Authors' Affiliations: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research; Academic Department of Biochemistry, Royal Marsden Foundation Trust, London, United Kingdom; and Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Clin Cancer Res. 2014 May 1;20(9):2485-94. doi: 10.1158/1078-0432.CCR-13-2602. Epub 2014 Mar 14.
To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor-positive (ER(+)) breast cancer.
Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER(+) early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67.
Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI.
Multiple processes and pathways are affected by AI treatment in ER(+) breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs.
研究代表关键生物学过程的基因模块与芳香化酶抑制剂（AI）在雌激素受体阳性（ER(+)）乳腺癌患者中的反应之间的潜在关联。
在术前环境中，从 69 名绝经后 ER(+)早期乳腺癌女性中获得了配对的基因表达和 Ki67 蛋白表达数据，这些患者在基线和阿那曲唑治疗后 2 周时接受了治疗。从已发表的研究中提取了功能基因模块（n = 26），并在消除增殖相关基因（PAG）前后计算了它们的模块评分。在阿那曲唑治疗前和治疗后 2 周评估 Ki67 和模块评分。使用无监督聚类评估模块与 Ki67 之间的关联。
基于增殖的模块与 Ki67 表达在治疗前和治疗过程中均高度相关。在基线时无论是否有 PAG，Ki67 表达与 ERG、ESR1.2、SET 和 PIK3CA 模块均呈显著负相关。测量雌激素信号的模块强烈预测了有或无 PAG 的治疗对增殖的抑制作用。胰岛素样生长因子-1（IGF-I）模块的基线表达预示着该模块内的 Ki67 相关基因发生新的耐药，这与对 AI 的耐药有关。治疗前高表达免疫.2.STAT1 模块预示着对治疗的增殖抑制反应不良。在 AI 治疗后，雌激素调节基因模块（ESR1、ESR1-2、SET 和 ERG）之间存在显著关联。
在 ER(+)乳腺癌中，多种过程和途径受到 AI 治疗的影响。与 ESR1 表达密切相关的模块可预测对 AI 的良好增殖抑制反应，但代表免疫活性和 IGF-I/MAPK 的模块可预测 Ki67 反应不良，支持将其与 AI 联合治疗作为治疗靶点。
