Resistance to Antiestrogen Therapy in Hormone Receptor-Positive Breast Cancer

激素受体阳性乳腺癌对抗雌激素治疗的耐药性

• 批准号: 7847493
• 负责人: Carlos L Arteaga
• 金额: $ 32.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7847493
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adjuvant; Antiestrogen Therapy; Aromatase Inhibitors; Biological Assay; Biological Markers; Breast Cancer Cell; Cancer cell line; Cell Proliferation; Clinical; Clinical Data; Clinical Trials; Data; Dependence; Disease; Drug resistance; ERBB2 gene; Endocrine; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen receptor positive; Estrogens; Exhibits; Formalin; Gene Expression Profile; Genes; HER2 inhibition; Hormonal; Hormone Receptor; Hormones; Immunohistochemistry; In complete remission; Inhibition of Cell Proliferation; Letrozole; Malignant Neoplasms; Mammary Neoplasms; Measures; Molecular; Molecular Profiling; Natural History; Neoadjuvant Therapy; PTEN gene; Pathologic; Pathway interactions; Patients; Pharmacodynamics; Proto-Oncogenes; Recurrence; Reproduction spores; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Specimen; Tamoxifen; Therapeutic; Treatment Failure; Tumor Tissue; Tyrosine Kinase Inhibitor; base; cancer cell; chemotherapy; deprivation; directed attention; gene discovery; hormone therapy; inhibitor/antagonist; lapatinib; malignant breast neoplasm; novel; overexpression; prospective; response; standard care; success; therapy design; tumor

The treatment for hormone receptor-positive breast cancer includes therapies designed to block estrogen action. Although these therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit ofe novo or acquired endocrine resistance. Studies with human breast cancer cell lines as well as molecular profiling of primary mammary tumors have identified molecular alterations associated with hormonal independence and drug resistance. One of these mechanisms is overexpression of the HER2 (ErbB2) protooncogene and its signaling network. Overexpression of HER2 is the only mechanism of antiestrogen resistance for which prospective clinical data exist. However, only <10% of hormone-dependent breast cancer express high levels of HER2, suggesting that for the majority of hormone-receptor positive breast cancers, mechanisms of escape from endocrine therapy remain to be discovered. In addition to the substantial improvements of antiestrogen therapy, assays have been developed to predict the odds of benefit from it. These assays do not identify the molecular alteration causally associated with treatment failure and tumor recurrence. More recently, cancer cell proliferation as measured by Ki67 immunohistochemistry in the tumor specimen after neoadjuvant hormonal therapy has been shown to correlate with disease-free and overall survival. These data suggest that pharmacodynamic biomarkers of the cellular and molecular effects of endocrine therapy in the breast tumor, likely because they incorporate the effects of therapy, can be used to identify cancers that are highly hormone-dependent and thus sensitive to endocrine treatment vs. those that are cfe novo resistant and/or destined to recur faster. We hypothesize that those tumors exhibiting a marked inhibition of cell proliferation are likely to do well on adjuvant hormonal therapy alone whereas those that do not, are destined to an early recurrence. To 1) determine if inhibition of HER2 function reverses resistance to endocrine therapy, and 2) discover novel mechanisms associated with resistance to endocrine therapy in hormone receptor-positive tumors without HER2 overexpression, we propose the following aims: Aim 1: To determine if combined neoadjuvant therapy with the aromatase inhibitor letrozole and the HER2 tyrosine kinase inhibitor lapatinib induces pathologic complete responses in hormone receptor-positive breast cancers that overexpress HER2 and establish biomarkers predictive of response to this therapy. Aim 2: To determine if the post-letrozole Ki67 in hormone receptor-positive/HER2-negative tumors mirrors the recurrence score as measured by RT-PCR of 21 selected genes in formalin-fixed tumor tissue sections and to use these biomarkers to discover gene expression signatures associated with hormonal dependence. Aim 3: To determine the mechanisms by which loss of PTEN in hormone receptor-positive breast cancer cells dysregulates phosphatidylinositol-3 kinase (PI3K) signaling and generates resistance to antiestrogens.

激素受体阳性乳腺癌的治疗包括阻断雌激素的治疗。 行动。尽管这些疗法改变了激素依赖型乳腺癌的自然病史， 许多肿瘤表现为新生或获得性内分泌抵抗。人乳腺癌细胞株的研究 以及对原发乳腺肿瘤的分子图谱分析，已经确定了与 具有荷尔蒙独立性和抗药性。这些机制之一是HER2的过度表达 (ERBB2)原癌基因及其信号网络。HER2的过度表达是HER2的唯一机制 存在预期临床数据的抗雌激素耐药性。然而，只有10%的激素依赖者 乳腺癌表达高水平的HER2，表明对于大多数激素受体阳性的人来说 乳腺癌，逃避内分泌治疗的机制仍有待发现。除 抗雌激素治疗的实质性改进，已经开发出预测 从中受益。这些检测并不能确定与治疗相关的分子改变。 失败和肿瘤复发。最近，Ki67测量了癌细胞的增殖 新辅助激素治疗后肿瘤标本中的免疫组织化学显示 与无病生存和总存活率相关。这些数据表明，药物动力学生物标记物 内分泌治疗在乳腺肿瘤中的细胞和分子效应，可能是因为它们包括 治疗的效果可以用来识别高度依赖激素的癌症，因此是敏感的。 内分泌治疗与CFE新耐药和/或注定复发更快的患者相比。我们假设 那些表现出明显抑制细胞增殖的肿瘤很可能在辅助性激素治疗中效果良好 单独进行治疗，而不进行治疗，注定会导致早期复发。以1)确定是否抑制 HER2功能逆转对内分泌治疗的抵抗，并2)发现与 激素受体阳性且无HER2过表达的肿瘤对内分泌治疗的抵抗 提出以下目标： 目的1：确定芳香化酶抑制剂来曲唑和HER2联合新辅助治疗 酪氨酸激酶抑制剂拉帕替尼诱导激素受体阳性患者的病理完全反应 过度表达HER2并建立生物标记物预测对该疗法的反应的乳腺癌。 目的2：确定来曲唑后Ki67在激素受体阳性/HER2阴性肿瘤中是否反映 应用RT-PCR检测福尔马林固定肿瘤组织切片中21个基因的复发分数 并使用这些生物标记物来发现与激素依赖相关的基因表达特征。 目的3：探讨激素受体阳性乳腺癌中PTEN基因缺失的机制 细胞调节磷脂酰肌醇-3激酶(PI3K)信号，并对抗雌激素产生抵抗。