Ruzzo Annamaria, Graziano Francesco, Loupakis Fotios, Rulli Eliana, Canestrari Emanuele, Santini Daniele, Catalano Vincenzo, Ficarelli Rita, Maltese Paolo, Bisonni Renato, Masi Gianluca, Schiavon Gaia, Giordani Paolo, Giustini Lucio, Falcone Alfredo, Tonini Giuseppe, Silva Rosarita, Mattioli Rodolfo, Floriani Irene, Magnani Mauro
Institute of Biochemistry G Fornaini, University of Urbino, Urbino, Italy.
J Clin Oncol. 2007 Apr 1;25(10):1247-54. doi: 10.1200/JCO.2006.08.1844.
The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy.
Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS).
In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes.
A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.
旨在研究对氟尿嘧啶/奥沙利铂活性可能有影响的基因多态性是否与接受一线奥沙利铂、亚叶酸钙和氟尿嘧啶姑息化疗的晚期结直肠癌患者的临床结局相关。
连续的患者被前瞻性纳入意大利中部的肿瘤内科病房。患者需经细胞学/组织学确诊为转移性疾病且至少有一个可测量病灶。外周血样本用于对胸苷酸合成酶、亚甲基四氢叶酸还原酶、着色性干皮病D组（XPD）、切除修复交叉互补组1（ERCC1）、X射线交叉互补组1、X射线交叉互补蛋白3、谷胱甘肽S-转移酶（GSTs）基因中的12种多态性进行基因分型。该研究的主要终点是调查基因型与无进展生存期（PFS）之间的关联。
在166例患者中，ERCC1 - 118 T/T、XPD - 751 A/C和XPD - 751 C/C基因型与不良的PFS独立相关。50例患者（31%）存在两种风险基因型（ERCC1 - 118 T/T与XPD - 751 A/C或XPD - 751 C/C组合）。这种基因分型显示对不良PFS有独立作用，风险比为2.84%，95%置信区间为1.47至5.45（P = 0.002）。神经毒性与GSTP1 - 105 A/G显著相关。GSTP1 - 105 G/G基因型携带者比GSTP1 - 105 A/G和GSTP1 - 105 A/A基因型携带者更容易发生3级神经毒性。
药物遗传学方法可能是优化晚期结直肠癌患者姑息化疗的一种创新策略。这些发现值得在更多前瞻性研究中得到证实。
