ER Reporter Genes To Predict Response To Endocrine Therapy

描述（由申请人提供）：雌激素受体（ER）活性通过许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。虽然雌激素受体是一个重要的治疗靶点，但只有20% - 50%的经免疫组化（IHC）检测为雌激素受体阳性的转移性乳腺癌患者对雌激素受体靶向内分泌治疗有反应。我们的目标是开发一种比免疫组化更准确的检测方法来预测先前辅助或姑息性内分泌治疗后复发的转移性乳腺癌妇女的内分泌敏感性。我们称之为二线内分泌治疗。我们的假设是，雌激素受体表达和活性最高的乳腺癌依赖于雌激素受体依赖途径，最容易受到内分泌治疗的影响，因此，测量雌激素受体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，我们从一个独立的公共微阵列数据集定义了一个多基因ER报告索引（Rl）。来自微阵列的ER mRNA （ESR1）水平可准确诊断FNAs或组织中的ER IHC状态。ESR1和Rl的测量结果具有重复性。在接受他莫昔芬辅助治疗的er阳性乳腺癌患者中，ESR1和Rl均与远端无复发生存（DRFS）独立相关。在未经治疗、淋巴结阴性、er阳性的乳腺癌中未见与DRFS的这种关联，因此不能归因于预后。我们观察到雌激素受体阳性晚期乳腺癌中雌激素受体与其转录输出（Rl）之间的关系分离。ESR1表达水平相似，但Rl随分期的进展而降低。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。我们建议在转移性（IV期）er阳性乳腺癌中单独测量ESR1和Rl的表达值，并将其作为联合报告因子指数（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，也与接受芳香酶抑制剂或雌激素受体调节剂治疗的患者亚群进行比较。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，以及何时改用细胞毒性化疗和/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.