Low Dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction

霍奇金淋巴瘤幸存者低剂量他莫昔芬可降低乳腺癌风险

基本信息

批准号：
7878876
负责人：
MELANIE R PALOMARES
金额：
$ 70.93万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7878876
关键词：
Adolescence Adopted Adult Adult Hodgkin&apos s Lymphoma Adverse effects Adverse event Age American Cancer Society BRCA1 gene BRCA2 gene Benign Bilateral Bilateral oophorectomy Biological Markers Blood Coagulation Factor Body mass index Breast Breast Cancer Early Detection Breast Cancer Prevention Breast Diseases Cancer Survivor Categories Characteristics Chemoprevention Chemopreventive Agent Chest Childhood Childhood Hodgkin&apos s Lymphoma Chronic Clinical Clinical Trials Collaborations Development Diagnosis Dose Endometrial Carcinoma Exposure to Family Cancer History Female Future Germ-Line Mutation Goals Growth Factor Health Histologic Hodgkin Disease Hormones Individual Informed Consent Institution Insulin Intervention Late Effects Life Link Lipids Magnetic Resonance Imaging Malignant Neoplasms Mammographic Density Mammography Mastectomy Measures Menopausal Status Menopause Modification Morbidity - disease rate Mutation Operative Surgical Procedures Outcome Patient Outcomes Assessments Phase Placebos Population Population Intervention Prophylactic treatment Quality of life Radiation Radiation therapy Randomized Recording of previous events Regimen Regional Disease Relapse Relative (related person)Reporting Research Research Infrastructure Risk Risk Reduction Safety Sample Size Screening procedure Subgroup Supportive care Survival Rate Survivors Symptoms Tamoxifen Testing Thromboembolism Tissues Vasomotor Venous Woman advanced disease arm base bone metabolism bone turnover breast density cancer diagnosis cancer risk cancer therapy childhood cancer survivor cohort cost disorder risk double-blind placebo controlled trial early onset emerging adult high risk improved indexing irradiation malignant breast neoplasm mortality mutation carrier oncology patient population public health relevance risk benefit ratio success young adult

项目摘要

DESCRIPTION (provided by applicant): Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction Mantle radiation has been a cornerstone of HL treatment; however, female survivors of HL treated with mantle irradiation before age 30 have a 20- to 55-fold increased risk of developing breast cancer (BC) - a risk that is comparable to that of BRCA mutation carrierrs Surgical prophylaxis is very effective in reducing the risk of BC, but such invasive strategies are not suitable for all women. Pharmacologic interventions exist, but only tamoxifen is approved for use in young women who have not yet reached menopause. Standard-dose tamoxifen (20 mg daily) is associated with undesirable side effects, but recent studies have laid convincing groundwork that tamoxifen at lower doses may be similarly efficacious in reducing BC risk with fewer side effects. We hypothesize that tamoxifen administered at a lower dose (5 mg daily) would be both an efficacious and safe non-surgical risk reduction intervention for female adult survivors of HL diagnosed during childhood or as a young adult. Thus, using a Phase IIb randomized, double-blind, placebo-controlled trial of low-dose tamoxifen (5 mg daily) in long-term female HL survivors treated with chest radiation, we aim to 1) Determine the impact of a two-year course of low-dose tamoxifen on well-established surrogate biomarkers of chemopreventive efficacy; 2) Establish the safety and tolerability of low-dose tamoxifen in this population; and, as an exploratory aim, 3) Examine the modifying effect of several well-defined demographic and clinical characteristics associated with radiation-related BC risk on the risk:benefit ratio from this intervention. Eligible subjects who provide informed consent will be randomized to 5 mg per day of tamoxifen versus placebo for two years. Outcomes will include several surrogate biomarkers of efficacy, including mammographic breast density (MBD, primary endpoint), breast cytomorphologic and proliferation measures, and insulin growth factors. Subjects will be carefully followed for safety and tolerability using patient-reported outcomes as well as lipid profiles, clotting factors, and markers of bone turnover as objective endpoints. Risk modifiers that will be examined include age, menopausal status, prior hormone use, body mass index, personal history of benign breast disease, and family history of cancer, as well as chest radiation dose, age at exposure, and latency from chest radiation. A sample size of 127 per arm will be able to detect a 20% reduction in MBD with low-dose tamoxifen relative to placebo with 80% power. We have identified over 900 potentially eligible subjects within our consortium of five institutions that have well-developed infrastructure to follow childhood cancer survivors long-term, thus demonstrating that we will have a sufficiently sized pool to draw the eligible patient population from and complete the study. At completion of this study, we hope to identify a well-tolerated risk reduction option for HL survivors that are at high risk for developing BC. Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction Public Health Relevance: Survival from Hodgkin lymphoma (HL) is excellent, but chest radiotherapy (RT) has been a cornerstone of treatment, and women with HL exposed to chest RT when they are young have a 20- to 55-fold increased risk of developing breast cancer (BC). Tamoxifen reduces the risk of BC by 50%, but at the cost of some undesirable side effects, while more recent studies suggest that lower dose tamoxifen may be similarly efficacious in reducing BC risk with fewer side effects. We believe that tamoxifen administered at 5 mg daily would be an ideal non-surgical risk reduction intervention for female HL survivors exposed to chest RT at high risk for BC; therefore, we plan to test this hypothesis in a Phase IIb clinical trial.

描述（由申请人提供）：霍奇金淋巴瘤幸存者中的低剂量他莫昔芬用于乳腺癌风险减少地幔辐射一直是HL治疗的基石；然而，在30岁之前用地幔辐射治疗的HL的女性幸存者患有20至55倍的乳腺癌风险（BC），这种风险与BRCA突变携带者的外科手术预防症的风险非常有效，在降低BC的风险方面非常有效，但这种侵入性策略并不适合所有女性。存在药理学干预措施，但只有他莫昔芬被批准用于尚未更年期的年轻女性。标准剂量的他莫昔芬（每天20毫克）与不良的副作用有关，但最近的研究令人信服地基础，较低剂量的他莫昔芬在降低卑诗省风险方面可能同样有效，而副作用较少。我们假设以较低剂量（每天5毫克）给药的他莫昔芬是对儿童期间诊断为HL的女性成年人幸存者的有效且安全的非手术风险降低干预措施。因此，使用IIB期为胸辐射治疗的长期女性HL幸存者的低剂量他莫昔芬（每天5毫克）的随机，双盲，安慰剂对照试验，我们的目标是1）确定低剂量的他莫昔芬对良好成熟的替代化学生物标志的两年培训的影响。 2）在该人群中建立低剂量他莫昔芬的安全性和耐受性；并且，作为探索性目的，3）检查与辐射相关的BC风险相关的几个定义明确的人口统计和临床特征对风险的修改效果：此干预措施的收益比率。提供知情同意的合格受试者将在两年内随机分配他莫昔芬与安慰剂的每天5毫克。结果将包括几种疗效的替代生物标志物，包括乳腺乳腺乳腺图密度（MBD，主要终点），乳房细胞学形态学和增殖度量以及胰岛素生长因子。使用患者报告的结果以及脂质曲线，凝结因子和骨转换标记作为目标终点，将仔细遵循受试者的安全性和耐受性。将要检查的风险修饰符包括年龄，更年期状态，先前的激素使用，体重指数，良性乳腺病的个人病史以及癌症的家族史以及胸部辐射剂量，暴露年龄以及胸部辐射的潜伏期。每只手臂的样本量127将能够检测到低剂量他莫昔芬的MBD降低20％，相对于安慰剂，其功率为80％。我们已经在我们的财团内确定了900多名潜在的符合条件的受试者，这些机构长期遵循了五个机构，这些机构长期遵循儿童癌症幸存者，从而表明我们将拥有足够尺寸的库来吸引合格的患者群体并完成这项研究。这项研究完成后，我们希望为HL幸存者确定一种耐受性良好的风险选择，这些HL幸存者有高风险的发展。霍奇金淋巴瘤幸存者中的低剂量他莫昔芬，乳腺癌风险降低公共卫生相关性：霍奇金淋巴瘤（HL）的生存非常好，但是胸部放射疗法（RT）是治疗的基石，当年轻时患有HL的女性暴露于胸部RT时，患有20至55倍的乳腺癌患风险增加了。他莫昔芬将BC的风险降低了50％，但以一些不良的副作用为代价，而最近的研究表明，较低剂量的他莫昔芬可能同样有效地降低BC风险，而副作用较少。我们认为，以每天5毫克服用的他莫昔芬是对暴露于BC高风险的胸部RT的女性HL幸存者的理想非手术风险降低干预措施；因此，我们计划在IIB期临床试验中检验这一假设。