Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Institute of Oncology Ljubljana, Ljubljana, Slovenia.
Radiol Oncol. 2014 Apr 25;48(2):163-72. doi: 10.2478/raon-2013-0086. eCollection 2014 Jun.
A combination of pemetrexed and cisplatin has been shown to improve the outcome in patients with malignant pleural mesothelioma (MPM), however, there is a great heterogeneity in treatment response among patients. The aim of our study was to evaluate the influence of polymorphisms in folate pathway and transporter genes on pemetrexed treatment outcome in Slovenian patients with MPM.
MPM patients treated with pemetrexed in the course of a prospective randomized clinical trial were genotyped for nineteen polymorphisms in five genes of folate pathway and six transporter genes. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity, while Cox regression was used to determine their influence on progression-free and overall survival.
Patients with at least one polymorphic MTHFD1 rs2236225 allele had a significantly lower response rate (p = 0.005; odds ratio [OR] = 0.12; 95% confidence interval [CI] = 0.03-0.54) and shorter progression-free survival (p = 0.032; hazard ratio [HR] = 3.10; 95% CI = 1.10-8.74) than non-carriers. Polymorphisms in transporter genes did not influence survival; however, several were associated with toxicity. Liver toxicity was significantly lower in carriers of polymorphic ABCC2 rs2273697 (p = 0.028; OR = 0.23; 95% CI = 0.06-0.85), SLCO1B1 rs4149056 (p = 0.028; OR = 0.23; 95% CI = 0.06-0.85) and rs11045879 (p = 0.014; OR = 0.18; 95% CI = 0.05-0.71) alleles compared to non-carriers, as well as in patients with SLCO1B1 GCAC haplotype (p = 0.048; OR = 0.17; 95% CI = 0.03-0.98). Gastrointestinal toxicity was much more common in patients with polymorphic ABCC2 rs717620 allele (p = 0.004; OR = 10.67; 95% CI = 2.15-52.85) and ABCC2 CAG haplotype (p = 0.006; OR = 5.67; 95% CI = 1.64-19.66).
MTHFD1 polymorphism affected treatment response and survival, while polymorphisms in ABCC2 and SLCO1B1 transporter genes influenced the risk for toxicity. These polymorphisms could serve as potential markers of pemetrexed treatment outcome in patients with MPM.
培美曲塞联合顺铂已被证实可改善恶性胸膜间皮瘤（MPM）患者的预后，但患者对治疗的反应存在很大的异质性。本研究的目的是评估叶酸途径和转运体基因中的多态性对斯洛文尼亚 MPM 患者培美曲塞治疗结果的影响。
在一项前瞻性随机临床试验中接受培美曲塞治疗的 MPM 患者，对五个叶酸途径基因和六个转运体基因中的 19 个多态性进行基因分型。使用逻辑回归评估多态性对治疗效果和毒性的影响，使用 Cox 回归确定它们对无进展生存期和总生存期的影响。
至少携带一个 MTHFD1 rs2236225 多态性等位基因的患者，其反应率显著降低（p = 0.005；比值比 [OR] = 0.12；95%置信区间 [CI] = 0.03-0.54），无进展生存期更短（p = 0.032；风险比 [HR] = 3.10；95% CI = 1.10-8.74），而非携带者。转运体基因的多态性不影响生存；然而，一些与毒性有关。与非携带者相比，ABCC2 rs2273697（p = 0.028；OR = 0.23；95% CI = 0.06-0.85）、SLCO1B1 rs4149056（p = 0.028；OR = 0.23；95% CI = 0.06-0.85）和 rs11045879（p = 0.014；OR = 0.18；95% CI = 0.05-0.71）等位基因携带者以及 SLCO1B1 GCAC 单倍型携带者（p = 0.048；OR = 0.17；95% CI = 0.03-0.98）发生肝毒性的风险显著降低。与非携带者相比，ABCC2 rs717620 多态性（p = 0.004；OR = 10.67；95% CI = 2.15-52.85）和 ABCC2 CAG 单倍型（p = 0.006；OR = 5.67；95% CI = 1.64-19.66）携带者的胃肠道毒性更常见。
MTHFD1 多态性影响治疗反应和生存，而 ABCC2 和 SLCO1B1 转运体基因的多态性影响毒性风险。这些多态性可以作为 MPM 患者培美曲塞治疗结果的潜在标志物。
