Randomized trial of toremifene to reduce high grade prostatic intraepithelial neoplasia (HGPIN) prior to radical prostatectomy (RP)

Abstract

5150 Background HGPIN may be a precursor lesion for prostate cancer (PCA). The selective estrogen-receptor modulator toremifene (TOR) has shown chemopreventive activity in preclinical models of PCA. The effect of TOR on HGPIN was studied in men with PCA prior to RP. Methods Men with biopsy-proven PCA, scheduled for RP were randomized (2:1) either to TOR 40 mg po qd for 3 to 6 weeks prior to RP or to no therapy. The primary endpoint was the proportion of HGPIN in the RP specimen. Planned sample sizes were 35 and 17 per arm respectively, providing 93% power if treatment increased the proportion of patients with no RP HGPIN from 15% to 35% and decreased the mean log nonzero HGPIN values from 1 to ¼ standard deviation. Expression of bcl2, ki67, and CD31 were determined on biopsy (BX), and RP tissues, separately for normal adjacent to tumor (NAT), HGPIN, and PCA tissues. Serum hormone levels and toxicity were also assessed. Results The treatment arm accrued 31 patients, the control arm 13 patients. RP HGPIN ranged from 0.5% to 12%. There was no difference in HGPIN means between treatment (3.8%) and control (3.3%) (P=0.77 one-sided Wilcoxon) HGPIN at baseline predicted HGPIN at RP (Spearman correlation=0.64, P=0.0005) but 66% of patients had no detected HGPIN at baseline. Bcl2, ki67, and CD31 were mutually positively correlated in all 3 tissues, in both BX and RP specimens. In both BX and RP specimens, bcl2 was highest by far in HGPIN, and lowest in PCA. Ki67 was lowest in NAT, elevated in HGPIN and highest in PCA. CD31 showed no differences. In treated patients but not in controls, dihydrotestosterone, testosterone, androstenedion, and estradiol increased significantly between baseline, day 14 and final. TOR was well tolerated. Conclusions These data do not support an effect of TOR on HGPIN over 3 to 6 weeks at 40 mg po qd. No significant financial relationships to disclose.