HG PIN is a well established pre-malignant lesion of the prostate because of its potential to progress to PCA (1,2). PIN is the abnormal proliferation within the prostatic ducts of pre-malignant foci of cellular dysplasia and carcinoma in-situ without stromal invasion (1). In the USA, approximately 1,300,000 prostate biopsies are performed annually to detect 189,000 new cases of PCA (3). The incidence ofHG PIN averages 9% (range 4-16%) ofprostate biopsies representing 115,000 new cases diagnosed each year (4). There is estimated to be 1,000,000 USA men with histologic proven HG PIN. The support for HG PIN as a PCA pre-malignant lesion is based on several lines of evidence derived from PCA animal models, epidemiological, morphologic, genetic, and molecular studies (4).

HG PIN is in the direct causal pathway to PCA, and its presence increases PCA risk (5). When HG PIN is found on needle biopsy, there is a 39.5%, 57.1%, and 80% risk of finding PCA on subsequent biopsies after 1 (6), 2 (7-9), and 10 years (10), respectively. The diagnosis ofHG PIN changes the patient's quality oflife, as there is great patient and physician anxiety about the concern that PCA may be imminent. Although there is no medical consensus for the standard of care of HG PIN, urologists recognize that HG PIN is a dangerous lesion and it should be aggressively managed. The patient must be subjected to more frequent biopsies and physician visits, as currently, the only way to diagnose whether HG PIN has progressed to PCA is by prostate biopsy. Although some urologists have advocated saturation biopsies (over 12 biopsy cores obtained) of the prostate following the diagnosis of HG PIN, the more common recommendation is repeated prostate biopsies every 3-6 mo for 2 years, then annually (8, 11).

Evidence for estrogen's role in PCA has emerged not only from animal studies, but also from epidemiological studies on diet in man (12). Phytoestrogens like soy are non-steroidal substances that have weak estrogenic activity. Essentially, they act like ER partial antagonists. Soy is consumed daily in large amounts in China and Japan, regions where the PCA incidence is low (13). A direct inverse correlation has been observed between serum levels of isoflavonoids from soy and PCA incidence (14). In addition to its anti-estrogenic effects, isoflavonoids have many other mechanisms that may account for this decrease in PCA (14). Generally, SERMs are considered, like phytoestrogens, to be "weak estrogens" because they possess both agonist and antagonist activities depending on the specific tissue type. SERMs possess the ability to suppress prostate carcinogenesis. Animal toxicity studies oftoremifene and raloxifene (LY156758) have revealed a dose dependent regression ofthe androgen dependent ventral prostate and seminal vesicles in SD rats (15). Wang, et al. (16) treated wild type mice with T propionate and E2 for 4 mo. These mice developed prostatic hyperplasia, HG PIN, and invasive PCA. Under the same treatment, mice (mice with genetically knocked out) develop prostatic hyperplasia, but not HG PIN or invasive PCA (16). Similarly, a prospective, placebo controlled study of transgenic adenocarcinoma mouse prostate (TRAMP), a PCA mouse model, has been shown to mimic human PCA. In toremifene-treated TRAMP mice a reduction in HG PIN, significant decrease in PCA incidence, and an increase in animal survival were observed (17). Thus, estrogenic signally through ERa may play a key role in the development ofHG PIN and PCA.

The purpose ofthis study was to investigate whether agents that block ERa may potentially prevent HG PIN and decrease PCA risk. Toremifene is a SERM

that antagonizes ERa in the prostate, and is safer than tamoxifen because it does not form DNA adducts (18). An exploratory Phase Ila trial was conducted in men who have HG PIN to determine whether toremifene can reduce HG PIN.

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