高的 AR:ERα 或 PDEF:ERα 比值预示着 ERα 阳性乳腺癌对他莫昔芬治疗的反应不佳。

A high AR:ERα or PDEF:ERα ratio predicts a sub-optimal response to tamoxifen therapy in ERα-positive breast cancer.

机构信息

Department of Breast Cancer Pathology and Research Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China.

Department of Pathology, Tianjin Union Medical Center, Tianjin People's Hospital, Tianjin, 300121, China.

出版信息

Cancer Chemother Pharmacol. 2019 Sep;84(3):609-620. doi: 10.1007/s00280-019-03891-6. Epub 2019 Jul 11.

DOI:10.1007/s00280-019-03891-6

PMID:31297554

Abstract

PURPOSE

Approximately 30% oestrogen receptor alpha (ERα)-positive breast cancer (BC) patients exhibit intrinsic or recurrent resistance to adjuvant endocrine therapy with tamoxifen. The androgen receptor (AR) is expressed in about 90% of ERα-positive patients, with particularly high expression in tamoxifen-resistant tumours. Prostate-derived Ets factor (PDEF), which is a co-regulator of AR, plays a role in tamoxifen resistance in ERα-positive BC. The purpose of this research was to analyse the potential roles of AR, PDEF and ERα levels in the response to tamoxifen resistance in ERα-positive BC.

METHODS

The nuclear AR:ERα and PDEF:ERα ratios were examined immunohistochemically in a cohort of 225 ERα-positive pre-menopausal BC patients who had received adjuvant tamoxifen therapy.

RESULTS

For both AR:ERα and PDEF:ERα ratios, the optimal cutoff value was 2.0. Patients receiving adjuvant tamoxifen treatment who had a high AR:ERα (≥ 2.0) (HR = 3.90) or PDEF:ERα ratio (≥ 2.0) (HR = 2.77) had a beyond twofold increased risk of failure. Both the AR:ERα ratio (P = 0.001) and PDEF:ERα ratio (P = 0.002) were independently associated with the risk of tamoxifen treatment failure. Furthermore, both a high ratio of AR:ERα (≥ 2.0) and PDEF:ERα (≥ 2.0) were associated with shorter disease-free survival (DFS) and shorter disease-specific survival (DSS). In addition, both the AR:ERα ratio and PDEF:ERα ratio were independent predictors of DFS (both P < 0.0001) and DSS (P = 0.001 and P < 0.0001, respectively).

CONCLUSIONS

AR:ERα and PDEF:ERα ratios are independent predictors of the response to conventional ERα-directed tamoxifen endocrine therapy.

摘要

目的

大约 30%的雌激素受体 alpha（ERα）阳性乳腺癌（BC）患者对他莫昔芬辅助内分泌治疗表现出固有或复发性耐药。雄激素受体（AR）在约 90%的 ERα 阳性患者中表达，在他莫昔芬耐药肿瘤中表达尤其高。前列腺衍生的 Ets 因子（PDEF）是 AR 的共调节因子，在 ERα 阳性 BC 的他莫昔芬耐药中发挥作用。本研究旨在分析 AR、PDEF 和 ERα 水平在 ERα 阳性 BC 对他莫昔芬耐药反应中的潜在作用。

方法

在 225 名接受辅助他莫昔芬治疗的绝经前 ERα 阳性 BC 患者队列中，用免疫组织化学法检测核 AR:ERα 和 PDEF:ERα 比值。

结果

对于 AR:ERα 和 PDEF:ERα 比值，最佳截断值均为 2.0。接受辅助他莫昔芬治疗的患者中，AR:ERα（≥2.0）（HR=3.90）或 PDEF:ERα 比值（≥2.0）（HR=2.77）较高的患者复发风险增加两倍以上。AR:ERα 比值（P=0.001）和 PDEF:ERα 比值（P=0.002）均与他莫昔芬治疗失败的风险独立相关。此外，AR:ERα 比值（≥2.0）和 PDEF:ERα 比值（≥2.0）均与无病生存期（DFS）和疾病特异性生存期（DSS）较短相关。此外，AR:ERα 比值和 PDEF:ERα 比值均是 DFS（均 P<0.0001）和 DSS（P=0.001 和 P<0.0001）的独立预测因子。