NOVEL BIOMARKERS FOR AROMATASE INHIBITOR THERAPY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 芳香化酶抑制剂是比他莫昔芬更有效的新辅助内分泌治疗，术前芳香化酶抑制剂治疗作为一种无毒的方法正在获得接受，以改善不适合保乳手术的雌激素受体阳性（ER+）肿瘤的绝经后老年妇女的手术结果。这种临床环境为研究在原发性肿瘤可以重复进行基因表达谱分析和预测性生物标志物分析的情况下对芳香酶抑制剂治疗的反应性的分子基础提供了重要机会。假设：基因表达谱可以区分ER+阳性、芳香化酶抑制剂敏感的乳腺癌与ER+、芳香化酶抑制剂抗性疾病。调查计划：在一项多中心II期研究中，90例需要新辅助治疗的ER+乳腺癌绝经后患者将在术前4个月接受来曲唑治疗。将在治疗前获得肿瘤活组织检查，并进行Affyssin基因芯片分析。基于结构化因子回归建模和类别成员预测算法的监督分析将用于搜索预测临床反应、放射学反应和治疗后增殖下降的基因表达谱。最具预测性基因的表达模式将通过原位mRNA杂交来确认。在一个月和手术时采集的治疗后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。反应性和非反应性肿瘤之间基因表达谱变化的差异将为这一重要临床问题的分子基础提供深入了解。长期目标：通过开发更有效的内分泌治疗方案，改善ER+乳腺癌老年患者的长期结局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）鉴定患有芳香酶抑制剂敏感性疾病的患者，其中辅助化疗可以安全地避免，以及c）导致对芳香酶抑制剂耐药性的了解，其可以通过未来的临床试验来解决。

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.