Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Adv Ther. 2011 Dec;28(12):1045-58. doi: 10.1007/s12325-011-0075-4. Epub 2011 Nov 7.
Third-generation aromatase inhibitors (AIs) have proven to be superior to tamoxifen in terms of time to disease progression in patients with hormone receptor (HR) positive (HR+) status and, nowadays, are used in the adjuvant and neoadjuvant settings, and first-line therapy for advanced breast cancer. Letrozole is a third generation AI, as are anastrozole and exemestane. In the past, clinical studies had demonstrated that letrozole was effective as a second-line treatment of metastatic breast cancer. In this paper, pharmacokinetic and pharmacodynamic properties of letrozole are reviewed along with its activity in preclinical and clinical settings. Additionally, the results of important clinical trials such as Breast International Group (BIG) 1-98, which tested the optimal initial adjuvant endocrine treatment and the sequential therapy with letrozole and tamoxifen, MA-17 that evaluates the benefits of extended adjuvant therapy, and other important studies in advanced and neoadjuvant disease, are reviewed. Safety comparisons of treatments are also addressed. Interestingly, about 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers are HR+. However, HER2 positivity is a marker of antiestrogen treatment resistance. Because of this, a dual treatment is a logical approach when both receptors are overexpressed. The combination of lapatinib and letrozole leads to a significant improvement in the overall disease outcome. Also, the combination of everolimus plus letrozole has been tested in this setting. In fact, the coadministration of both agents seems to increase the efficacy of letrozole in newly-diagnosed HR+ patients. Once resistance to sequential trastuzumab and AI as monotherapy has been found, trastuzumab and letrozole combined in HR+ and HER2+ patients with advanced breast cancer can overcome resistance to both drugs administered as single agents, according to recently reported results.
第三代芳香化酶抑制剂（AIs）已被证明在激素受体（HR）阳性（HR+）患者的疾病进展时间方面优于他莫昔芬，如今已被用于辅助和新辅助治疗以及晚期乳腺癌的一线治疗。来曲唑是第三代 AI，阿那曲唑和依西美坦也是第三代 AI。过去，临床研究已经证明来曲唑作为转移性乳腺癌的二线治疗是有效的。本文回顾了来曲唑的药代动力学和药效学特性及其在临床前和临床环境中的活性。此外，还回顾了重要临床试验的结果，例如乳腺癌国际研究组织（BIG）1-98 试验，该试验测试了最佳的初始辅助内分泌治疗和来曲唑与他莫昔芬的序贯治疗，MA-17 试验评估了延长辅助治疗的益处，以及其他在晚期和新辅助疾病中的重要研究。还讨论了治疗方法的安全性比较。有趣的是，约 50%的人表皮生长因子受体 2 阳性（HER2+）乳腺癌是 HR+。然而，HER2 阳性是抗雌激素治疗耐药的标志物。因此，当两个受体都过表达时，双重治疗是一种合理的方法。拉帕替尼和来曲唑的联合治疗显著改善了整体疾病结局。此外，在这种情况下还测试了依维莫司联合来曲唑的组合。事实上，两种药物的联合似乎增加了来曲唑在新诊断的 HR+患者中的疗效。根据最近的报告结果，一旦发现对曲妥珠单抗和 AI 序贯单药治疗的耐药性，曲妥珠单抗和来曲唑联合用于 HR+和 HER2+的晚期乳腺癌患者可以克服两种药物作为单一药物给药的耐药性。
