Biologic and Patient Variation Affecting Breast Cancer Treatment Efficacy

除非黑色素瘤皮肤癌外，乳腺癌是 妇女，全世界每年约有170万新诊断病例。在过去的几十年里，有 然而，被诊断为乳腺癌的女性的5年存活率有了实质性的改善 乳腺癌复发的长期风险仍然很高(大约20年内有20%-40%)。有一个 缺乏有关乳腺癌复发的流行病学信息，需要确定可修改的 影响乳腺癌复发风险的患者和肿瘤特征。绝经前妇女 被诊断为雌激素受体阳性的乳腺癌患者服用他莫昔芬长达十年以预防 乳腺癌复发。之前的研究表明，患者的依从性很低，但 绝经前妇女尚未接受评估。对他莫昔芬治疗的耐药性可能是由于 雌激素相关代谢物在肿瘤内的表达。预测他莫昔芬耐药性的生物标志物 将确定患者是否愿意接受额外的治疗以防止复发。这件事的首要目标是 研究建议是评估生物标记物、患者特征和治疗相关因素，以帮助 解释辅助内分泌治疗在预防乳腺癌复发方面的效果差异。至 为了实现这一目标，该项目将利用丹麦医疗登记系统的资源，该系统包括 几乎完整的关于乳腺癌复发信息的高质量数据。目标1a将描述趋势 在过去35年的乳腺癌复发和目标1b将评估人群水平的影响 介绍三种生物标志物驱动的辅助治疗--他莫昔芬、芳香酶抑制剂和曲妥珠单抗-- 使用丹麦癌症登记处的汇总水平数据对乳腺癌复发风险进行评估。这些目标将 使用泊松回归描述乳腺癌复发随时间的趋势，并将估计 他莫昔芬、芳香酶抑制剂和曲妥珠单抗的引入对人群水平的因果影响 如指南对每种辅助治疗的适应症有任何重大变化。这一目标将使用新的 制定趋势中趋势分析方法，以估计引入每一项措施对人口水平的影响 辅助治疗。目的2将研究坚持内分泌治疗对乳腺癌的影响 仅在绝经前队列中复发。AIM 3将评估两种酶17β- 调节雌激素相关肿瘤内浓度的羟基类固醇脱氢酶1和2 代谢产物作为他莫昔芬抵抗标记物在绝经前队列中的应用。由此产生的结果是 拟议的研究项目将为乳腺癌复发的流行病学提供洞察力。此外，它还 将有助于更好地理解患者坚持辅助内分泌治疗对风险的影响 复发的可能性以及肿瘤内雌激素相关代谢物浓度对 他莫昔芬耐药性，这可能导致识别新的治疗靶点。

Aside from non-melanoma skin cancer, breast carcinoma is the most commonly diagnosed malignancy among women, with approximately 1.7 million new diagnoses annually worldwide. Over the past decades there have been substantial improvements in the 5-year survival rates for women diagnosed with breast cancer, however the long-term risk of breast cancer recurrence remains high (20–40% over approximately 20 years). There is a dearth of information regarding the epidemiology of breast cancer recurrence, and a need to identify modifiable patient and tumor characteristics that affect the risk of breast cancer recurrence. Premenopausal women diagnosed with estrogen receptor positive breast cancer are prescribed tamoxifen for up to ten years to prevent breast cancer recurrence. Previous studies suggest that patient adherence is low, yet the impact among premenopausal women has not yet been evaluated. Resistance to tamoxifen therapy may arise from increased intratumoral expression of estrogen-related metabolites. Biomarkers that are predictive of tamoxifen resistance would identify patients amenable to additional therapies to prevent recurrence. The overarching goal of this research proposal is to evaluate biomarkers, patient characteristics, and treatment-related factors that help explain the variation in effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence. To address this goal, this project will leverage resources from the Danish healthcare registry system, which includes nearly complete high-quality data with information on breast cancer recurrence. Aim 1a will describe the trends in breast cancer recurrence over the past 35 years and aim 1b will estimate the population-level effect of the introduction of three biomarker-driven adjuvant therapies—tamoxifen, aromatase inhibitors, and trastuzumab— on breast cancer recurrence risk using summary level data from the Danish Cancer Registry. These aims will describe the trends in breast cancer recurrence over time, using Poisson regression and will estimate the population-level causal effect of the introductions of tamoxifen, aromatase inhibitors, and trastuzumab as well as any major changes in guidelines to the indication for each adjuvant therapy. This aim will use the newly developed trend-in-trend analytic method to estimate the population-level impact of the introduction of each adjuvant therapy. Aim 2 will investigate the impact of adherence to endocrine therapy on breast cancer recurrence in an exclusively premenopausal cohort. Aim 3 will evaluate the effect of two enzymes, 17β- hydroxysteroid dehydrogenase 1 and 2, that regulate the intratumoral concentration of estrogen-related metabolites as markers of tamoxifen resistance in an exclusively premenopausal cohort. The results from this proposed research project will provide insight into the epidemiology of breast cancer recurrence. Furthermore, it will lead to improved understanding of the effect of patient adherence to adjuvant endocrine therapy on the risk of recurrence as well as the contribution of intratumoral concentrations of estrogen-related metabolites on tamoxifen resistance, which may lead to identification of new therapeutic targets.