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: 7953937
• 负责人: MATTHEW J ELLIS
• 金额: $ 0.58万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953937
• 关键词: Address; Adjuvant Chemotherapy; Aftercare; Algorithms; Aromatase Inhibitors; Biological Markers; Biopsy; Breast Cancer Treatment; Breast-Conserving Surgery; Clinical; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Disease; Disease Resistance; Estrogen receptor positive; Estrogens; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Grant; In Situ; Institution; Investigation; Lead; Letrozole; Mass Spectrum Analysis; 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; biomedical resource; 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 芳香酶抑制剂比他莫昔芬更有效的新辅助内分泌疗法更有效，术前芳香酶抑制剂的治疗已成为一种无毒方法，可作为一种无毒的方法来改善雌激素后妇女患有雌激素受体阳性（ER+）肿瘤的外科手术结果，这些方法不符合乳腺癌的培训。这种临床环境为研究对芳香酶抑制剂疗法的反应性的分子基础打开了一个重要的机会，在可以反复访问原发性肿瘤以进行基因表达分析和预测性生物标志物分析的情况下。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与ER+，芳香酶抑制剂抗性疾病。调查计划：在多中心2期研究中，需要新辅助治疗的90例绝经后患有ER+乳腺癌患者需要新辅助治疗。治疗前将获得肿瘤活检，并进行Affymetrix Genechip分析。基于结构化因子回归模型和类成员预测算法的监督分析将用于搜索预测临床反应，放射学反应和治疗增殖的下降的基因表达谱。最预测基因的表达模式将通过原位mRNA杂交确认。治疗后的样本在一个月和手术时将用于进一步研究不对雌激素剥夺治疗反应的ER+肿瘤的性质。反应和非反应肿瘤之间基因表达谱变化的差异将为这一重要的临床问题提供分子基础的见解。长期目标：通过开发更有效的内分泌治疗方案来改善长期结局并降低老年人+乳腺癌患者的乳腺癌治疗的毒性。芳香酶抑制剂治疗的准确预测性生物标志物将允许：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）鉴定芳香酶抑制剂敏感性疾病的患者可以安全地避免使用辅助性，从而可以避免使用抗毒剂，从而逐步抗衡。