Abstract：
OBJECTIVE: Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.
METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98).
CONCLUSIONS: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.
METHODS: We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.
RESULTS: Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95-1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98-1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64-1.07) and mortality (HR: 0.77, 95% CI 0.60-0.98).
CONCLUSIONS: Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.
摘要：
目的：紫杉烷为主的化疗是绝经前乳腺癌的主要治疗方法。虽然不一致，研究表明，变异等位基因通过降低OATP转运蛋白的功能（限制肝脏摄取）改变药代动力学，CYP-450酶（阻碍药物代谢），和ABC运输机（减少通关）。DNA修复酶的功能降低可能通过剂量限制毒性而妨碍有效性。我们调查了单核苷酸多态性（SNP）是否与诊断为乳腺癌的绝经前妇女的乳腺癌复发或死亡率相关。
方法：我们在2007-2011年期间对丹麦诊断为非远处转移性乳腺癌的绝经前妇女进行了一项基于人群的队列研究，当时指南推荐了辅助联合化疗（紫杉烷，蒽环类药物,和环磷酰胺）。使用存档的福尔马林固定石蜡包埋的原发性肿瘤组织，我们使用TaqMan分析对26个SNP进行基因分型。丹麦卫生登记处提供了乳腺癌复发（截至2017年9月25日）和死亡（截至2019年12月31日）的数据。我们拟合Cox回归模型来计算各基因型复发和死亡率的粗风险比(HR)和95%置信区间(CI)。
结果：在2,262名女性中，在随访期间有249例复发（累计发生率：13%）和259例死亡（累计发生率：16%）（中位数为7.0年和10.1年，分别)。GSTP1rs1138272（HR：1.30，95％CI0.95-1.78）和CYP3Ars10273424（HR：1.33，95％CI0.98-1.81）的变异携带者的死亡率增加。SLCO1B1rs2306283（编码OATP1B1）变异携带者的复发率（HR：0.82，95％CI0.64-1.07）和死亡率（HR：0.77，95％CI0.60-0.98）降低。
结论：多西他赛的有效性受GSTP1、CYP3A、和SLCO1B1在绝经前女性非远处转移性乳腺癌中，可能与多西他赛药代动力学改变有关。这些SNP可以帮助确定个体从基于紫杉烷的化疗中获益。
方法：我们在2007-2011年期间对丹麦诊断为非远处转移性乳腺癌的绝经前妇女进行了一项基于人群的队列研究，当时指南推荐了辅助联合化疗（紫杉烷，蒽环类药物,和环磷酰胺）。使用存档的福尔马林固定石蜡包埋的原发性肿瘤组织，我们使用TaqMan分析对26个SNP进行基因分型。丹麦卫生登记处提供了乳腺癌复发（截至2017年9月25日）和死亡（截至2019年12月31日）的数据。我们拟合Cox回归模型来计算各基因型复发和死亡率的粗风险比(HR)和95%置信区间(CI)。
结果：在2,262名女性中，在随访期间有249例复发（累计发生率：13%）和259例死亡（累计发生率：16%）（中位数为7.0年和10.1年，分别)。GSTP1rs1138272（HR：1.30，95％CI0.95-1.78）和CYP3Ars10273424（HR：1.33，95％CI0.98-1.81）的变异携带者的死亡率增加。SLCO1B1rs2306283（编码OATP1B1）变异携带者的复发率（HR：0.82，95％CI0.64-1.07）和死亡率（HR：0.77，95％CI0.60-0.98）降低。
结论：多西他赛的有效性受GSTP1、CYP3A、和SLCO1B1在绝经前女性非远处转移性乳腺癌中，可能与多西他赛药代动力学改变有关。这些SNP可以帮助确定个体从基于紫杉烷的化疗中获益。
