Center for Cancer and Hematologic Disease, 1930 E. Route 70, Cherry Hill, NJ 08003, USA.
Breast Cancer Res. 2010;12(3):R26. doi: 10.1186/bcr2570. Epub 2010 May 10.
Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes.
We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables.
In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen.
These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer.
环磷酰胺为基础的辅助化疗是治疗淋巴结阳性乳腺癌的主要方法，但并非普遍有效预防复发。药物代谢的遗传多态性是治疗失败的一种可能机制。我们假设，激活环磷酰胺的药物代谢酶（CYPs）或代谢（GSTs）的功能单核苷酸多态性（SNPs）解释了一些观察到的疾病结果的可变性。
我们对 350 名参加多中心、随机、辅助乳腺癌化疗试验（ECOG-2190/INT-0121）的女性进行了回顾性队列研究。该试验中的受试者接受标准剂量环磷酰胺、多柔比星和氟尿嘧啶（CAF）治疗，随后进行观察或高剂量环磷酰胺和噻替哌联合干细胞挽救治疗。我们使用来自存档标本的骨髓干细胞衍生基因组 DNA 对 CYP2B6、CYP2C9、CYP2D6、CYP3A4、CYP3A5、GSTM1、GSTT1 和 GSTP1 进行基因分型。使用 Cox 回归模型计算基因型（单独或组合）与无病生存（DFS）或总生存（OS）之间的关联，同时调整混杂的临床变量。
在全多变量分析中，至少有一种 CYP3A4 * 1B 变异等位基因的女性与野生型 * 1A/* 1A 的女性相比，DFS 明显更差（多变量危险比 2.79；95%CI 1.52, 5.14）。CYP2D6 基因型对计划接受他莫昔芬治疗的雌激素受体（ER）阳性肿瘤患者的这种关联没有影响。
这些数据支持这样的假设，即环磷酰胺代谢的遗传多态性独立影响乳腺癌辅助化疗的结果。
