Breast Cancer Prevention by Letrozole in High Risk Women

描述（由申请人提供）：目前，除了停止使用激素外，估计有25%的绝经后妇女采用激素替代来缓解围绝经期症状，几乎没有乳腺癌预防策略选择。对许多人来说，甚至是乳腺癌高风险的女性，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雌二醇大部分来自局部产生，芳香化酶负责大部分雄激素在局部转化为雌二醇。考虑到肿瘤发展中增殖的生物学意义，以及乳腺癌治疗试验中增殖减少与临床获益之间的关联，我们在一项单臂先导研究中测试了芳香酶抑制剂用于高危绝经后妇女慢性激素替代治疗的化学预防的概念，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，尽管在来曲唑治疗期间继续激素替代，Ki-67表达平均降低2.5%。尽管Ki-67显著降低，但围绝经期症状变化不大。我们现在希望在一项随机、安慰剂对照的多机构II期试验中正式检验这一策略。我们的主要目的是确定6个月的来曲唑是否会降低接受雌激素或雌激素加黄体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于调节其他风险生物标志物，如乳房x线摄影密度和血清生物利用雌二醇和睾酮；和/或使接受雌激素替代疗法的妇女的症状和生活质量恶化。如果在雌激素替代治疗的同时加入芳香酶抑制剂的策略能够得到验证，它有可能影响数百万绝经后妇女，提供雌激素替代治疗的健康优势，同时避免乳腺癌发展风险的增加。

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.