Goekkurt E, Al-Batran S-E, Mogck U, Pauligk C, Hartmann J T, Kramer M, Jaeger E, Ehninger G, Stoehlmacher J
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden, Germany.
Ann Oncol. 2009 Mar;20(3):481-5. doi: 10.1093/annonc/mdn667. Epub 2008 Dec 12.
Docetaxel-based chemotherapy regimens have demonstrated activity in advanced gastric cancer (AGC). However, a high rate of grade 3/4 hematotoxicity was reported with these regimens. Our purpose was to identify pharmacogenetic markers with potential to detect patients with increased risk to encounter severe hematotoxicity following treatment with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT).
Polymorphisms of genes involved in DNA repair, drug transport and metabolism were determined in 50 AGC patients receiving FLOT within a phase II trial. DNA was extracted from peripheral blood. Genotyping was carried out using PCR-based techniques.
Patients possessing TS-group A genotypes (2R/2R, 2R/3RC, 3RC/3RC) were at increased risk for grade 3/4 hematotoxicity compared with patients harboring a TS-group B genotype (2R/3RG, 3RC/3RG, 3RG/3RG). In all, 59% (20 of 34) of patients with TS-group A genotypes developed grade 3/4 hematotoxicity compared with 25% (4 of 16) of those having TS-group B genotypes (P=0.035). Grade 3/4 neutropenia occurred in 53% (18 of 34) of TS-group A patients compared with 19% (3 of 16) in TS-group B patients (P=0.032). Multivariate analyses identified TS-group A genotypes as significant predictors of grade 3/4 overall hematotoxicity {odds ratio (OR) 4.62 [95% confidence interval (CI) 1.22; 17.44], P=0.024} and neutropenia [OR 5.74 (95% CI 1.03; 32.08), P=0.047].
TS-promoter polymorphisms may be associated with hematotoxicity in AGC patients receiving FLOT.
基于多西他赛的化疗方案已在晚期胃癌（AGC）中显示出活性。然而，这些方案报告了较高的3/4级血液毒性发生率。我们的目的是确定药物遗传学标志物，以检测接受5-氟尿嘧啶、亚叶酸钙、奥沙利铂和多西他赛（FLOT）治疗后发生严重血液毒性风险增加的患者。
在一项II期试验中，对50例接受FLOT治疗的AGC患者进行了参与DNA修复、药物转运和代谢的基因多态性检测。从外周血中提取DNA。使用基于PCR的技术进行基因分型。
与携带TS-B组基因型（2R/3RG、3RC/3RG、3RG/3RG）的患者相比，具有TS-A组基因型（2R/2R、2R/3RC、3RC/3RC）的患者发生3/4级血液毒性的风险增加。总体而言，59%（34例中的20例）具有TS-A组基因型的患者发生了3/4级血液毒性，而具有TS-B组基因型的患者为25%（16例中的4例）（P=0.035）。53%（34例中的18例）的TS-A组患者发生了3/4级中性粒细胞减少，而TS-B组患者为19%（16例中的3例）（P=0.032）。多变量分析确定TS-A组基因型是3/4级总体血液毒性{比值比（OR）4.62 [95%置信区间（CI）1.22；17.44]，P=0.024}和中性粒细胞减少[OR 5.74（95%CI 1.03；32.08），P=0.047]的显著预测因素。
TS启动子多态性可能与接受FLOT治疗的AGC患者的血液毒性有关。
