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

描述（由申请人提供）：低剂量他莫昔芬在霍奇金淋巴瘤幸存者中用于降低乳腺癌风险。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）的风险增加了20- 55倍，这一风险与BRCA突变携带者相当。手术预防在降低BC风险方面非常有效，但这种侵入性策略并不适用于所有女性。药物干预是存在的，但只有他莫昔芬被批准用于尚未绝经的年轻女性。标准剂量的他莫昔芬（每天20毫克）与不良副作用有关，但最近的研究已经奠定了令人信服的基础，即低剂量的他莫昔芬在降低BC风险方面可能同样有效，副作用更少。我们假设，低剂量的他莫昔芬（每天5mg）对于儿童期或青年期诊断为HL的成年女性幸存者来说，是一种既有效又安全的非手术风险降低干预措施。因此，我们采用IIb期随机、双盲、安慰剂对照试验，对长期接受胸部放疗的女性HL幸存者进行低剂量他莫昔芬（每天5mg）治疗，目的是：1)确定2年低剂量他莫昔芬疗程对化学预防疗效替代生物标志物的影响；2)确定低剂量他莫昔芬在该人群中的安全性和耐受性；并且，作为探索性目的，3)检查与辐射相关BC风险相关的几个明确定义的人口统计学和临床特征对该干预的风险：收益比的修改作用。提供知情同意的符合条件的受试者将随机分为每天5mg的他莫昔芬和安慰剂，为期两年。结果将包括几种替代疗效的生物标志物，包括乳房x线摄影乳腺密度（MBD，主要终点），乳腺细胞形态学和增殖测量，以及胰岛素生长因子。将使用患者报告的结果、脂质谱、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。将检查的危险修饰因素包括年龄、绝经状态、先前使用激素、体重指数、个人良性乳房疾病史和癌症家族史，以及胸部辐射剂量、暴露年龄和胸部辐射潜伏期。每组127人的样本量将能够检测到低剂量他莫昔芬相对于安慰剂减少20%的MBD，功率为80%。我们已经在我们的五家机构联盟中确定了900多名潜在的符合条件的受试者，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，从而表明我们将有足够的规模来吸引符合条件的患者人群并完成研究。在这项研究完成后，我们希望为发展为BC的高风险HL幸存者确定一种耐受性良好的风险降低选择。低剂量他莫昔芬用于霍奇金淋巴瘤幸存者降低乳腺癌风险

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.