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.

除了非黑色素瘤皮肤癌，乳腺癌是最常见的恶性肿瘤， 女性，全球每年约有170万例新诊断。在过去的几十年里， 然而，被诊断患有乳腺癌的妇女的5年生存率有了实质性的改善， 乳腺癌复发的长期风险仍然很高（在大约20年内为20-40%）。有一个 缺乏关于乳腺癌复发流行病学的信息，需要确定可改变的 患者和肿瘤特征影响乳腺癌复发的风险。绝经前妇女 被诊断为雌激素受体阳性的乳腺癌患者， 乳腺癌复发以前的研究表明，患者的依从性很低，但影响 尚未对绝经前妇女进行评估。对他莫昔芬治疗的抵抗可能来自于 雌激素相关代谢物的肿瘤内表达。预测他莫昔芬耐药的生物标志物 将确定适合额外治疗以防止复发的患者。这个项目的首要目标是 研究建议是评估生物标志物，患者特征和治疗相关因素， 解释辅助内分泌治疗在预防乳腺癌复发中的有效性变化。到 为了实现这一目标，该项目将利用丹麦医疗保健注册系统的资源，其中包括 几乎完整的高质量数据，包含有关乳腺癌复发的信息。目标1a将描述趋势 在过去35年中乳腺癌复发率和目标1b将估计人口水平的影响， 引入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 引入他莫昔芬、芳香酶抑制剂和曲妥珠单抗的人群水平因果效应 作为每种辅助治疗适应症指南的任何重大变化。这一目标将使用新的 发展趋势中趋势分析方法，以估计引进每一种技术对人口水平的影响 辅助治疗目标2将调查坚持内分泌治疗对乳腺癌的影响 仅在绝经前队列中复发。目的3评价两种酶17β- 羟基类固醇脱氢酶1和2，调节雌激素相关的肿瘤内浓度 代谢物作为他莫昔芬耐药的标志物在绝经前的队列中。结果是 建议的研究项目将深入了解乳腺癌复发的流行病学。而且 将导致更好地理解患者坚持辅助内分泌治疗对风险的影响， 以及肿瘤内雌激素相关代谢物浓度对复发的影响。 他莫昔芬耐药性，这可能导致新的治疗靶点的鉴定。