Fabian Carol J, Kimler Bruce F, Anderson Julie, Tawfik Ossama W, Mayo Matthew S, Burak William E, O'Shaughnessy Joyce A, Albain Kathy S, Hyams David M, Budd G Thomas, Ganz Patricia A, Sauter Edward R, Beenken Samuel W, Grizzle William E, Fruehauf John P, Arneson Dora W, Bacus James W, Lagios Michael D, Johnson Karen A, Browne Doris
University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Clin Cancer Res. 2004 Aug 15;10(16):5403-17. doi: 10.1158/1078-0432.CCR-04-0171.
Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer.
In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase IB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers.
In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry.
Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemoprevention agent.
阿佐昔芬是一种新型选择性雌激素受体调节剂，具有强大的乳腺抗雌激素活性且无子宫激动剂活性，被作为一种潜在的化学预防药物进行研究。我们对阿佐昔芬在新诊断为原位导管癌或T1/T2浸润性癌的女性患者中进行了多机构评估。
在IA期试验中，50名绝经前或绝经后女性在活检和再次切除之间的间隔期被随机分为每日服用10毫克、20毫克或50毫克阿佐昔芬，或作为未治疗对照组入组。在IB期试验中，76名绝经后女性被随机分为服用20毫克阿佐昔芬组和匹配的安慰剂组。在入组时和再次切除时采集的血清标本检测各种激素和生长因子。对活检组织（雌激素受体阳性和/或孕激素受体阳性）和再次切除标本进行免疫组织化学评估，以检测增殖情况（通过MIB-1检测Ki-67和增殖细胞核抗原）及其他生物标志物。
在两项试验中，均观察到血清性激素结合球蛋白增加，胰岛素样生长因子（IGF）-I及IGF-I:IGF结合蛋白-3比值降低（与对照组/安慰剂组相比，P<0.007）。对于IA期45名可评估女性，阿佐昔芬（尤其是20毫克剂量）组增殖指数降低比对照组更普遍。对于IB期58名可评估女性，与安慰剂组无变化相比，阿佐昔芬组雌激素受体表达降低（P = 0.0068）。然而，阿佐昔芬组增殖指数降低与安慰剂组无统计学差异，这可能是由于入组前停止激素替代疗法的混杂效应所致。
鉴于此处报道的良好副作用特征和生物标志物调节作用，阿佐昔芬仍是作为乳腺癌化学预防药物进行进一步研究的合理候选药物。
