析被用作研究与药物反应相关的多基因变异贡献的合理工具。
在 279 名接受卡培他滨、奥沙利铂和贝伐单抗（CAPOX-B）治疗的未经治疗的 mCRC 患者中，分析了编码药物靶点、通路分子和解毒酶的 17 个基因中的多态性。多因子降维分析用于确定无进展生存期（PFS）的遗传相互作用谱。
中位 PFS 为 10.9 个月（95%置信区间 9.4-12.4）。由 TYMS 增强子区域和 VEGF +405G>C 多态性组成的遗传相互作用谱与 PFS 显著相关。有利和不利遗传谱的中位 PFS 分别为 13.3 个月（95%置信区间 11.4-15.3）和 9.7 个月（95%置信区间 7.6-11.8），PFS 的风险比为 1.58（95%置信区间 1.14-2.19）。研究的多态性均与 PFS 无关。
我们的结果支持 TYMS 增强子区域和 VEGF +405G>C 多态性之间的遗传相互作用作为预测 CAPOX-B 在 mCRC 患者中的疗效的指标。
