ER Reporter Genes To Predict Response To Endocrine Therapy

ER 报告基因预测内分泌治疗的反应

• 批准号: 7286829
• 负责人: William F Symmans
• 金额: $ 13.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-11 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7286829
• 关键词: Address; Adjuvant; Aromatase Inhibitors; Biological Assay; Breast Cancer Cell; Clinical; Complex; Cytotoxic Chemotherapy; Data Set; Diagnosis; Dissociation; Distant; ESR1 gene; Endocrine; Estrogen Receptor Modulators; Estrogen Receptors; Estrogen receptor positive; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Grant; Growth; Human; Immunohistochemistry; Measurement; Measures; Messenger RNA; Molecular; Molecular Profiling; Negative Axillary Lymph Node; Neoplasm Metastasis; Oncologist; Output; Pathway interactions; Patients; Population; Prospective Studies; Purpose; Rate; Reaction Time; Recurrence; Relapse; Relative (related person); Reporter; Reporter Genes; Role; Staging; Tamoxifen; Testing; Therapeutic Agents; Tissues; Transcript; Transcriptional Activation; Transcriptional Regulation; Week; Woman; base; concept; hormone therapy; indexing; malignant breast neoplasm; outcome forecast; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Estrogen receptor (ER) activity determines growth, survival, and differentiation in ER-positive breast cancer cells through transcriptional control of numerous genes. Although ER is an important therapeutic target, only 20% - 50% of women with metastatic breast cancer that is ER-positive by immunohistochemistry (IHC) will respond to ER-targeted endocrine therapies. We aim to develop a more accurate test than IHC to predict endocrine sensitivity in women with metastatic breast cancer that has recurred after a prior adjuvant or palliative endocrine therapy. We are calling this second-line endocrine therapy. Our hypothesis is that breast cancers with greatest expression and activity of ER are addicted to ER-dependent pathways and are most susceptible to an endocrine therapy, and so an assay that measures the output from ER-related transcription will predict response to endocrine therapy. To address this, we defined a multigene ER reporter index (Rl) from an independent public microarray dataset. Levels of ER mRNA (ESR1) from microarrays accurately diagnosed ER IHC status in FNAs or tissues. Measurements of ESR1 and Rl were reproducible. ESR1 and Rl were both independently related to distant relapse-free survival (DRFS) in women with ER-positive breast cancer who received adjuvant tamoxifen therapy. This association with DRFS was not seen in untreated, node-negative, ER-positive breast cancers, and so cannot be attributed to prognosis. We observed dissociation of the relationship between ER and its transcriptional output (Rl) in ER-positive breast cancers of advanced stage. ESR1 expression levels were similar, but Rl was lower with advancing stage. This may contribute to decreased sensitivity to endocrine therapy in ER-positive metastatic breast cancers. We propose to measure ESR1 and Rl expression values independently, and as a combined reporter index (CRI), in metastatic (stage IV) ER-positive breast cancer and compare those measurements with response to second-line endocrine therapy in general, and also in subsets of patients treated with an aromatase inhibitor or an estrogen receptor modulator. In the future, a more predictive test for endocrine sensitivity in relapsed ER-positive breast cancer would help oncologists to determine when to continue with a sequence of different endocrine therapies for metastatic breast cancer, and when to switch treatment to cytotoxic chemotherapy and/or other molecular therapies.

描述（由申请人提供）：雌激素受体（ER）活性通过众多基因的转录控制决定ER阳性乳腺癌细胞的生长、存活和分化。尽管 ER 是一个重要的治疗靶点，但免疫组织化学 (IHC) 检测结果呈 ER 阳性的转移性乳腺癌女性中，只有 20% - 50% 会对针对 ER 的内分泌治疗产生反应。我们的目标是开发一种比 IHC 更准确的测试，以预测在先前辅助或姑息内分泌治疗后复发的转移性乳腺癌女性的内分泌敏感性。我们称之为二线内分泌治疗。我们的假设是，ER 表达和活性最高的乳腺癌沉迷于 ER 依赖性途径，并且最容易受到内分泌治疗的影响，因此测量 ER 相关转录输出的测定将预测对内分泌治疗的反应。为了解决这个问题，我们从独立的公共微阵列数据集中定义了多基因 ER 报告指数 (Rl)。微阵列中的 ER mRNA (ESR1) 水平可准确诊断 FNA 或组织中的 ER IHC 状态。 ESR1 和 R1 的测量结果是可重复的。 ESR1 和 R1 均与接受他莫昔芬辅助治疗的 ER 阳性乳腺癌女性的远处无复发生存期 (DRFS) 独立相关。在未经治疗的淋巴结阴性、ER 阳性乳腺癌中未发现这种与 DRFS 的关联，因此不能归因于预后。我们观察到晚期 ER 阳性乳腺癌中 ER 与其转录输出 (R1) 之间关系的分离。 ESR1表达水平相似，但R1随着阶段进展而降低。这可能导致 ER 阳性转移性乳腺癌对内分泌治疗的敏感性降低。我们建议在转移性（IV 期）ER 阳性乳腺癌中独立测量 ESR1 和 Rl 表达值，并将其作为联合报告指数 (CRI)，并将这些测量值与一般二线内分泌治疗的反应进行比较，并且在使用芳香酶抑制剂或雌激素受体调节剂治疗的患者亚群。未来，对复发性 ER 阳性乳腺癌的内分泌敏感性进行更具预测性的测试将有助于肿瘤学家确定何时继续对转移性乳腺癌进行一系列不同的内分泌治疗，以及何时将治疗改为细胞毒性化疗和/或其他治疗分子疗法。