Goekkurt Eray, Al-Batran Salah-Eddin, Hartmann Jörg T, Mogck Ulrike, Schuch Gunter, Kramer Michael, Jaeger Elke, Bokemeyer Carsten, Ehninger Gerhard, Stoehlmacher Jan
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden 01307, Germany.
J Clin Oncol. 2009 Jun 10;27(17):2863-73. doi: 10.1200/JCO.2008.19.1718. Epub 2009 Mar 30.
To evaluate the association of germ-line polymorphisms of genes that may impact treatment outcome of platinum and fluorouracil combination chemotherapy in advanced gastric cancer (AGC).
Blood samples of 156 patients enrolled onto a phase III study comparing fluorouracil, leucovorin, and oxaliplatin with fluorouracil, leucovorin, and cisplatin were collected. Polymorphisms within genes of TS, MTHFR, MTR, OPRT, XPD, ERCC1, XRCC1, XPA, GSTP1, GSTT1, and GSTM1 were genotyped using polymerase chain reaction-based techniques.
Median overall survival (OS) was 11.8 months (95% CI, 9.75 to 13.79 months) and median progression-free survival (PFS) was 5.8 months (95% CI, 4.99 to 6.61 months). The TS-3R/+6 haplotype (P = .004), the GSTT1 deletion polymorphism (P = .015), and genotypes of OPRT-Gly213Ala (P = .003) and XRCC1-Arg399Gln (P = .023) could be identified as independent predictors of OS. For PFS analyses, the TS-3R/+6 haplotye (P = .003) and MTR-A2756G (P = .01) were identified as independent positive predictors. The association between the GSTT1 deletion polymorphism and PFS showed only borderline significance (P = .053). Treatment related hematotoxicity in terms of grade 3/4 leukopenia was lowest among TS-3R/+6 haplotype carriers (P = .037). Grade 3/4 neutropenia was directly associated with the MTR-2756G/G genotype (P = .011), GSTP1-105Ile/Ile genotype (P = .02), and with the ERCC1-118T/8092C-haplotype (P = .042). In addition, significant associations between GSTP1-105Ile/Ile genotype and neurotoxicity and between the XPD-Asn312/751Gln haplotype and nephrotoxicity could be identified (P = .028 and P = .005, respectively).
These findings underline the hypothesis that germ-line polymorphisms may play an important role in individualizing chemotherapy in AGC and deserve further prospective evaluation in AGC patients.
评估可能影响晚期胃癌（AGC）铂类与氟尿嘧啶联合化疗治疗结果的基因种系多态性之间的关联。
收集了156例参加一项III期研究患者的血样，该研究比较了氟尿嘧啶、亚叶酸钙和奥沙利铂与氟尿嘧啶、亚叶酸钙和顺铂的疗效。使用基于聚合酶链反应的技术对TS、MTHFR、MTR、OPRT、XPD、ERCC1、XRCC1、XPA、GSTP1、GSTT1和GSTM1基因内的多态性进行基因分型。
中位总生存期（OS）为11.8个月（95%CI，9.75至13.79个月），中位无进展生存期（PFS）为5.8个月（95%CI，4.99至6.61个月）。TS-3R/+6单倍型（P = .004）、GSTT1缺失多态性（P = .015）以及OPRT-Gly213Ala（P = .003）和XRCC1-Arg399Gln（P = .023）的基因型可被确定为OS的独立预测因素。对于PFS分析，TS-3R/+6单倍型（P = .003）和MTR-A2756G（P = .01）被确定为独立的阳性预测因素。GSTT1缺失多态性与PFS之间的关联仅具有临界显著性（P = .053）。在TS-3R/+6单倍型携带者中，3/4级白细胞减少方面的治疗相关血液毒性最低（P = .037）。3/4级中性粒细胞减少与MTR-2756G/G基因型（P = .011）、GSTP1-105Ile/Ile基因型（P = .02）以及ERCC1-118T/8092C单倍型（P = .042）直接相关。此外，可确定GSTP1-105Ile/Ile基因型与神经毒性以及XPD-Asn312/751Gln单倍型与肾毒性之间存在显著关联（分别为P = .028和P = .005）。
这些发现强调了种系多态性可能在AGC化疗个体化中起重要作用这一假设，值得在AGC患者中进行进一步的前瞻性评估。
