Jaremko Malgorzata, Justenhoven Christina, Schroth Werner, Abraham Benny K, Fritz Peter, Vollmert Caren, Illig Thomas, Simon Wolfgang, Schwab Matthias, Brauch Hiltrud
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
Pharmacogenet Genomics. 2007 Jul;17(7):529-38. doi: 10.1097/FPC.0b013e32801233fc.
Outcome and survival in anthracycline-based and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer are unpredictable. Insights into treatment prediction are expected from studies searching for an association between genetic polymorphisms and treatment outcome effects. A common feature of treatment with chemoreagents is therapeutically induced DNA damage. Therefore, we tested the hypothesis of a relationship between event-free survival and genotype distributions of seven polymorphic DNA repair enzymes and four cell cycle regulators.
This case-case comparison included 180 patients with primary invasive breast cancer diagnosed between 1986 and 2000 and subjected to adjuvant chemotherapy (anthracycline/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil). Ninety-two patients were reported without recurrence and 88 were reported with recurrences or dead. Median clinical follow-up was 61.7 months. Constitutional DNA isolated from archived tissues was genotyped at 19 loci by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Statistical analyses included adjusted risk estimates, Kaplan-Meier analyses, Cox proportional hazard model, and permutation testing.
Carriers of the XRCC1_1196_AA genotype had a reduced risk for recurrence/death (odds ratio adjusted 0.19; 95% confidence interval: 0.06-0.61), which was observed in survival analyses of all patients (P=0.003) and patients treated with chemotherapy but not radiotherapy (P=0.006). Multivariate analysis confirmed XRCC1 as a potential treatment predictor (hazard ratio 0.62; 95% confidence interval: 0.43-0.89). The result was stable upon permutation testing. No other significant associations were observed.
The DNA repair enzyme XRCC1 is a potential treatment predictor for the outcome and survival of anthracycline and cyclophosphamide/methotrexate/5-fluorouracil-based chemotherapy of invasive breast cancer.
蒽环类药物联合环磷酰胺及环磷酰胺/甲氨蝶呤/5-氟尿嘧啶方案治疗浸润性乳腺癌的疗效和生存率难以预测。通过研究基因多态性与治疗效果之间的关联有望获得治疗预测方面的见解。化疗药物治疗的一个共同特征是治疗性诱导DNA损伤。因此，我们检验了无事件生存期与7种多态性DNA修复酶和4种细胞周期调节因子的基因型分布之间存在关联的假设。
本病例对照研究纳入了1986年至2000年间诊断为原发性浸润性乳腺癌并接受辅助化疗（蒽环类药物/环磷酰胺或环磷酰胺/甲氨蝶呤/5-氟尿嘧啶）的180例患者。报告92例患者无复发，88例患者复发或死亡。中位临床随访时间为61.7个月。通过基质辅助激光解吸/电离飞行时间质谱法对存档组织中分离的基因组DNA在19个位点进行基因分型。统计分析包括调整后的风险估计、Kaplan-Meier分析、Cox比例风险模型和置换检验。
XRCC1_1196_AA基因型携带者复发/死亡风险降低（调整后的优势比为0.19；95%置信区间：0.06 - 0.61），在所有患者的生存分析中（P = 0.003）以及接受化疗但未接受放疗的患者中（P = 0.006）均观察到这一结果。多变量分析证实XRCC1是一个潜在的治疗预测指标（风险比为0.62；95%置信区间：0.43 - 0.89）。经置换检验，结果稳定。未观察到其他显著关联。
DNA修复酶XRCC1是蒽环类药物联合环磷酰胺及环磷酰胺/甲氨蝶呤/5-氟尿嘧啶方案治疗浸润性乳腺癌疗效和生存率的潜在治疗预测指标。
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