Drug therapies for eradicating high-grade prostatic intraepithelial neoplasia in the prevention of prostate cancer

Abstract

High-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor to invasive prostate cancer observed as an isolated entity in a growing subset of men undergoing prostate biopsy. The presence of HGPIN predicts an increased risk of 1) coexisting occult prostate cancer at baseline and 2) delayed progression to prostate cancer. As such, men with HGPIN represent a population at high risk for the development of prostate cancer. Because the current recommended therapy is observation and delayed-interval biopsies until cancer develops, a well-tolerated therapeutic agent capable of interrupting the progression of HGPIN to cancer is highly desirable. Given the known cancer-stimulatory effects of estrogens in the prostate, the use of selective estrogen receptor modulators (SERMs) to provide an antiestrogen effect represents a novel strategy for prostate cancer prevention. Recent phase II data from trials using toremifene in the treatment of men with HGPIN validate the use of SERMs as a rational and provocative strategy for the prevention of prostate cancer.

Figure 1

On binding to a ligand, the androgen receptor (AR) disassociates from an inactive complex in the cytosol, translocates to the nucleus, and binds to the promoter sequence of target genes at the steroid response element. It is through activation and repression of target genes that steroids initiate programs of cell growth or differentiation. ARE, androgen response element; DHT, dihydrotestosterone; HSP, heat shock protein; P, promoter.

Figure 2

Comparison of overall cancer incidence on follow-up biopsy between men treated with placebo and those given increasing doses of daily toremifene. A significant reduction in cancers diagnosed was observed among men treated with 20 mg of toremifene daily. Data from Steiner MS et al.

Figure 3

A depiction of cancer diagnosis on serial biopsy among men treated with placebo or 20 mg toremifene daily. Although the incidence of cancer did not differ between groups at 6-month biopsy, a 48.2% reduction in cancer diagnosis among men treated with 20 mg of daily toremifene was observed at 12-month biopsy. Data from Steiner MS et al.

Figure 4

Comparison of cancer incidence on 1-year follow-up biopsy between men treated with placebo and those given increasing doses of toremifene. A significant reduction in cancers diagnosed was observed among men treated with 20 mg of toremifene daily. CMH, Cochran-Mantel-Haenszel. Data from Steiner MS et al.