PCa Commentary

"High Grade Prostatic Intraepithelial Neoplasia Is A Disease"... And When Appropriate Therapies Become Available, It Merits Treatment. (January 2005)

The quoted declarative, somewhat arresting, statement above is the title of Mitchell Steiner’s discussion in Current Urology Reports, Feb. 2001, and sets the stage for his subsequent work and that of others implicating the role of estrogen in the genesis of HGPIN - and hence prostate cancer - and the potential role of the estrogen blocker, Toremifene to arrest this process. The hypothesis that PIN is both a marker and a precursor to cancer is being increasingly strengthened by many lines of evidence, admittedly falling short of an ultimate observation capturing in time-lapse photography this transition correlated with sequential gene expression profiles. In his article, “High-grade prostatic intraepithelial neoplasia”, Modern Pathology, 2004;17, Bostwick sets out the varied evidence that convinces him of this progression, concluding with “Most patients with PIN [HGPIN] will develop carcinoma with 10 years”. Histologically, he defines, “PIN is the abnormal proliferation withinA the prostatic ducts, ductules, and large acini of premalignant foci of cellular dysplasia and carcinoma in situ without stromal invasion”. Whereas normal prostate cellular proliferation occurs in the basal cell layers, in “PIN the greatest proliferation occurs on the luminal surface, similar to preinvasion lesions in colon (tubular adenoma) and other sites [ie uterine cervix, bladder in situ carcinoma ].” Isolated HGPIN does not elevate PSA. As PIN spreads it replaces the luminal epithelium, initially preserving the basal cell layer, subsequently progressively fragmenting it; and then, in full transition to cancer, invading through the basement membrane into the stroma, and promoting angiogenesis. The guilt of PIN as a transitional precursor to cancer is suggested epidemiologically by the recognition of its well established association with cancer, by its progressive morphologic similarity to cancer, and by its sequential acquisition of prostate cancer’s signature genetic alterations, the increasing expression of the enzyme AMACR (upregulated 9 to 55 fold in PC), and the progressive silencing of the gene glutathone S transferase P1, a protector from cellular oxidative damage.

A proposed biologic mechanism to explain this putative example of the classic transition - hyperplasia, dysplasia, carcinoma in situ and invasion - has been suggested by Steiner and others and surprisingly the finger points toward estrogen as an instigating factor. Steiner’s article, “Selective estrogen receptor modulators for chemoprevention of prostate cancer”, UROLOGY 57, Suppl.1 April 2001, records that “Both animal models and human epidemiologic studies have implicated estrogen as an initiator of prostate cancer”, and reminds us that “In the aging male, prostate cancer occurs in an environment of rising estrogen and decreasing testosterone.” In the male, and in the female, estradiol interfaces with the two estrogen receptors, ER alpha and ER beta, in each case with slightly different results based on unique tissue specificities and coactivator enlistment. Activation of “ER alpha stimulates transcription and cellular proliferation, while ER beta quenches ER alpha activation. In an environment of rising estrogen, androgen receptors in the prostate cell are upregulated thereby increasing sensitivity to androgens. Whereas ER beta resides in the luminal epithelial cell, ER alpha is found in the stroma and its activation elicits the proliferative peptide cytokines insulin like growth factor and epidermal growth factor, and the inhibitory transforming growth factor beta. These molecules affect the luminal cells in a paracrine fashion. As the title of the article suggests evidence is accumulating that this adverse process can be counteracted by inhibitory antagonists of the prostate’s estrogen receptors.

“Selective Estrogen Receptor Modulator” (SERM) is the term for the evolving repertoire of drugs, such as well known Tamoxifen; and the most studied SERM in chemoprevention of prostate cancer is Toremifene (“Acapodene”, GTx Inc.). SERMs have weak affinity for estrogen receptors - functioning as partial antagonists much like genistein (soy) - and preempt the ligand pocket thereby preventing attachment and signaling by the more avid estradiol. Toremifene primarily antagonizes ER alpha. Kawashima, Urol Res.2004, Aug, reports that the anti-androgenic aspect of anti-estrogens may function by inhibiting AR-mediated transcription.

“Phase IIA Clinical Trial to Test the Efficacy and Safety of Toremifene in Men with High-Grade Prostatic Intraepithelial Neoplasia” by Drs. Steiner and Pound, Department of Urology, University of Tennessee, reported findings in 18 men with HGPIN [based on > 6 core biopsies] using 60 mg/day of Toremifene (“Acapodene”,GTx,Inc.) for 120 days. “After Toremifene treatment, 72% of these 18 men (vs. 17.9% of historical controls) had no HGPIN on subsequent [8 core] biopsies.” Four (22%) showed a limited response (defined as a > 25% reduction in HGPIN), and one had stable disease. In this small study “No changes were noted for libido, erectile function, and hot flashes. ... Mean total testosterone was significantly increased [5.5 ng/mL]...at day 120.” Slight, but significant, reductions in hemoglobin and platelets were seen.

This early “proof-of-concept” trial was followed by the IIb double-blind, placebo-controlled, one-year trial using 20 mg Toremifene in 514 men with HGPIN. The trial end point was the diagnosis of prostate cancer. At the 2004 Fourth International Prostate Cancer Congress Dr.Steiner, CEO GTx, reported “a statistically and clinically significant reduction of prostate cancer cumulative risk at one year in the “Acapodene” 20mg arm compared to placebo, 24.4% vs 31.2%, respectively (p<0.05)”. An additional observation was that longer usage increased the likelihood of risk reduction. The side effects - fatigue, hot flashes, nausea - were mild, < 5%, and very similar in both arms. A definitive large-scale Phase III trial is planned and Dr. Bob Boger (GTx, Inc.) has indicated that this will include sites in the Northwest.

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