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

Purpose Approximately 30% oestrogen receptor alpha (ER alpha)-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 ER alpha-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 ER alpha-positive BC. The purpose of this research was to analyse the potential roles of AR, PDEF and ER alpha levels in the response to tamoxifen resistance in ER alpha-positive BC. Methods The nuclear AR:ER alpha and PDEF:ER alpha ratios were examined immunohistochemically in a cohort of 225 ER alpha-positive pre-menopausal BC patients who had received adjuvant tamoxifen therapy. Results For both AR:ER alpha and PDEF:ER alpha ratios, the optimal cutoff value was 2.0. Patients receiving adjuvant tamoxifen treatment who had a high AR:ER alpha (>= 2.0) (HR = 3.90) or PDEF:ER alpha ratio (>= 2.0) (HR = 2.77) had a beyond twofold increased risk of failure. Both the AR:ER alpha ratio (P = 0.001) and PDEF:ER alpha ratio (P = 0.002) were independently associated with the risk of tamoxifen treatment failure. Furthermore, both a high ratio of AR:ER alpha (>= 2.0) and PDEF:ER alpha (>= 2.0) were associated with shorter disease-free survival (DFS) and shorter disease-specific survival (DSS). In addition, both the AR:ER alpha ratio and PDEF:ER alpha ratio were independent predictors of DFS (both P < 0.0001) and DSS (P = 0.001 and P < 0.0001, respectively). Conclusions AR:ER alpha and PDEF:ER alpha ratios are independent predictors of the response to conventional ER alpha-directed tamoxifen endocrine therapy.