The Magnitude of Androgen Receptor Positivity in Breast Cancer is Critical for Reliable Prediction of Disease Outcome

Purpose: Consensus is lacking regarding the androgen receptor (AR) as a prognostic marker in breast cancer. The objectives of this study were to comprehensively review the literature on AR prognostication and determine optimal criteria for AR as an independent predictor of breast cancer survival. Experimental Design: AR positivity was assessed by immunostaining in two clinically-validated primary breast cancer cohorts (training cohort n=219; validation cohort n=418; 77% and 79% estrogen receptor alpha (ERα) positive, respectively). The optimal AR cut-point was determined by ROC analysis in the training cohort and applied to both cohorts. Results: AR was an independent prognostic marker of breast cancer outcome in 22/46 (48%) of previous studies that performed multivariate analyses. Most studies used cut-points of 1% or 10% nuclear positivity. Herein, neither 1 nor 10% cut-points were robustly prognostic. ROC analysis revealed a higher AR cut-point (78% positivity) provided optimal sensitivity and specificity to predict breast cancer survival in the training (HR 0.41, P=0.015) and validation (HR 0.50, P=0.014) cohorts. Ten-fold cross validation confirmed the robustness of this AR cut-point. Patients with ERα positive tumors and AR positivity >78% had the best survival in both cohorts (P<0.0001). Among the combined ERα positive cases, those with comparable or higher levels of AR (AR:ERα positivity ratio >0.87) had the best outcomes (P<0.0001). Conclusions: This study defines an optimal AR cut-point to reliably predict breast cancer survival. Testing this cut-point in prospective cohorts is warranted for implementation of AR as a prognostic factor in the clinical management of breast cancer.

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