文章：

芳香酶抑制剂治疗乳腺癌：来自实验室的教训

Aromatase inhibitors for breast cancer: lessons from the laboratory

原文发布日期：2003-11-01

DOI: 10.1038/nrc1211

类型: Review Article

开放获取: 否

要点：

1. Aromatase inhibitors act through pure oestrogen deprivation to achieve an endocrine response in oestrogen receptor (ER)-positive breast cancer.
2. Both experimental and clinical data now confirm that aromatase inhibitors achieve greater responses compared with the non-steroidal ER antagonist tamoxifen. This difference might be related to the partial agonist effects of tamoxifen, which can limit its clinical effectiveness.
3. Aromatase activity in peripheral tissues and local malignant and normal breast tissue supplies breast cancer cells with the oestrogen that stimulates cancer growth. The molecular control of this process in breast cancer seems to involve increased COX2 expression.
4. High plasma oestradiol levels are now known to be associated with an increased risk of breast cancer in postmenopausal women. So, use of aromatase inhibitors might provide a novel prevention strategy in the future.
5. Clinical trials have confirmed that aromatase inhibitors are more effective and better tolerated than tamoxifen in postmenopausal women with early or advanced ER-positive breast cancer. As such, aromatase inhibitors are set to replace tamoxifen as the standard of care for these patients.
6. In ER-positive breast carcinomas that co-express the growth-factor receptors EGFR and/or ERBB2, oestrogen deprivation might be more effective than tamoxifen at inhibiting tumour growth. This is consistent with emerging data that confirm cross-talk between growth-factor-receptor and steroid-receptor pathways that leads to tamoxifen resistance as a result of an increased agonist response.
7. Acquisition of resistance during long-term oestrogen deprivation might also involve cross-talk pathways. ER expression might be increased in these cells, with receptors becoming activated and hypersensitive to low residual levels of oestradiol. Strategies to prevent this occurring with various signal-transduction inhibitors and oestrogen-receptor downregulators are now being tested.

要点翻译：

1. 芳香化酶抑制剂通过纯粹的雌激素剥夺作用，在雌激素受体（ER）阳性乳腺癌中产生内分泌治疗反应。
2. 目前实验和临床数据均证实，相较于非甾体类ER拮抗剂他莫昔芬，芳香化酶抑制剂能获得更显著的治疗反应。这种差异可能与他莫昔芬的部分激动剂效应有关，该特性可能限制其临床疗效。
3. 外周组织及局部恶性/正常乳腺组织中的芳香化酶活性为乳腺癌细胞提供刺激癌生长的雌激素。该过程在乳腺癌中的分子调控机制似乎涉及COX2表达的上调。
4. 现已明确，绝经后女性血浆雌二醇水平升高与乳腺癌风险增加相关。因此，芳香化酶抑制剂未来可能提供一种新型预防策略。
5. 临床试验证实，对于患有早期或晚期ER阳性乳腺癌的绝经后女性，芳香化酶抑制剂比他莫昔芬更有效且耐受性更佳。因此，芳香化酶抑制剂将取代他莫昔芬成为这类患者的标准治疗方案。
6. 在同时表达生长因子受体EGFR和/或ERBB2的ER阳性乳腺癌中，雌激素剥夺疗法可能比他莫昔芬更能有效抑制肿瘤生长。这与最新研究数据一致：生长因子受体与类固醇受体通路之间存在交互对话，通过增强激动剂反应导致他莫昔芬耐药。
7. 长期雌激素剥夺治疗中获得性耐药的形成可能也涉及这些交互通路。此类癌细胞中ER表达可能增加，受体被激活并对残余低浓度雌二醇产生超敏反应。目前正在测试采用多种信号转导抑制剂和雌激素受体下调剂来预防这一现象的应对策略。

英文摘要：

Endocrine therapy with tamoxifen has been the mainstay of treatment for hormone-sensitive breast cancer for more than 20 years. An alternative strategy of oestrogen deprivation in postmenopausal women with aromatase inhibitors is set to replace tamoxifen based on better efficacy and a delay in the emergence of endocrine resistance. There are fundamental differences in how tamoxifen and aromatase inhibitors alter oestrogen-receptor signalling. Understanding the response and resistance to these different therapies is central to further improving therapeutic options for women with breast cancer.

摘要翻译： 

他莫昔芬内分泌治疗已成为激素敏感性乳腺癌的主要治疗手段超过20年。对于绝经后女性，采用芳香化酶抑制剂进行雌激素剥夺的替代策略，因其疗效更佳且能延缓内分泌耐药的出现，有望取代他莫昔芬。他莫昔芬与芳香化酶抑制剂在改变雌激素受体信号传导方面存在根本性差异。深入理解对这些不同治疗的反应与耐药机制，是进一步优化乳腺癌女性治疗选择的关键。

原文链接：

Aromatase inhibitors for breast cancer: lessons from the laboratory