Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.
Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-10-0281
复制
发表时间：
2010-12-15
期刊：
影响因子：
--
通讯作者：
Ambrosone CB
中科院分区：
文献类型：
--
作者：
Yao S;Barlow WE;Albain KS;Choi JY;Zhao H;Livingston RB;Davis W;Rae JM;Yeh IT;Hutchins LF;Ravdin PM;Martino S;Lyss AP;Osborne CK;Abeloff M;Hortobagyi GN;Hayes DF;Ambrosone CB
目前尚无明确的遗传标记可用于预测含环磷酰胺(CP)的乳腺癌辅助治疗后的预后。在西南肿瘤组试验(S8897)的一项辅助研究中，我们调查了CP药代动力学途径中4个基因的功能多态与血液毒性和无病生存(DFS)的关系。胚系DNA来自458名复发风险高的女性，并随机分为CAF组和CMF±他莫昔芬组，以及874名预后良好且未接受辅助治疗的女性。通过Logistic回归和COX比例风险回归，评估治疗组中3级和4级血液毒性的优势比，以及与所选功能多态相关的DFS的风险比。与AA基因携带者相比，携带至少一个GSTP1变异G等位基因的女性发生3、4级中性粒细胞减少症(OR=0.63，95%CI=0.41~0.97)和白细胞减少症(OR=0.59，95%CI=0.39~0.89)的风险降低。在治疗或未治疗组中，没有发现SNPs与毒性或存活率之间的其他关联。已知的CP药代动力学相关基因的遗传变异可能不会对乳腺癌患者的DFS产生重大影响。具有变异的GSTP1等位基因的女性发生高度血液毒性的风险较低，这表明遗传标记与临床因素相结合可能有助于确定使用含CP疗法较不容易发生不良血液毒性的女性亚群。
There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a Southwest Oncology Group trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematological toxicity and disease-free survival (DFS). Germline DNA was available from 458 women who were at high risk of relapse and randomized to CAF vs CMF ± tamoxifen and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematological toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6, CYP3A4, GSTA1, and GSTP1 were estimated by logistic regression and Cox proportional hazard regression. Compared to women with AA genotypes, those with at least one GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia (OR=0.63, 95% CI=0.41–0.97) and leucopenia (OR=0.59, 95% CI=0.39–0.89). No other associations between SNPs and toxicity or survival were found in the treated or untreated group. Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high grade hematological toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematological toxicities with CP-containing therapies.