Breast Cancer Prevention by Letrozole in High Risk Women

高危女性来曲唑预防乳腺癌

• 批准号: 7498535
• 负责人: CAROL J. FABIAN
• 金额: $ 47.34万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498535
• 关键词: Address; Adverse effects; Androgens; Aromatase; Aromatase Inhibitors; Benign; Bioavailable; Biological Markers; Blood Circulation; Breast; Breast Cancer Prevention; Breast Cancer Treatment; C-reactive protein; Characteristics; Chemoprevention; Chronic; Climacteric; Clinical; Clinical Trials; Deterioration; Development; Disease; Dose; End Point; Enzymes; Epithelium; Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Replacement Therapy; Estrogens; Family history of; Fatigue; Fine needle aspiration biopsy; Fright; Genes; Health; High Density Lipoprotein Cholesterol; High Risk Woman; Hormone replacement therapy; Hormones; Hot flushes; Human; Hyperplasia; Label; Letrozole; Life; Mammary Gland Parenchyma; Mammographic Density; Measurement; Menopausal Symptom; Menopausal hot flushes; Nuclear; Pain; Perimenopause; Phase; Phase II Clinical Trials; Pilot Projects; Placebo Control; Placebos; Postmenopause; Premalignant; Prevention strategy; Production; Progestins; Proliferation Marker; Proliferative Type Breast Fibrocystic Change; Quality of life; Raloxifene; Randomized; Recording of previous events; Relative (related person); Replacement Therapy; Research Personnel; Risk; Risk Reduction; Score; Serum; Sulfatases; Symptoms; TFF1 gene; Tamoxifen; Testing; Testosterone; Tissues; Upper arm; Woman; Work; base; bone turnover; concept; hormone therapy; improved; indexing; malignant breast neoplasm; neoplastic; pilot trial; pre-clinical; programs; treatment trial

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.

描述（由申请人提供）：目前，估计有25％的绝经后妇女的乳腺癌预防策略选项很少，这些妇女替代了激素以缓解上膜症状症状，而除了停止使用激素外。对于许多人来说，即使是乳腺癌发展的高风险的女性，停止使用激素的使用可能意味着她们的生活质量会大大降低。绝经后妇女的乳房中大多数雌二醇来自局部生产，芳香化酶酶造成了雄激素向雌二醇的大部分局部转化。鉴于增殖在肿瘤发育中的生物学意义，以及在乳腺癌治疗试验中的增殖减少与临床益处之间的关联，我们测试了高危后女性在慢性激素替代治疗中的芳香酶抑制剂进行化学预防的概念。在基线时，通过随机的周围细针吸入（RPFNA）以及六个月的芳香酶抑制剂LeTrozole获得良性乳房组织。尽管在letrozole治疗过程中持续替换激素，但我们观察到KI-67表达的平均降低了2.5％。尽管乳腺KI-67急剧减少，但绝经症症状的变化很小。现在，我们希望在随机的，安慰剂对照的多机构II期试验中正式测试该策略。我们的主要目的是确定雌激素或雌激素和孕激素替代疗法相对于留下的六个月的letrozole六个月的LeTrozole是否会减少增生组织中的KI-67。重要的次要目的是确定LeTrozole是否有利地调节了其他风险生物标志物，例如乳房X线摄影密度和血清生物利用性雌二醇和睾丸激素。和/或女性在雌激素替代疗法中的症状和生活质量恶化。如果可以验证将芳香酶抑制剂添加到伴随雌激素替代疗法中的策略，则它有可能影响数百万个绝经后妇女，从而提供雌激素替代疗法的健康优势，同时避免增加乳腺癌的风险增加。