Oesterreich Steffi, Henry N Lynn, Kidwell Kelley M, Van Poznak Catherine H, Skaar Todd C, Dantzer Jessica, Li Lang, Hangartner Thomas N, Peacock Munro, Nguyen Anne T, Rae James M, Desta Zeruesenay, Philips Santosh, Storniolo Anna M, Stearns Vered, Hayes Daniel F, Flockhart David A
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, Magee Womens Research Institute, University of Pittsburgh Cancer Institute (UPCI), 204 Craft Avenue, Pittsburgh, PA, 15261, USA.
Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
Breast Cancer Res Treat. 2015 Nov;154(2):263-73. doi: 10.1007/s10549-015-3608-8. Epub 2015 Nov 4.
Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (-3.2 %) compared to exemestane-treated patients (-1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.
激素受体（HR）阳性绝经后乳腺癌患者的辅助治疗包括芳香化酶抑制剂（AI）。非甾体类AI来曲唑和甾体类AI依西美坦均可降低血清雌激素浓度，但有证据表明依西美坦对骨骼的损害可能较小。我们假设单核苷酸多态性（SNP）可预测AI对骨转换的影响。早期HR阳性乳腺癌患者参加了一项依西美坦与来曲唑对比的随机试验。确定了AI对骨密度（BMD）和骨转换标志物（BTM）的影响，以及24个候选基因中的SNP与BMD或BTM变化之间的关联。在503名入组患者中，分别有123例接受来曲唑治疗和101例接受依西美坦治疗的患者可获得配对的BMD数据，分别有175例和173例患者可获得配对的BTM数据。与依西美坦治疗的患者（-1.0%）相比，来曲唑治疗的患者腰椎BMD的平均变化显著更大（-3.2%）（p = 0.0016）。依西美坦治疗的患者尿N-端肽显著升高（p = 0.001），而来曲唑治疗的患者未升高。ESR1中的两个SNP（rs4870061和rs9322335）和ESR2中的一个SNP（rs10140457）与来曲唑治疗患者的BMD降低有关。在依西美坦治疗的患者中，ESR1（Rs2813543）和CYP19A1（Rs6493497）中的SNP与骨密度降低有关。与来曲唑相比，依西美坦对骨密度的负面影响较小，AI治疗对骨骼的影响可能受雌激素受体（ER）途径中的基因变异影响。
