ER Reporter Genes To Predict Response To Endocrine Therapy

描述（由申请人提供）：雌激素受体（ER）活性通过转录控制许多基因决定ER阳性乳腺癌细胞的生长、存活和分化。虽然ER是一个重要的治疗靶点，但只有20% - 50%的转移性乳腺癌患者（免疫组织化学（IHC）显示ER阳性）对ER靶向内分泌治疗有反应。我们的目标是开发一种比IHC更准确的检测方法，以预测在既往辅助或姑息性内分泌治疗后复发的转移性乳腺癌患者的内分泌敏感性。我们称之为二线内分泌治疗。我们的假设是，具有最大ER表达和活性的乳腺癌对ER依赖性途径成瘾，并且对内分泌治疗最敏感，因此测量ER相关转录的输出的测定将预测对内分泌治疗的响应。为了解决这一问题，我们从独立的公共微阵列数据集定义了多基因ER报告指数（RI）。来自微阵列的ER mRNA（ESR 1）水平准确地诊断FNA或组织中的ER IHC状态。ESR 1和R1的测量是可再现的。ESR 1和R1均与接受他莫昔芬辅助治疗的ER阳性乳腺癌妇女的无远处复发生存期（DRFS）独立相关。这种与DRFS的相关性在未经治疗的、淋巴结阴性的、ER阳性的乳腺癌中未见，因此不能归因于预后。我们观察到在ER阳性的晚期乳腺癌中ER与其转录产物（RI）之间的关系分离。ESR 1表达水平相似，但R1随着分期的进展而降低。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。我们提出在转移性（IV期）ER阳性乳腺癌中独立地测量ESR 1和R1表达值，并作为组合报告指数（CRI），并将这些测量结果与对一般二线内分泌疗法的响应进行比较，并且还在用芳香酶抑制剂或雌激素受体调节剂治疗的患者亚组中进行比较。在未来，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，以及何时将治疗转换为细胞毒性化疗和/或其他分子治疗。

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.