BACKGROUND Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance. METHODS Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67. RESULTS High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2- tumours. In HER2- tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) including PERP and YWHAQ, the two most significant, and the transcription co-regulators (SAP130, HDAC4, and NCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, and IGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2- and HER2+ patients. CONCLUSIONS There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors. TRIAL REGISTRATION ISRCTN, ISRCTN63882543, registered on 18 December 2007.

中文翻译：

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芳香酶抑制剂治疗对绝经后患者ER +乳腺癌中整体基因表达的影响及其与抗增殖反应的关系。

背景技术内分泌疗法可将乳腺癌死亡率降低40％，但耐药性仍然是主要的临床问题。在这项研究中，我们试图研究芳香化酶抑制剂（AI）治疗对基因表达的影响，并确定代表与早期AI治疗耐药相关的关键生物学途径的基因模块。方法对基线和手术时从254例ER阳性原发性乳腺癌患者中随机分组接受2周术前AI（n = 198）或不接受术前治疗（对照n = 56）。调整了AI组的数据，以消除对照组中确定的与人工过程相关的变化。通过增殖标志物Ki67的变化评估反应。结果较高的基线ESR1表达与HER2 +肿瘤而非HER2-肿瘤中更好的AI反应有关。在HER2肿瘤中，与抗增殖反应不良（p <0.005）相关的48个基因的基线表达，包括两个最重要的PERP和YWHAQ，以及转录共调节子（SAP130，HDAC4和NCOA7），它们排在前16位最重要的。在较差的AI应答者中，测量细胞增殖，生长因子信号传导（ERBB2-GS，RET / GDNF-GS和IGF-1-GS）和免疫活性（STAT1-GS）的基线基因特征评分显着更高。如预期的那样，两周的AI导致参与细胞增殖和ER信号转导的基因下调。2周AI后E2F激活和TP53功能障碍的特征评分与HER2-和HER2 +患者的AI反应差有关。结论短短2周的AI治疗后，适应性机制存在高度异质性。但是，所有这些似乎都集中在细胞周期调控上。我们的数据支持对AI短期暴露后E2F签名是否可以识别出最有可能从早期添加CDK4 / 6抑制剂中受益的患者的评估。试用注册号为ISRCTN，ISRCTN63882543，于2007年12月18日注册。