Breast Cancer Prevention by Letrozole in High Risk Women

描述（由申请人提供）：目前，估计有25%的绝经后妇女接受激素替代治疗以缓解围绝经期症状，除了停止使用激素外，几乎没有乳腺癌预防策略选择。对于许多人来说，即使是乳腺癌高危女性，停止使用激素可能意味着生活质量的急剧下降。绝经后妇女乳房中的大多数雌二醇来自局部产生，芳香化酶负责雄激素向雌二醇的大部分局部转化。鉴于增殖在肿瘤发展中的生物学意义，以及增殖减少与乳腺癌治疗试验中临床获益之间的相关性，我们在一项单臂试点研究中测试了芳香酶抑制剂用于长期激素替代治疗的高危绝经后妇女的化学预防的概念，其中增殖标志物Ki-67的减少是主要终点。在基线和芳香化酶抑制剂来曲唑治疗6个月后，通过随机乳晕周围细针穿刺（RPFNA）获得良性乳腺组织。我们观察到平均2.5%的Ki-67表达减少，尽管在来曲唑治疗期间继续激素替代。尽管乳腺Ki-67显著降低，但围绝经期症状几乎没有变化。我们现在希望在一项随机、安慰剂对照的多机构II期试验中正式测试这一策略。我们的主要目的是确定相对于安慰剂，来曲唑治疗6个月是否能降低接受雌激素或雌激素加孕酮替代治疗的女性增生组织中的Ki-67。重要的次要目的是确定来曲唑是否有利地调节其他风险生物标志物，如乳腺摄影密度和血清生物可利用的雌二醇和睾酮;和/或雌激素替代治疗的女性的乳腺癌症状和生活质量。如果芳香化酶抑制剂与雌激素替代疗法联合使用的策略能够得到验证，它有可能影响数百万绝经后妇女，提供雌激素替代疗法的健康优势，同时避免乳腺癌发生风险的增加。

DESCRIPTION (provided by applicant): At present there are few breast cancer prevention strategy options for the estimated 25% of post- menopausal women who take hormone replacement for relief of perimenopausal symptoms, other than to discontinue their use of hormones. For many, even women at high risk for development of breast cancer, discontinuing hormone use may mean a dramatic reduction in their quality of life. The majority of estradiol in the breast in post-menopausal women is derived from local production, with the aromatase enzyme responsible for much of the local conversion of androgens to estradiol. Given the biologic significance of proliferation in neoplastic development, and the association between proliferation reduction and clinical benefit in breast cancer treatment trials, we tested the concept of an aromatase inhibitor for chemoprevention in high-risk post-menopausal women on chronic hormone replacement therapy in a single arm pilot study, in which reduction in the proliferation marker Ki-67 was the primary endpoint. Benign breast tissue was obtained by random periareolar fine needle aspiration (RPFNA) at baseline and again after six months of treatment with the aromatase inhibitor letrozole. We observed an average 2.5% reduction in Ki-67 expression despite continuation of hormone replacement during letrozole treatment. Despite dramatic reductions in breast Ki-67 there was little change in perimenopausal symptoms. We now wish to formally test this strategy in a randomized, placebo-controlled multi-institutional Phase II trial. Our primary aim is to determine if six months of letrozole will reduce Ki-67 in hyperplastic tissue in women on estrogen or estrogen plus progestin replacement therapy relative to placebo. Important secondary aims are to determine if letrozole favorably modulates other risk biomarkers such as mammographic density and serum bioavailable estradiol and testosterone; and/or worsens symptoms and quality of life in women on estrogen replacement therapy. If the strategy of addition of an aromatase inhibitor to concomitant estrogen replacement therapy can be validated, it has the potential to impact millions of post-menopausal women, providing the health advantages of estrogen replacement therapy while avoiding an increase in risk for development of breast cancer.