Biomarkers to Improve Targeting of Breast Cancer Prevention in Women with Atypical Hyperplasia

摘要 每年约有100，000名女性被诊断患有乳腺非典型增生（AH），这是一种良性的乳腺增生。 乳腺病变与随后患乳腺癌的风险增加四倍相关。使用 他莫昔芬作为AH诊断后的癌症预防治疗与超过50%的 降低随后的乳腺癌发病率。然而，服用他莫昔芬和类似的预防措施， 治疗仍然很低，部分原因是缺乏准确确定哪些女性最适合的方法。 乳腺癌（BC）的风险，以及哪些妇女将对预防治疗产生有益的反应。我们 提出一个高度转化的项目来解决这些关键障碍。我们将通过识别 良性乳腺组织中的分子特征，将1）改善患有乳腺癌的女性的个体化BC风险预测， AH，2）作为与预防治疗的有益反应相关的生物标志物，和3）允许 评估对预防治疗的个体化反应，即使是在短期治疗后。在 具体目标1，我们将为AH女性开发一种乳腺癌风险预测模型， 基于NanoString的基因表达测定与临床和组织学变量相结合;具体 目的2，我们将利用一个新开发的良性乳腺组织队列，以确定生物标志物，预测 对他莫昔芬的有益反应;在具体目标3中，我们将进行他莫昔芬的随机临床试验 与毒性较低的新型他莫昔芬代谢物相比。这项在AH女性中进行的试验将确定是否有益于 仅在治疗4周后就观察到对他莫昔芬的生物标记应答。我们提议的 研究将开发与AH女性直接相关的生物标志物，并实施 这些临床方法将对BC预防领域产生强有力和持续的影响。

ABSTRACT Approximately 100,000 women per year are diagnosed with atypical hyperplasia (AH) of the breast, a benign breast lesion that is associated with a fourfold increase in risk of subsequent breast cancer. Usage of tamoxifen as cancer prevention therapy following AH diagnosis has been linked to a greater than 50% reduction in subsequent breast cancer incidence. However, uptake of tamoxifen and similar prevention therapies remains low, due in part to a lack of methods to accurately determine which women are at greatest risk for breast cancer (BC), and which women will have a beneficial response to prevention therapy. We propose a highly translational project to address these critical barriers. We will accomplish this by identifying molecular features in benign breast tissue that will 1) improve individualized BC risk prediction for women with AH, 2) serve as biomarkers associated with beneficial response to prevention therapy, and 3) permit assessment of individualized response to prevention therapy, even after a short period of treatment. In Specific Aim 1, we will develop a breast cancer risk prediction model for women with AH that incorporates a NanoString-based gene expression assay in combination with clinical and histological variables; in Specific Aim 2, we will utilize a newly developed benign breast tissue cohort to identify biomarkers that predict beneficial response to tamoxifen; in Specific Aim 3, we will conduct a randomized clinical trial of tamoxifen versus a novel tamoxifen metabolite with less toxicity. This trial in women with AH will determine if beneficial biomarker responses to tamoxifen are observed after only four weeks of treatment. Together, our proposed studies will develop biomarkers that will have immediate relevance to women with AH, and implementation of these approaches in the clinic will have a powerful and sustained impact on the field of BC prevention.