Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance
Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance
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DOI：
10.1007/s10549-008-9897-4
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Richer, Jennifer K.
中科院分区：
文献类型：
--
作者：
Harvell, Djuana M. E.;Spoelstra, Nicole S.;Richer, Jennifer K.
大约30%的雌激素受体（ER）阳性乳腺癌患者表现出对内分泌治疗的新发或内在耐药。本研究的目的是在开始激素治疗之前，确定区分ER+抗性和ER+反应性肿瘤的基因。先前未经治疗的绝经后ER+乳腺癌患者在新辅助治疗环境中单独使用芳香酶抑制剂阿司美坦或与抗雌激素他莫昔芬联合治疗4个月。通过基因表达谱分析来自同一患者的匹配的治疗前和治疗后肿瘤样品，并将其与对治疗的反应相关联。通过雌激素阻断治疗实现的肿瘤缩小相关的基因被鉴定，与治疗抗性相关的基因也被鉴定。微阵列预测分析（PAM）确定了50个基因，可以预测ER+肿瘤的新辅助内分泌治疗的反应或内在抗性，其中8个先前已被认为是乳腺癌中有用的生物标志物。总之，我们确定了与内分泌治疗反应相关的基因，这些基因可以区分ER+、激素反应性乳腺癌和表现出内在或新生耐药的ER+肿瘤。我们认为，雌激素信号通路是异常的ER+肿瘤的内在阻力。最后，研究显示在无应答ER+肿瘤中"脂肪生成途径"的上调，其可作为内在抗性的标志物。该途径可能代表治疗干预的替代靶点。
Approximately 30% of patients with estrogen receptor (ER) positive breast cancers exhibit de novo or intrinsic resistance to endocrine therapies. The purpose of this study was to define genes that distinguish ER+ resistant from ER+ responsive tumors, prior to the start of hormone therapies. Previously untreated post-menopausal patients with ER+ breast cancers were treated for 4 months in a neoadjuvant setting with the aromatase inhibitor exemestane alone, or in combination with the antiestrogen tamoxifen. Matched pre- and post-treatment tumor samples from the same patient, were analyzed by gene expression profiling and were correlated with response to treatment. Genes associated with tumor shrinkage achieved by estrogen blockade therapy were identified, as were genes associated with resistance to treatment. Prediction Analysis of Microarrays (PAM) identified 50 genes that can predict response or intrinsic resistance to neoadjuvant endocrine therapy of ER+ tumors, 8 of which have been previously implicated as useful biomarkers in breast cancer. In summary, we identify genes associated with response to endocrine therapy that may distinguish ER+, hormone responsive breast cancers, from ER+ tumors that exhibit intrinsic or de novo resistance. We suggest that the estrogen signaling pathway is aberrant in ER+ tumors with intrinsic resistance. Lastly, the studies show upregulation of a "lipogenic pathway'' in non- responsive ER+ tumors that may serve as a marker of intrinsic resistance. This pathway may represent an alternative target for therapeutic intervention.