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

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.

Keywords: Androgen receptor; Breast cancer; Oestrogen receptor alpha; Prostate-derived Ets factor; Tamoxifen.