Celebrating the 80th anniversary of hormone ablation for prostate cancer

In this special issue of Endocrine-Related Cancer, we are celebrating the 80th anniversary of hormone ablation as treatment for metastatic prostate cancer. Our understanding has evolved from the observation that androgen withdrawal, either surgical or pharmacological, resulted in prostatic atrophy in animal models, to its application in patients, to investigation of the mysterious way in which prostate cancer escapes androgen dependence. We are now in an era of novel AR pathway inhibitors, combination of androgen ablation with chemotherapy, PARP inhibitors, immunotherapies, guided radiotherapy, and novel drug application based upon genetic testing of individual tumors. In this Anniversary Issue, we bring together a collection of eight reviews that cover not only the history of 80 years of progress after the initial identification of androgen ablation as an effective treatment of prostate cancer, but subsequent improvements in the understanding of the biology of the disease, development of novel treatment paradigms, resistance to those treatments and disease progression following that resistance.

Effect of FSH supplementation on the GnRH antagonist suppressed growth of PC-3 cell xenografts in nude mice.

e630 Background: One of the fundamental differences between GnRH agonist and antagonist treatment is the permanent suppression of FSH by antagonist, while a rebound in FSH secretion has been documented upon agonist treatments. To assess the potential beneficial effects of permanent FSH suppression in the hormone ablation treatment of prostate cancer we studied the effect of the GnRH antagonist degarelix in the absence and presence of FSH supplementation on the growth of PC-3 human prostate cancer cell xenografts in nude mice. Methods: Intact (n = 20) and gonadectomized (n = 20) nude male mice were inoculated with 2 x 106PC-3 cells. Half of each group received degarelix treatment at 10 mg/kg body weight s.c. In a second experiment (n = 10/group), degarelix treatment was supplemented with recombinant human FSH at10 IU/kg/day using i.p. ALZET osmotic minipumps. Tumor growth in both experiments was monitored for 4 weeks by external inspection and caliper measurement, after which the mice were sacrificed. Results: The first experiment demonstrated that degarelix treatment significantly reduced tumor growth by 33% and 35%, respectively, in intact and gonadectomized mice as compared to non-treated controls (p<0.0001 for each). In the second experiment, FSH reversed the inhibitory effect of degarelix in intact mice. Conclusions: These results demonstrated that the suppression of PC-3 xenograft growth by GnRH antagonist treatment was completely inhibited by concomitant FSH treatment. The findings prove experimentally the principle that combined FSH and LH suppression by GnRH antagonist could offer an advantage over the isolated LH suppression by GnRH agonist upon prostate cancer treatment. [Table: see text]

Metastatic prostate cancer in transsexual diagnosed after three decades of estrogen therapy.

The incidence of prostate cancer in transsexual patients is very low with only few reported cases. Many years before presenting with prostate cancer, these patients receive hormone ablation as a part of their gender therapy. Their disease is already defined as castrate resistant, and the treatment and follow-up of such patients remains a challenge. We report a case of a male-to-female transgender woman who was diagnosed with metastatic prostate cancer, 31 years post-feminization.

Incidental prostate cancer in patients with radical cystectomy for bladder cancer.

225 Background: Radical cystectomy is the gold standard surgical treatment for invasive bladder cancer. Prostate adenocarcinoma is often found incidentally in the cystoprostatectomy specimen. The clinical significance of this type of cancer has not been well characterized. We reviewed the cohort of male patients with bladder cancer who underwent radical cystectomy and found to have incidental prostate adenocarcinoma. Methods: 1,964 patients with primary transitional cell carcinoma of bladder underwent radical cystectomy between 1971 and 2008 with a median follow-up of 12.1 yrs (0.1-36) at USC. 1553 of them were male (79%) and 559 (36%) had incidental pathologic prostate adenocarcinoma (PC-group). Prostate and bladder cancer characteristics, recurrence and overall survival (OS) in the cohort of PC-group are reviewed. Results: Median age in the PC-group was 69 yo (35-92). The incidental PC was organ confined (OC) in 527 patients (94%). 32 (6%) had non-OC prostate cancer, treated by adjuvant radiation (5), hormone ablation (3) with a median follow-up of 3.9 yrs (0.1-16). Median pre-op PSA was 1.66 (0.01-83) in PC-group and 1.31 (0.01-33.2) in non-PC group. Gleason score was ≤ 6 in 458 (82%), 7 in 78 (14%) and ≥ 8 in 12 (2%) cases. Reviewing bladder cancer in the PC vs. non-PC group, 84 and 83% had high-grade cancer, 63 and 58% had associated CIS, 41 and 36% had multifocal disease and 29 and 27% had LVI respectively (P > 0.05). Incidental PC did not have significant effect on recurrence (P=0.3) and OS (P=0.4) after cystectomy for bladder urothelial cancer. No patient died of PC. 5-year OS rate was 60 ± 2% in both PC and non-PC groups. 10-year OS rate was also comparable at 42 ± 2% in PC and 44 ± 2% in non-PC-group. Conclusions: Incidental prostate adenocarcinoma is reported in more than one third of patients who undergo radical cystectomy for bladder cancer. It is organ confined in most of the cases and has no correlation with bladder cancer stage. Outcome of patients with incidental prostate adenocarcinoma at the time of radical cystectomy relies exclusively on the bladder cancer.

Treatment-Induced Bone Loss and Fractures in Cancer Patients Undergoing Hormone Ablation Therapy: Efficacy and Safety of Denosumab

Hormone ablation therapy (HALT) for breast or prostate cancer accelerates the development of osteoporosis in both men and women by causing estrogen deficiency, which increases the risk for fracture by promoting bone resorption mediated by osteoclasts. Denosumab, a fully human monoclonal antibody that inhibits osteoclast formation and function, increases bone mass in patients undergoing hormone ablation therapy. In the HALT study of 1,468 men with prostate cancer on androgen-deprivation therapy, denosumab significantly reduced the risk of new vertebral fractures, increased bone mineral density (BMD), and reduced markers of bone turnover. In a study of 252 women with breast cancer undergoing adjuvant aromatase inhibitor (AI) therapy, denosumab increased BMD at 12 and 24 months, overall and in all patient subgroups. The overall rates of adverse events were similar to placebo. Clinicians should consider fracture risk assessment and therapies such as denosumab to increase bone mass in patients on hormone ablation therapy who are at high risk for fracture.

Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer

Advanced prostate tumors, which are androgen dependent, are often initially treated in the clinic with hormone ablation therapy, either through surgical castration or administration of small-molecule antiandrogens. Most tumors respond favorably to these treatments, exhibiting regression of the tumor, amelioration of symptoms, and a decrease of prostate-specific antigen in patient sera. However, with time, the majority of tumors recur in a more aggressive, castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the cancer, and patients ultimately succumb to metastatic disease. The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer. Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory proteins. This review will summarize the most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate carcinoma.