Challenges in the endocrine management of breast cancer
Challenges in the endocrine management of breast cancer
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DOI：
10.1016/s0960-9776(03)80158-3
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发表时间：
2003-08-01
期刊：
影响因子：
3.9
通讯作者：
Smith, IE
中科院分区：
文献类型：
--
作者：
Mouridsen, HT;Rose, C;Smith, IE
乳腺癌内分泌治疗的目的是通过抑制雌激素与特定雌激素受体的结合或抑制其合成来阻断雌激素对肿瘤细胞的作用。他莫昔芬是一种选择性雌激素受体调节剂，是激素受体阳性乳腺癌的标准内分泌治疗，无论是辅助治疗还是转移性治疗。他莫昔芬抑制雌激素与受体的结合，从而抑制激素的作用。然而，由于他莫昔芬也是弱雌激素，它可能不是最佳效果，并增加子宫内膜癌和中风的风险。此外，患者可能难治性或对他莫昔芬治疗产生耐药性。由于芳香化酶抑制剂（AI）阻断雌激素的合成并且没有内在的雌激素活性，因此它们可能比他莫昔芬更有效。它们不同的作用机制和化学结构也可能规避他莫昔芬耐药性。因此，目前正在评估人工智能作为他诺昔芬治疗的替代方案。最近建立了一个临床前模型来比较AIs和抗雌激素在不同治疗方案中的疗效，并协助设计临床试验。目前使用MCF-7Ca异种移植模型的研究正在探索联合和顺序治疗对肿瘤生长的影响。AIs治疗激素受体阳性乳腺癌的疗效首次在五项多中心二线试验中得到证实，该试验纳入了数百名经他莫昔芬治疗失败的绝经后转移性乳腺癌患者。最近，阿那曲唑在一线随机III期临床试验中对患有激素受体阳性或未知转移性乳腺癌的绝经后妇女的疗效至少与他诺昔芬相当，而来曲唑则表现出优越性。类固醇AI依西美坦目前正在评估中。来曲唑是唯一一种在新辅助治疗环境下进行随机III期试验的人工智能药物。在这项试验中，更多的患者使用来曲唑而不是他莫昔芬进行保乳手术。较小的II期研究也表明阿那曲唑和依西美坦在新辅助治疗中都是有效的。由于新辅助试验允许乳腺组织的时间取样，来曲唑III期试验的亚研究已经检查了诸如雌激素受体、孕激素受体和表皮生长因子受体家族成员HER-1和HER-2等生物标志物对患者反应的影响。目前正在对辅助治疗进行评估，Arimidex，他莫昔芬单独或联合（ATAC）试验的初步结果已经报告。在转移性乳腺癌患者的试验中，AIs已被证明与他莫昔芬一样安全。正在进行的辅助治疗的临床试验包括终器官效应的伴随研究，特别是骨代谢和脂质代谢评估。生活质量评估也是主要临床试验的一部分。与来曲唑相比，阿那曲唑的头对头生活质量评估表明患者更倾向于来曲唑。这些评估也清楚地表明患者积极参与治疗决策的渴望。2003爱思唯尔科学有限公司版权所有。
The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tarnoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tarnoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions. (C) 2003 Elsevier Science Ltd. All rights reserved.