Schneider P G, Jackisch C, Brandt B
Department of Obstetrics and Gynecology, University of Muenster, Germany.
Int J Fertil Menopausal Stud. 1994;39 Suppl 2:115-27.
Hormonal therapy for breast cancer began more than a century ago with the observation that bilateral oophorectomy caused tumor regression in selected premenopausal patients. In the first half of this century, besides extending ablation of ovarian function to photon irradiation, surgical adrenalectomy and hyophysectomy were introduced, and hormonal additive therapy was established. Regression rates for advanced breast cancer with all types of endocrine therapy at this point did not exceed 35%. The demonstration that adjuvant systemic therapy can prolong the disease-free interval and improve overall survival has been a major advance in the management of breast cancer, the rationale was to control or eliminate micrometastases before tumor recurrence. The nonsteroidal antiestrogen tamoxifen was chosen for the majority of studies since the mid-1970s. Since the first report of successful treatment of metastatic breast cancer, the number of treated women worldwide has reached over 3,000,000. Objective response rate (CR+PR following UICC) in unselected patients is 34%. Tamoxifen has been used successfully to treat both pre- and postmenopausal women with all stages of the disease. In an overview analysis of 30,000 patients from 40 trials of adjuvant tamoxifen, a significant increase was found in both disease-free and overall survival. When patients were separated by nodal status, statistically significant increases were observed in disease-free and overall survival for both node-positive and node-negative patients. Women over 50 appear to benefit most from tamoxifen treatment experiencing highly significant increases in disease-free and overall survival regardless of nodal status. However, since tamoxifen primarily acts as a cytostatic and not cytotoxic agent, most patients ultimately experience disease recurrence or progression during or after therapy. Newer antiestrogens include trioxifene, toremifene, and droloxifene (3-OH-tamoxifen). Randomized, prospective studies are still under way to establish their clinical superiority (or lack of it). Progestins exert direct antiproliferative effects on human breast cancer cell lines. They may also exert direct antiestrogenic action by increasing the oxidative activity of 17 beta-hydroxy-steroid-dehydrogenase, thereby facilitating the conversion of estradiol to estrone. Progestins may exert additional antiestrogenic effects by suppressing estrogen receptor levels. As they also cause estrogen deprivation indirectly through suppression of pituitary ACTH secretion, resulting in reduced production of adrenal androgen precursors, both low- and high-dose regimens have been studied. Aromatase inhibition in premenopausal women interrupts estrogen biosynthesis; the reflex rise in FSH then stimulates production of new aromatase enzyme, and the LH increment results in enhanced ovarian steroidogenesis, counteracting the inhibitory action of aromatase-blocking drugs on the ovary.(ABSTRACT TRUNCATED AT 400 WORDS)
乳腺癌的激素治疗始于一个多世纪前，当时观察到双侧卵巢切除术可使部分绝经前患者的肿瘤消退。在本世纪上半叶，除了将卵巢功能的消融扩展到光子照射外，还引入了手术去肾上腺术和垂体切除术，并确立了激素辅助治疗。此时，所有类型内分泌治疗的晚期乳腺癌缓解率均未超过35%。辅助性全身治疗可延长无病间期并提高总生存率，这一证明是乳腺癌治疗的一项重大进展，其基本原理是在肿瘤复发前控制或消除微转移。自20世纪70年代中期以来，大多数研究选择了非甾体类抗雌激素药物他莫昔芬。自首次报道成功治疗转移性乳腺癌以来，全球接受治疗的女性人数已超过300万。未经选择的患者客观缓解率（按照国际抗癌联盟标准为完全缓解+部分缓解）为34%。他莫昔芬已成功用于治疗各期绝经前和绝经后女性患者。在对40项他莫昔芬辅助治疗试验的30000名患者进行的综述分析中，发现无病生存期和总生存期均显著延长。当按淋巴结状态对患者进行分组时，淋巴结阳性和淋巴结阴性患者的无病生存期和总生存期均有统计学意义的显著延长。50岁以上的女性似乎从他莫昔芬治疗中获益最大，无论淋巴结状态如何，其无病生存期和总生存期均有高度显著的延长。然而，由于他莫昔芬主要起细胞生长抑制剂而非细胞毒性剂的作用，大多数患者最终在治疗期间或治疗后会出现疾病复发或进展。新型抗雌激素药物包括三苯氧胺、托瑞米芬和屈洛昔芬（3-羟基他莫昔芬）。随机前瞻性研究仍在进行，以确定它们的临床优势（或是否缺乏优势）。孕激素对人乳腺癌细胞系有直接的抗增殖作用。它们还可能通过增加17β-羟基类固醇脱氢酶的氧化活性发挥直接的抗雌激素作用，从而促进雌二醇向雌酮的转化。孕激素可能通过抑制雌激素受体水平发挥额外的抗雌激素作用。由于它们还通过抑制垂体促肾上腺皮质激素分泌间接导致雌激素缺乏，从而减少肾上腺雄激素前体的产生，因此对低剂量和高剂量方案均进行了研究。绝经前女性的芳香化酶抑制可中断雌激素生物合成；促卵泡生成素的反射性升高随后刺激新的芳香化酶产生，促黄体生成素的增加导致卵巢类固醇生成增强，抵消了芳香化酶阻断药物对卵巢的抑制作用。（摘要截选至400字）
