Joerger M, Huitema A D R, Boot H, Cats A, Doodeman V D, Smits P H M, Vainchtein L, Rosing H, Meijerman I, Zueger M, Meulendijks D, Cerny T D, Beijnen J H, Schellens J H M
Department of Medical Oncology and Hematology, Cantonal Hospital, Rorschacherstr. 95, 9007, St. Gallen, Switzerland,
Cancer Chemother Pharmacol. 2015 Apr;75(4):763-72. doi: 10.1007/s00280-015-2698-7. Epub 2015 Feb 13.
This work was initiated to extend data on the effect of pharmacogenetics and chemotherapy pharmacokinetics (PK) on clinical outcome in patients with gastrointestinal malignancies.
We assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, GSTM1, GSTT1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2 and UGT2B7) in 64 patients with metastatic colorectal cancer (CRC) receiving capecitabine/oxaliplatin and 76 patients with advanced gastroesophageal cancer (GEC) receiving epirubicin/cisplatin/capecitabine, respectively. Plasma concentrations of anticancer drugs were measured for up to 24 h, and results were submitted to population PK analysis. We calculated the association between gene polymorphisms, chemotherapy exposure, tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests.
Patients with a low clearance of 5FU were at increased risk of neutropenia (P < 0.05) and hand-foot syndrome (P = 0.002). DPYD T85C, T1896C and A2846T mutant variants were associated with diarrhea (P < 0.05) and HFS (P < 0.02), and IVS14+1G>A additionally with diarrhea (P < 0.001). The TYMS 2R/3G, 3C/3G or 3G/3G promoter variants were associated with worse PFS in the CRC (HR = 2.0, P < 0.01) and GEC group (HR = 5.4, P < 0.001) and worse OS in the GEC group (HR = 4.7, P < 0.001). The GSTP1 A313G mutant variant was associated with a higher PFS (HR = 0.55, P = 0.001) and OS (HR = 0.60, P = 0.002) in the CRC group.
Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.
开展本研究以扩充关于药物遗传学和化疗药代动力学（PK）对胃肠道恶性肿瘤患者临床结局影响的数据。
我们评估了64例接受卡培他滨/奥沙利铂治疗的转移性结直肠癌（CRC）患者和76例接受表柔比星/顺铂/卡培他滨治疗的晚期胃食管癌（GEC）患者的16个基因（TYMS、MTHFR、GSTP1、GSTM1、GSTT1、DPYD、XRCC1、XRCC3、XPD、ERCC1、RECQ1、RAD54L、ABCB1、ABCC2、ABCG2和UGT2B7）中的44个基因多态性。测量了长达24小时的抗癌药物血浆浓度，并将结果进行群体PK分析。我们使用适当的统计检验计算了基因多态性、化疗暴露、肿瘤反应、无进展生存期（PFS）、总生存期（OS）和化疗相关毒性之间的关联。
5-氟尿嘧啶清除率低的患者发生中性粒细胞减少（P < 0.05）和手足综合征（P = 0.002）的风险增加。DPYD基因的T85C、T1896C和A2846T突变变体与腹泻（P < 0.05）和手足综合征（P < 0.02）相关，而IVS14 + 1G>A还与腹泻（P < 0.001）相关。TYMS基因的2R/3G、3C/3G或3G/3G启动子变体与CRC组（HR = 2.0，P < 0.01）和GEC组较差的PFS（HR = 5.4，P < 0.001）以及GEC组较差的OS（HR = 4.7，P < 0.001）相关。GSTP1基因的A313G突变变体与CRC组较高的PFS（HR = 0.55，P = 0.001）和OS（HR = 0.60，P = 0.002）相关。
DPYD、TYMS和GSTP1的种系多态性对接受基于卡培他滨化疗的晚期结直肠癌或胃食管癌患者的毒性和临床结局有显著影响。这些数据应在前瞻性临床研究中进一步验证。
