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：
8518048
负责人：
MELANIE R PALOMARES
金额：
$ 57.14万
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/8518048
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 history of 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 Relative (related person)Reporting Research Research Infrastructure Risk Risk Reduction Safety Sample Size 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 screening success young adult young woman

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

描述（由申请人提供）：霍奇金淋巴瘤幸存者中使用低剂量他莫昔芬可降低乳腺癌风险地幔放射一直是 HL 治疗的基石；然而，在 30 岁之前接受地幔照射治疗的 HL 女性幸存者，患乳腺癌 (BC) 的风险增加 20 至 55 倍，这一风险与 BRCA 突变携带者的风险相当。手术预防对于降低乳腺癌 (BC) 的风险非常有效。 BC 的风险，但这种侵入性策略并不适合所有女性。存在药物干预措施，但只有他莫昔芬被批准用于尚未绝经的年轻女性。标准剂量他莫昔芬（每天 20 毫克）与不良副作用相关，但最近的研究奠定了令人信服的基础，即较低剂量的他莫昔芬可能同样有效地降低 BC 风险，且副作用较少。我们假设，对于儿童期或年轻时诊断出的 HL 女性成年幸存者来说，较低剂量（每天 5 毫克）的他莫昔芬给药将是一种有效且安全的非手术风险降低干预措施。因此，通过对接受胸部放射治疗的长期女性 HL 幸存者进行低剂量他莫昔芬（每日 5 毫克）的 IIb 期随机、双盲、安慰剂对照试验，我们的目标是 1) 确定两种方案的影响：低剂量他莫昔芬对已确定的化学预防功效替代生物标志物的一年疗程； 2) 确定低剂量他莫昔芬在该人群中的安全性和耐受性；作为探索性目标，3) 检查与辐射相关 BC 风险相关的几个明确的人口和临床特征对本干预措施的风险：效益比的改变作用。提供知情同意书的合格受试者将被随机分配到每天 5 毫克的他莫昔芬组与安慰剂组，为期两年。结果将包括几个功效的替代生物标志物，包括乳房X线照相乳腺密度（MBD，主要终点）、乳腺细胞形态和增殖测量以及胰岛素生长因子。将使用患者报告的结果以及血脂谱、凝血因子和骨转换标志物作为客观终点，仔细跟踪受试者的安全性和耐受性。将检查的风险修正因素包括年龄、绝经状况、既往激素使用情况、体重指数、良性乳腺疾病个人史和癌症家族史，以及胸部辐射剂量、暴露年龄和胸部辐射潜伏期。每只手臂 127 个样本量将能够检测到低剂量他莫昔芬相对于安慰剂 80% 的功效使 MBD 降低 20%。我们已经在由五个机构组成的联盟中确定了超过 900 名潜在合格受试者，这些机构拥有完善的基础设施来长期跟踪儿童癌症幸存者，从而表明我们将拥有足够规模的池来吸引合格的患者群体并完成研究。在这项研究完成后，我们希望为患有 BC 高风险的 HL 幸存者找到一种耐受性良好的降低风险方案。霍奇金淋巴瘤幸存者使用低剂量他莫昔芬可降低乳腺癌风险