Leyland-Jones Brian, Gray Kathryn P, Abramovitz Mark, Bouzyk Mark, Young Brandon, Long Bradley, Kammler Roswitha, Dell'Orto Patrizia, Biasi Maria Olivia, Thürlimann Beat, Lyng Maria B, Ditzel Henrik J, Harvey Vernon J, Neven Patrick, Treilleux Isabelle, Rasmussen Birgitte Bruun, Maibach Rudolf, Price Karen N, Coates Alan S, Goldhirsch Aron, Pagani Olivia, Viale Giuseppe, Rae James M, Regan Meredith M
Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA,
Breast Cancer Res Treat. 2015 Jun;151(2):373-84. doi: 10.1007/s10549-015-3378-3. Epub 2015 May 3.
To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.
为了确定细胞色素P450 19A1（CYP19A1）基因多态性是否与芳香化酶活性异常以及芳香化酶抑制剂的肌肉骨骼和骨骼副作用相关。从参加BIG 1-98试验的4861例激素受体阳性绝经后乳腺癌妇女的肿瘤标本中分离DNA，这些患者接受他莫昔芬和/或来曲唑治疗5年。使用基于聚合酶链反应（PCR）的方法对肿瘤进行6种CYP19A1基因多态性的基因分型。使用Cox比例风险模型评估与无乳腺癌间期（BCFI）、无远处复发间期（DRFI）、肌肉骨骼和骨骼不良事件（AE）的相关性。所有统计检验均为双侧检验。总体上未观察到CYP19A1基因型与BCFI或DRFI之间存在关联。观察到携带rs700518变异的他莫昔芬治疗患者发生乳腺癌事件的风险降低（BCFI中CC/TC与TT相比：风险比[HR] 0.53，95%置信区间[CI] 0.34 - 0.82，交互作用P = 0.08），但来曲唑治疗患者未观察到该现象。携带rs700518变异CC/TC的患者与TT相比，发生肌肉骨骼AE的风险增加（HR 1.22，95% CI 1.03 - 1.45，P = 0.02），与治疗无关。携带rs4646变异的他莫昔芬治疗患者发生骨骼AE的风险降低（AA/CA与CC相比：HR 0.76，95% CI 0.59 - 0.98），而rs10046次要等位基因（C）增加与骨骼AE风险增加相关（HR 1.28，95% CI 1.07 - 1.52）。rs936308变异与来曲唑治疗患者骨骼AE风险降低相关（GG/GC与CC相比：HR 0.73，95% CI 0.54 - 0.99），与他莫昔芬治疗患者不同（GG/GC与CC相比：HR 1.32，95% CI 0.92 - 1.90，交互作用P = 0.01）。CYP19A1 rs700518变异在他莫昔芬治疗患者中与BCFI、DRFI相关，且与治疗无关的肌肉骨骼AE相关。单核苷酸多态性（SNP）rs4646、rs10046和rs936308与骨骼AE相关。
