Breast Cancer Prevention by Letrozole in High Risk Women

描述(申请人提供)：目前，估计有25%的绝经后妇女接受激素替代以缓解围绝经期症状，除了停止使用激素外，几乎没有预防乳腺癌的策略选择。对于许多人来说，即使是患乳腺癌的高危女性，停止使用激素可能意味着她们的生活质量大幅下降。绝经后妇女乳房中的大部分雌二醇来自局部生产，芳香酶负责将雄激素局部转化为雌二醇。鉴于增殖在肿瘤发展中的生物学意义，以及在乳腺癌治疗试验中增殖减少与临床益处之间的关联，我们在一项单臂先导性研究中测试了芳香酶抑制剂的概念，该概念用于对接受慢性激素替代治疗的高危绝经后妇女进行化学预防，其中增殖标记物Ki-67的减少是主要终点。良性乳腺组织在基线时通过随机乳晕周围细针抽吸术(RPFNA)获得，并在芳香酶抑制剂来曲唑治疗6个月后再次获得。我们观察到，尽管在来曲唑治疗期间继续使用激素替代，Ki-67的表达仍平均减少了2.5%。尽管乳腺癌Ki-67水平显著降低，但围绝经期症状几乎没有变化。我们现在希望在一项随机的、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与安慰剂相比，来曲唑6个月是否会减少接受雌激素或雌激素+孕激素替代治疗的女性增生组织中的Ki-67。重要的次要目标是确定来曲唑是否有利于调节其他风险生物标记物，如乳房X光摄影密度和血清生物可利用雌二醇和睾酮；和/或恶化接受雌激素替代治疗的妇女的症状和生活质量。如果在雌激素替代疗法的同时增加芳香酶抑制剂的策略能够得到验证，它将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.