Biologic and Patient Variation Affecting Breast Cancer Treatment Efficacy

影响乳腺癌治疗效果的生物学和患者变异

• 批准号: 9760646
• 负责人: Lindsay Jane Collin
• 金额: $ 4.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-08 至 2021-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760646
• 关键词: Accounting; Address; Adherence; Adjuvant; Adjuvant Therapy; Affect; Age; Aromatase Inhibitors; Behavioral; Biological; Biological Assay; Biological Markers; Breast Cancer Epidemiology; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer survivor; Breast Carcinoma; Cancer Cell Growth; Characteristics; Clinical Trials; Data; Data Quality; Denmark; Diagnosis; Disease; Drug resistance; Effectiveness; Enzymes; Estradiol; Estrogen Metabolism; Estrogen Receptor alpha; Estrogen receptor positive; Estrogens; Estrone; Exposure to; Goals; Guidelines; Healthcare; Hydroxysteroid Dehydrogenases; Individual; Lead; Malignant Neoplasms; Measures; Metabolic Pathway; Methodology; Molecular; Nature; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacoepidemiology; Population; Population-Based Registry; Premenopause; Prognostic Marker; Protocols documentation; Radiation therapy; Recurrence; Registries; Research Project Grants; Research Proposals; Resistance; Resources; Risk; Sampling; Skin Carcinoma; Survival Rate; System; Tamoxifen; Therapeutic; Time; Time trend; Trastuzumab; Treatment Efficacy; Tumor Biology; Tumor Markers; Variant; Woman; alternative treatment; analytical method; base; biomarker-driven; breast cancer diagnosis; cancer recurrence; chemotherapy; cohort; compliance behavior; epidemiology study; follow-up; high risk; hormone therapy; improved; improved outcome; insight; interest; malignant breast neoplasm; mortality; neoplasm registry; new therapeutic target; outcome forecast; patient variability; population based; precision medicine; predictive marker; prevent; social; survivorship; therapeutic target; time use; treatment duration; trend; tumor; tumor growth

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.

除非黑色素瘤皮肤癌外，乳腺癌是最常见的恶性肿瘤 女性，全球每年约有 170 万新诊断病例。过去几十年来有 然而，被诊断患有乳腺癌的女性的 5 年生存率有了显着提高 乳腺癌复发的长期风险仍然很高（大约 20 年复发 20-40%）。有一个 缺乏有关乳腺癌复发流行病学的信息，需要确定可修改的方法 影响乳腺癌复发风险的患者和肿瘤特征。绝经前女性 被诊断患有雌激素受体阳性乳腺癌的患者会服用他莫昔芬长达十年，以预防 乳腺癌复发。先前的研究表明，患者依从性较低，但对患者的影响 尚未对绝经前妇女进行评估。对他莫昔芬治疗的抵抗可能是由于增加 雌激素相关代谢物的瘤内表达。预测他莫昔芬耐药性的生物标志物 将确定适合接受额外治疗以防止复发的患者。本次活动的总体目标是 研究计划是评估生物标志物、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有效性差异。到 为了实现这一目标，该项目将利用丹麦医疗保健登记系统的资源，其中包括 几乎完整的高质量数据，其中包含有关乳腺癌复发的信息。目标 1a 将描述趋势 过去 35 年乳腺癌复发率，目标 1b 将估计乳腺癌在人群层面的影响 引入三种生物标志物驱动的辅助疗法——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数据来评估乳腺癌复发风险。这些目标将 使用泊松回归描述乳腺癌随时间复发的趋势，并估计 他莫昔芬、芳香酶抑制剂和曲妥珠单抗的引入在人群水平上的因果效应 每种辅助治疗适应症指南的任何重大变化。该目标将使用新的 开发了趋势分析方法来估计每种技术的引入对人口水平的影响 辅助治疗。目标 2 将调查坚持内分泌治疗对乳腺癌的影响 完全绝经前队列中的复发。目标 3 将评估两种酶 17β- 的效果 羟基类固醇脱氢酶 1 和 2，调节雌激素相关的瘤内浓度 代谢物作为绝经前队列中他莫昔芬耐药性的标志物。由此得出的结果 拟议的研究项目将深入了解乳腺癌复发的流行病学。此外，它 将有助于更好地了解患者坚持辅助内分泌治疗对风险的影响 复发以及雌激素相关代谢物的瘤内浓度对肿瘤的影响 他莫昔芬耐药性，这可能导致新的治疗靶点的确定。