Image analysis of androgen receptor immunostaining in metastatic prostate cancer heterogeneity as a predictor of response to hormonal therapy

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Abstract
Background. Reliable predictors of the response of prostate cancer to androgen ablation therapy are lacking. The goals of this study were to determine whether nuclear androgen receptor (AR) concentrations in metastatic prostate cancer varied within and between specimens and to correlate this information with the response to therapy. Methods. AR concentration was evaluated by computer‐assisted image analysis of immunohistochemical staining intensity in 200 malignant epithelial nuclei of each of 17 specimens of Stage D2 prostate cancer obtained before hormonal therapy. The data were correlated with the time to tumor progression (relapse) after hormonal therapy. Results. AR staining intensity varied within specimens, and the variance of staining intensity was significantly greater (P = 0.03) in the poor responders (n = 8; time to progression, < 20 months) than in the good responders (n = 9; time to progression, ≥ 20 months). The kurtosis was significantly lower in poor responders (P = 0.04). However, the mean AR staining intensity was not significantly different among patients. The frequency distribution plots of good responders were generally uniform and unimodal, but those of poor responders were flattened (more platykurtic), dispersed, and highly variable. Thus, the AR concentration per cell was significantly more heterogeneous in poor responders. Variance was a significant predictor of response. Five of 6 patients with a high variance (defined as variance greater than the mean) were poor responders, whereas 8 of 11 patients with a low variance were good responders (an overall classification accuracy of 13 of 17, 76%). Conclusions. The greater AR heterogeneity in poor responders may reflect a greater genetic instability in tumors that have progressed further toward androgen in‐dependence and may be a valuable predictor of progression.