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

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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.

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Acknowledgements

We thank the BC patients and their families. They generously donated valuable tissue samples.

Funding

This study was funded by National Natural Science Foundation of China (Grant Numbers 81172532, 81602340).

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Authors and Affiliations

  1. 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

    Lu Cao, Guomin Xiang, Fang Liu, Cong Xu, Jing Liu, Qingxiang Meng & Yun Niu

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

    Shuhua Lyu

  3. Department of Breast Oncology, 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

    Shuling Wang

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  1. Lu Cao
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Correspondence to Yun Niu.

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Cao, L., Xiang, G., Liu, F. et al. A high AR:ERα or PDEF:ERα ratio predicts a sub-optimal response to tamoxifen therapy in ERα-positive breast cancer. Cancer Chemother Pharmacol 84, 609–620 (2019). https://doi.org/10.1007/s00280-019-03891-6

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