Novel Biomarkers for Aromatase Inhibitor Therapy

描述(由申请人提供)： 背景：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被认为是一种无毒的方法，可以改善患有雌激素受体阳性(ER+)肿瘤的老年妇女的手术结果，这些妇女不符合保乳手术的条件。这一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机会，在这种情况下，原发肿瘤可以被重复获取以进行基因表达谱分析和预测性生物标记物分析。 假设：基因表达谱可以区分ER+阳性、芳香酶抑制剂敏感的乳腺癌和ER+、芳香酶抑制剂耐药的疾病。 研究计划：在一项多中心第二阶段研究中，90名需要新辅助治疗的绝经后ER+乳腺癌患者将在手术前4个月接受来曲唑治疗。肿瘤活检将在治疗前获得，并接受Affymetrix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、放射反应和治疗后增殖下降的基因表达谱。最具预测性的基因的表达模式将通过原位mRNA杂交得到确认。治疗后一个月和手术时采集的样本将用于进一步调查雌激素剥夺治疗无效的ER+肿瘤的性质。有反应和无反应的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洞察。 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疗效并减少其毒性。芳香酶抑制剂治疗的准确预测生物标志物将允许：a)更多地使用新辅助内分泌治疗作为一种改善手术结果的无毒手段，b)确定芳香酶抑制剂敏感疾病患者可以安全地避免辅助化疗，以及c)深入了解芳香酶抑制剂耐药性，可通过未来的临床试验解决。

DESCRIPTION (provided by applicant): Background: 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.