Endocrine therapy is important for management of patients with estrogen receptor (ER)–positive breast cancer; however, positive ER staining does not reliably predict therapy response. We assessed the potential to improve prediction of response to endocrine treatment of a novel test that quantifies functional ER pathway activity from mRNA levels of ER pathway–specific target genes. ER pathway activity was assessed on datasets from three neoadjuvant-treated ER-positive breast cancer patient cohorts: Edinburgh: 3-month letrozole, 55 pre-/2-week/posttreatment matched samples; TEAM IIa: 3- to 6-month exemestane, 49 pre-/28 posttreatment paired samples; and NEWEST: 16-week fulvestrant, 39 pretreatment samples. ER target gene mRNA levels were measured in fresh-frozen tissue (Edinburgh, NEWEST) with Affymetrix microarrays, and in formalin-fixed paraffin-embedded samples (TEAM IIa) with qRT-PCR. Approximately one third of ER-positive patients had a functionally inactive ER pathway activity score (ERPAS), which was associated with a nonresponding status. Quantitative ERPAS decreased significantly upon therapy (P < 0.001 Edinburgh and TEAM IIa). Responders had a higher pretreatment ERPAS and a larger 2-week decrease in activity (P = 0.02 Edinburgh). Progressive disease was associated with low baseline ERPAS (P = 0.03 TEAM IIa; P = 0.02 NEWEST), which did not decrease further during treatment (P = 0.003 TEAM IIa). In contrast, the staining-based ER Allred score was not significantly associated with therapy response (P = 0.2). The ERPAS identified a subgroup of ER-positive patients with a functionally inactive ER pathway associated with primary endocrine resistance. Results confirm the potential of measuring functional ER pathway activity to improve prediction of response and resistance to endocrine therapy.

中文翻译：

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雌激素受体通路活性评分预测原发性乳腺癌新辅助内分泌治疗的临床反应或耐药性

内分泌治疗对于雌激素受体 (ER) 阳性乳腺癌患者的管理很重要；然而，阳性 ER 染色不能可靠地预测治疗反应。我们评估了改进对内分泌治疗反应预测的潜力，该测试从 ER 通路特异性靶基因的 mRNA 水平量化功能性 ER 通路活性。在来自三个新辅助治疗的 ER 阳性乳腺癌患者队列的数据集上评估了 ER 通路活性：爱丁堡：3 个月来曲唑，55 个治疗前/2 周/后匹配样本；TEAM IIa：3 至 6 个月依西美坦，49 个治疗前/28 个治疗后配对样本；最新：16 周氟维司群，39 个预处理样品。用 Affymetrix 微阵列在新鲜冷冻组织（爱丁堡，最新）中测量内质网靶基因 mRNA 水平，并在福尔马林固定的石蜡包埋样品 (TEAM IIa) 中使用 qRT-PCR。大约三分之一的 ER 阳性患者具有功能失活的 ER 通路活动评分 (ERPAS)，这与无反应状态有关。定量 ERPAS 在治疗后显着下降（P < 0.001 Edinburgh 和 TEAM IIa）。应答者的治疗前 ERPAS 较高，且 2 周内活动减少幅度较大（P = 0.02 Edinburgh）。疾病进展与低基线 ERPAS 相关（P = 0.03 TEAM IIa；P = 0.02 NEWEST），在治疗期间没有进一步降低（P = 0.003 TEAM IIa）。相比之下，基于染色的 ER Allred 评分与治疗反应没有显着相关性（P = 0.2）。ERPAS 确定了一个 ER 阳性患者亚组，其功能失活的 ER 通路与原发性内分泌抵抗相关。