NOVEL BIOMARKERS FOR AROMATASE INHIBITOR THERAPY

用于芳香酶抑制剂治疗的新型生物标志物

• 批准号: 7721520
• 负责人: MATTHEW J ELLIS
• 金额: $ 0.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721520
• 关键词: Address; Adjuvant Chemotherapy; Algorithms; Aromatase Inhibitors; Biological Markers; Biopsy; Breast Cancer Treatment; Breast-Conserving Surgery; Class; Clinical; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Disease; Disease Resistance; Disease regression; Estrogen receptor positive; Estrogens; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Grant; In Situ; Institution; Investigation; Lead; Letrozole; Messenger RNA; Modeling; Molecular; Molecular Profiling; Nature; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; Patients; Pattern; Phase II Clinical Trials; Postmenopause; Primary Neoplasm; Research; Research Personnel; Resistance; Resources; Sampling; Source; Structure; Tamoxifen; Toxic effect; Treatment Protocols; United States National Institutes of Health; Woman; base; deprivation; hormone therapy; improved; insight; malignant breast neoplasm; novel; older patient; response; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aromatase inhibitors are more effective neoadjuvant endocrine therapy than tamoxifen and preoperative aromatase inhibitor treatment is gaining acceptance as a non-toxic approach to improving surgical outcomes in older postmenopausal women with estrogen receptor positive (ER+) tumors who are not eligible for breast conserving surgery. This clinical setting opens a significant opportunity to investigate the molecular basis for responsiveness to aromatase inhibitor therapy in a situation where the primary tumor can be repeatedly accessed for gene expression profiling and predictive biomarker analysis. Hypothesis: Gene expression profiling can distinguish between ER+ positive, aromatase inhibitor sensitive breast cancer from ER+, aromatase inhibitor resistant disease. Plan of investigation: Ninety postmenopausal patients with ER+ breast cancer requiring neoadjuvant treatment will receive four months preoperative letrozole in a multi-center Phase 2 study. Tumor biopsies will be obtained before treatment and subjected to Affymetrix GeneChip analysis. Supervised analyses, based on structured factor regression modeling and class membership predictor algorithms, will be used to search for gene expression profiles that predict clinical response, radiological response and a decline in proliferation with treatment. The expression patterns of the most predictive genes will be confirmed by in situ mRNA hybridization. Post-treatment samples taken at one month and at surgery will be used to further investigate the nature of ER+ tumors that do not respond to estrogen deprivation treatment. Differences in the changes in gene expression profiles between responding and non-responding tumors will provide insight into the molecular basis for this important clinical problem. Long-term objectives: To improve long-term outcomes and reduce the toxicity of breast cancer treatment in older patients with ER+ breast cancer by developing more effective endocrine therapy regimens. Accurate predictive biomarkers for aromatase inhibitor therapy would allow: a) increased use of neoadjuvant endocrine therapy as a non-toxic means to improve surgical outcomes, b) the identification of patients with aromatase inhibitor-sensitive disease in whom adjuvant chemotherapy can be safely avoided and c) lead to insights into aromatase inhibitor resistance that can be addressed by future clinical trials.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 芳香酶抑制剂是比他莫昔芬更有效的新辅助内分泌治疗，术前芳香酶抑制剂治疗作为一种无毒方法正在获得认可，可以改善患有雌激素受体阳性 (ER+) 肿瘤且不适合保乳手术的老年绝经后女性的手术结果。这种临床环境为研究芳香酶抑制剂治疗反应的分子基础提供了一个重要的机会，在这种情况下，可以重复访问原发肿瘤以进行基因表达谱和预测性生物标志物分析。假设：基因表达谱分析可以区分 ER+ 阳性、芳香酶抑制剂敏感乳腺癌和 ER+、芳香酶抑制剂耐药性疾病。研究计划：在一项多中心 2 期研究中，90 名需要新辅助治疗的绝经后 ER+ 乳腺癌患者将在术前四个月接受来曲唑治疗。在治疗前获得肿瘤活检并进行 Affymetrix 基因芯片分析。基于结构化因子回归模型和类别成员预测算法的监督分析将用于搜索基因表达谱，以预测临床反应、放射学反应和治疗后增殖的下降。最有预测性的基因的表达模式将通过原位 mRNA 杂交来确认。治疗后一个月和手术时采集的样本将用于进一步研究对雌激素剥夺治疗无反应的 ER+ 肿瘤的性质。有反应和无反应肿瘤之间基因表达谱变化的差异将为深入了解这一重要临床问题的分子基础提供依据。长期目标：通过开发更有效的内分泌治疗方案，改善老年 ER+ 乳腺癌患者的长期结果并降低乳腺癌治疗的毒性。芳香酶抑制剂治疗的准确预测生物标志物将允许：a）增加使用新辅助内分泌治疗作为改善手术结果的无毒手段，b）识别可以安全避免辅助化疗的芳香酶抑制剂敏感疾病患者，c）深入了解芳香酶抑制剂耐药性，可以通过未来的临床试验来解决。