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: 7147737
• 负责人: William F Symmans
• 金额: $ 16.97万
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147737
• 关键词: breast neoplasms; clinical research; reporter genes

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）活性通过对许多基因的转录控制来决定ER阳性乳腺癌细胞中的生长，存活和分化。尽管ER是一个重要的治疗靶点，但只有20％至50％的转移性乳腺癌女性因免疫组织化学（IHC）而呈ER阳性，这将对靶向ER靶向的内分泌疗法反应。我们旨在制定比IHC更准确的测试，以预测在先前的辅助或姑息性内分泌治疗后复发的转移性乳腺癌女性内分泌敏感性。我们称这种二线内分泌疗法。我们的假设是，ER表达最大和活性的乳腺癌对ER依赖性途径上瘾，并且最容易受到内分泌治疗的影响，因此，一种测量与ER相关转录的输出的测定法可以预测对内分泌治疗的反应。为了解决这个问题，我们定义了一个独立的公共微阵列数据集中的多基因ER记者索引（RL）。微阵列中的ER mRNA（ESR1）水平准确地诊断为FNA或组织中的ER IHC状态。 ESR1和RL的测量值可再现。 ESR1和RL均与接受辅助性他莫昔芬治疗的ER阳性乳腺癌女性中的无遥远无复发生存期（DRF）独立相关。这种与DRF的关联在未处理的，节点阴性的，ER阳性的乳腺癌中没有看到，因此不能归因于预后。我们观察到ER及其转录输出（RL）之间的关系分离，在ER阳性乳腺癌的晚期乳腺癌中。 ESR1表达水平相似，但是随着前进阶段的RL较低。这可能导致对ER阳性转移性乳腺癌中内分泌疗法的敏感性降低。我们建议在转移（IV期）ER阳性乳腺癌中独立测量ESR1和RL表达值，并作为一个组合的报告基因指数（CRI）（CRI），并将这些测量与对二线内分泌治疗的反应进行比较，以及在与二线内分泌治疗的反应中，以及与芳香族酶抑制剂或雌激素抑制剂或雌激素受体调节器的子群中的测量。将来，对复发性ER阳性乳腺癌中内分泌敏感性的更为预测性测试将有助于肿瘤学家确定何时继续进行转移性乳腺癌的不同内分泌疗法，以及何时将治疗切换为细胞毒性化学疗法和/或其他分子疗法。