Department of Clinical Medicine and Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus University, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark.
Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark.
Breast Cancer Res Treat. 2022 Jul;194(2):353-363. doi: 10.1007/s10549-022-06596-2. Epub 2022 Apr 30.
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.
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.
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).
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.
紫杉烷类化疗是治疗绝经前乳腺癌的主要方法。尽管研究结果不一致，但有研究表明，变异等位基因通过降低 OATP 转运体（限制肝摄取）、CYP-450 酶（阻碍药物代谢）和 ABC 转运体（降低清除率）的功能，改变药物的药代动力学。DNA 修复酶功能下降可能通过剂量限制毒性而降低药物的疗效。我们研究了单核苷酸多态性（SNP）是否与绝经前诊断为乳腺癌的女性的乳腺癌复发或死亡率有关。
我们进行了一项基于人群的队列研究，纳入了 2007 年至 2011 年期间在丹麦被诊断为非远处转移性乳腺癌的绝经前女性，当时的指南建议采用辅助联合化疗（紫杉烷类、蒽环类药物和环磷酰胺）。我们使用存档的福尔马林固定石蜡包埋的原发肿瘤组织，通过 TaqMan 分析检测 26 个 SNP 的基因型。丹麦健康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。我们使用 Cox 回归模型计算了不同基因型的复发和死亡率的粗危险比（HR）和 95%置信区间（CI）。
在 2262 名女性中，249 名女性在随访期间（中位随访时间分别为 7.0 年和 10.1 年）出现复发（累积发生率为 13%），259 名女性死亡（累积发生率为 16%）。GSTP1 rs1138272（HR：1.30，95%CI 0.95-1.78）和 CYP3A rs10273424（HR：1.33，95%CI 0.98-1.81）变异携带者的死亡率增加。SLCO1B1 rs2306283（编码 OATP1B1）的变异携带者复发（HR：0.82，95%CI 0.64-1.07）和死亡率（HR：0.77，95%CI 0.60-0.98）降低。
在非远处转移性乳腺癌的绝经前女性中，GSTP1、CYP3A 和 SLCO1B1 的 SNP 影响多西他赛的疗效，可能与多西他赛的药代动力学改变有关。这些 SNP 可能有助于确定患者从紫杉烷类化疗中获益的情况。
