Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncología, Valencia, Spain.
BMC Cancer. 2010 Feb 9;10:36. doi: 10.1186/1471-2407-10-36.
Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC.
We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood.
Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009).
Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.
芳香酶（CYP19A1）调节雌激素的生物合成。CYP19A1 的多态性与乳腺癌（BC）的发病机制有关。用来曲唑抑制芳香酶是治疗绝经后妇女雌激素依赖性 BC 的最佳选择。我们评估了 CYP19A1 的一系列多态性及其对早期 BC 新辅助来曲唑治疗反应的影响。
我们分析了 95 例连续的绝经后 II-III 期 ER/PgR[+]BC 患者，这些患者接受新辅助来曲唑治疗。根据世界卫生组织（WHO）标准，在第 4 个月通过影像学评估治疗反应。从外周血中提取 DNA，评估 CYP19A1 外显子 7（rs700519）和 3'-UTR 区（rs10046 和 rs4646）的三个多态性。
35 名女性（36.8%）对来曲唑有影像学反应。组织病理学和免疫组织化学参数，包括激素受体状态，与来曲唑的反应无关。只有 rs4646 多态性的遗传变异（AC/AA）与来曲唑反应不良相关（p=0.03）。18 名患者（18.9%）疾病进展。与携带参考变异纯合子的患者相比，携带 rs4646 遗传变异（AC/AA）的患者无进展生存期较低（p=0.0686）。在来曲唑诱导后未手术的老年患者组中，这种影响尤其显著（p=0.009）。
我们的研究表明，rs4646 多态性可识别出一组对新辅助来曲唑反应不良且预后不良的 II-III 期 ER/PgR[+]BC 患者。测试 rs4646 多态性可能是指导老年 BC 患者治疗的有用工具。
