Sudbury Regional Hospital, Regional Cancer Program, Sudbury, ON, Canada.
J Cancer Res Clin Oncol. 2011 Mar;137(3):543-50. doi: 10.1007/s00432-010-0915-7. Epub 2010 May 28.
Inter-individual variations in treatment efficacy may be influenced by polymorphisms in DNA repair genes. We investigated the association of 3 functional polymorphisms in the nucleotide excision repair (NER) pathway with survival outcome of 95 patients with metastatic breast cancer (MBC) treated with DNA-damaging chemotherapy.
ERCC1 8092 C/A, ERCC2 Asp312Asn and ERCC2 Lys751Gln were determined using Taqman-based genotyping assays. Genotype associations with breast cancer-specific survival (BCSS) and progression-free survival (PFS) were evaluated using Kaplan-Meier estimates and hazard ratios calculated using Cox regression analysis. Tests for trend were conducted by calculating P-values for the HR coefficient in proportional hazards regression models.
ERCC2 Lys751Gln was significantly associated with BCSS (median: 24.8 months for AA/AC combined and 14.2 months for CC, HR: 1.9 (95% CI 1.06-3.26)). Median BCSS decreased with increasing number of designated adverse genotypes for the 3 polymorphisms (P (trend) = 0.003). Risk estimates for PFS were nonsignificantly elevated and were significantly elevated for BCSS for patients with 2 (HR = 2.21, 95% CI: 1.04-4.72) or 3 (HR = 6.67, 95% CI: 2.19-20.29) adverse genotypes. In treatment subgroup analysis, risk estimates for BCSS were significantly elevated for patients with 3 adverse genotypes treated with cyclophosphamide, mitoxantrone and vinblastine (HR: 11.9, 95% CI 1.77-79.51) and P (trend) = 0.02 for increasing number of adverse genotypes. Risk of progression was significantly increased for patients with 1 adverse genotype treated with cyclophosphamide, mitoxantrone and carboplatin (HR: 3.5, 95% CI 1.19-10.6) and P (trend) = 0.02 for increasing number of adverse genotypes.
Polymorphisms in NER pathway may impact survival outcome for patients with MBC following treatment with DNA-damaging chemotherapy. These results provide support for a polygenic pathway approach for assessing the prognostic and predictive potential of polymorphisms in treatment outcome.
治疗效果的个体间差异可能受 DNA 修复基因多态性的影响。我们研究了核苷酸切除修复（NER）途径中 3 种功能性多态性与 95 例接受 DNA 损伤化疗的转移性乳腺癌（MBC）患者生存结局的相关性。
采用 Taqman 基因分型检测 ERCC1 8092 C/A、ERCC2 Asp312Asn 和 ERCC2 Lys751Gln。使用 Kaplan-Meier 估计和 Cox 回归分析计算风险比（HR）评估基因型与乳腺癌特异性生存（BCSS）和无进展生存（PFS）的相关性。通过在比例风险回归模型中计算 HR 系数的 P 值来进行趋势检验。
ERCC2 Lys751Gln 与 BCSS 显著相关（中位数：AA/AC 组合为 24.8 个月，CC 为 14.2 个月，HR：1.9（95%CI 1.06-3.26））。随着 3 种多态性指定不良基因型数量的增加，BCSS 中位数降低（P（趋势）=0.003）。对于 PFS 的风险估计略有升高，对于有 2 种（HR=2.21，95%CI：1.04-4.72）或 3 种（HR=6.67，95%CI：2.19-20.29）不良基因型的患者，BCSS 的风险估计显著升高。在治疗亚组分析中，对于接受环磷酰胺、米托蒽醌和长春碱治疗的 3 种不良基因型患者，BCSS 的风险估计显著升高（HR：11.9，95%CI 1.77-79.51），且随着不良基因型数量的增加 P（趋势）=0.02。对于接受环磷酰胺、米托蒽醌和卡铂治疗且有 1 种不良基因型的患者，进展风险显著升高（HR：3.5，95%CI 1.19-10.6），且随着不良基因型数量的增加 P（趋势）=0.02。
NER 途径中的多态性可能会影响接受 DNA 损伤化疗的 MBC 患者的生存结局。这些结果为评估治疗结果中多态性的预后和预测潜力的多基因途径方法提供了支持。
