Longitudinal analysis of androgen deprivation of prostate cancer cells identifies pathways to androgen independence

BACKGROUND: Following androgen ablation therapy, the majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. METHODS: To identify molecular targets that promote prostate cancer cell survival and contribute to androgen independence, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and following the emergence of a highly proliferative, androgen-independent prostate cancer cell phenotype (LNCaP-AI). RESULTS: We discovered alterations in gene expression for molecules associated with promoting prostate cancer cell growth and survival, and regulating cell cycle progression and apoptosis. Additionally, expression of AR co-regulators, adrenal androgen metabolizing enzymes, and markers of neuroendocrine disease were significantly altered. CONCLUSIONS: These findings contribute greatly to our understanding of androgen-independent prostate cancer. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the adaptive response to androgen deprivation; it provides a more dynamic illustration of genes which contribute to disease progression in addition to specific genes which constitute an androgen-independent phenotype.     

Prostate-specific antigen and androgen deprivation therapy

Summary Prostate-specific antigen (PSA) is a kallikrein-like serine protease that, for all practical purposes, is specific for prostatic tissue. PSA is usually detected at low concentrations (0.0–4.0 ng/ml) in the serum and is the most important tumor marker for detecting otherwise unsuspected prostate cancer; it also useful for monitoring the response of prostate cancer to various types of therapy. Androgen deprivation therapy (ADT) includes bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens, and 5-alpha-reductase inhibitors. Treatment of benign prostatic hypertrophy (BPH) or prostate cancer with ADT usually decreases the serum PSA concentration. Recent basic science research has demonstrated that the expression of the PSA gene is controlled by androgens acting via the androgen receptor. Therefore, in some patients a low serum PSA concentration will be the result of hormonal down-regulation of the genetic expression of PSA and not the result of the antitumorigenic activity of the therapy. Nevertheless, in spite of the direct effect of ADT on PSA expression, PSA remains a valuable prostate cancer tumor marker for prognosticating the response to ADT and portending clinical progression after this type of treatment for most patients.     

Gleason score predicts androgen independent progression after androgen deprivation therapy

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.     

Hematological changes during androgen deprivation therapy

Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.     

Effect of androgen deprivation on penile ultrastructure

Aim: To investigate the ultrastructural changes of penile corpus cavernosum and tunica albuginea in rats treated with castration or finasteride. Methods: Eighteen male Sprague-Dawley rats of nine weeks old were randomly divided into three groups with 6 rats each. Group A served as the control, Group B was castrated and Group C, treated with finasteride. Four weeks later, rats were anesthetized and blood samples obtained for the determination of serum testosterone (T) and dihydrotestosterone (DHT) levels; penile tissues were taken for scanning electron microscopy. Results: The T, free T and DHT levels in Group B and the DHT level in Group C were significantly lower than those in Group A (P<0.05). The tunica albuginea was significantly thinner in Group B than that in Group A (P<0.05), but there was no significant difference between Group C and Group A (P>0.05). Elastic fibers in the tunica albuginea of Group A were very rich and arranged regularly and undulatedly, but in Group B, most of the elastic fibers     

Impact of androgen deprivation therapy on sexual function

Many patients with prostate cancer for whom androgen deprivation therapy (ADT) is indicated are young and desire to remain sexually active. In such patients, the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life. Providing the appropriate treatment options in this patient population is therefore essential. Nevertheless, treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care. In this paper, we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment.     

Duration of androgen deprivation therapy with maximum androgen blockade for localized prostate cancer

Background

In this study, by comparing TVT surgery and TOT surgery for stress urinary incontinence in women, the characteristics and learning curves of both operative methods were studied.

Methods

A total of 83 women with stress urinary incontinence treated with tension-free vaginal tape (TVT) (n = 38) or transobturator tape (TOT) (n = 45) at Saiseikai Central Hospital between April 2004 and September 2009 were included. We compare the outcomes and learning curves between TVT surgery and TOT surgery. In statistical analysis, Student's t test, Fisher's exact test, and Mann-Whitney's U test were used.

Results

The surgical durations were 37.4 ± 15.7 minutes with TVT surgery and 31.0 ± 8.3 minutes with TOT surgery. A longer period of time was required for TVT surgery (p = 0.025). The residual urine at post-operative day 1 was higher in TVT surgery (25.9 ± 44.2 ml) than in TOT surgery (10.6 ± 19.2 ml) (p = 0.0452). The surgical duration of TVT surgery was shortened after the operator had performed 15 operations (p = 0.019).

Conclusions

In comparison of TVT surgery and TOT surgery, the surgical duration of TVT surgery was longer and the residual urine of TVT surgery was higher at post-operative day 1. Surgical experience could shorten the duration of TVT surgery.     

Metabolic and cardiovascular effects of androgen deprivation therapy

Prostate cancer is the most common gender-specific malignancy in men in the USA. Androgen-deprivation therapy (ADT) is commonly used in the treatment of metastatic or recurrent prostate cancer. The use of ADT is increasing with the advocacy of adjuvant and neoadjuvant ADT for treating asymptomatic patients with locally advanced prostate cancer. Although the use of ADT has resulted in improved survival in men with advanced prostate cancer, ADT, with its resulting severe hypogonadism, causes profound metabolic side-effects. We comprehensively reviewed previous reports using Medline searches of English-language literature (1950 to the present), with the keywords 'hypogonadism', 'testosterone', 'androgen deprivation therapy', 'hormonal treatment', 'prostate cancer', 'diabetes', 'metabolic syndrome', and 'cardiovascular disease'. Men with prostate cancer who undergo long-term ADT are at greater risk of developing dyslipidaemia, insulin resistance, hyperglycaemia and metabolic syndrome. These metabolic and physiological changes are a direct result of the induced severe hypogonadism and might predispose patients to a greater risk of cardiovascular morbidity and mortality. There is a need for prospective studies aimed and designed to investigate the metabolic and cardiovascular adverse effects of ADT, and assess the benefit/risk ratio, especially in special populations such as diabetics.     

Information needs of men on androgen deprivation therapy

Study Type – Needs assessment survey Level of Evidence 2b What's known on the subject? and What does the study add? Although androgen deprivation therapy (ADT) is widely used to treat men with prostate cancer, little is known about the information needs of patients on ADT. We found that patients are generally very satisfied with using ADT and expressed minimal decisional regret with its use up to four years later. For men receiving ADT in the adjuvant setting, their survival estimates with the addition of ADT were quite reasonable when compared to findings in randomized trails. A key area to enhance patient education appears to be side effects, especially around hot flashes and fatigue, which were also the most bothersome treatment sequelae for patients.

OBJECTIVE

• ? To evaluate information needs of men receiving androgen deprivation therapy (ADT).

PATIENTS AND METHODS

• ? A cross‐sectional survey was distributed to English‐speaking prostate cancer patients receiving ADT adjuvant to radical therapy or for biochemical relapse.
• ? Three cohorts were recruited based on duration of ADT use: <6 months (cohort 1), 6–18 months (cohort 2) and 18 months to 4 years (cohort 3).
• ? Several validated questionnaires were used, including the Control Preferences Scale (CPS), Satisfaction with Treatment Decision Scale (SWD) and Decisional Regret Scale (DRS).
• ? Patients on adjuvant ADT were asked to estimate their overall survival with and without ADT.

RESULTS

• ? Eighty‐five men were recruited, of whom 91.8% were receiving a gonadotrophin‐releasing hormone agonist, 4.7% were receiving anti‐androgen monotherapy and 3.5% were receiving combined androgen blockade.
• ? Patients preferred the following decision‐making roles: 23.5% active, 50.6% collaborative, 27.0% passive.
• ? Mean patient satisfaction for ADT use was high at 24.0/30 and decisional regret was low at 7.9/25.
• ? There was a perceived overall survival benefit of 3.9–6.9% at 5 years, 3.6–17.8% at 10 years and 5.7–18.1% at 15 years with the addition of adjuvant ADT.
• ? Hot flushes and fatigue were reported as the most common theoretical adverse effects as well as those experienced most commonly by patients.

CONCLUSIONS

• ? Patients on ADT were generally satisfied with their decisions to start ADT and expressed minimal decisional regret up to 4 years later.
• ? A key area to enhance patient education appears to be adverse effects, especially around hot flushes and fatigue.

     

Pre-treatment testosterone levels: significance in androgen deprivation therapy

From June 1982 to February 1985, 53 patients with stage D2 carcinoma of the prostate confirmed by tissue biopsy, elevated prostatic acid phosphatase and a positive bone scan were initiated on androgen deprivation therapy. Before commencement of treatment all patients underwent determination of serum testosterone levels at 8 a.m. Of the patients 23 received 200 mcg. buserelin per day, 17 received 1 mg. diethylstilbestrol 3 times daily, 6 received 40 mg. megestrol acetate 4 times daily, 2 received 1 mg. leuprolide per day and 5 underwent bilateral orchiectomy. Evaluation of the best response in each patient revealed 3 (6 per cent) complete and 17 (32 per cent) partial responses, while 22 patients (41 per cent) remained stable and 11 (21 per cent) had progression. Pre-treatment serum testosterone levels ranged from 150 to 879 ng. per dl. The mean serum testosterone level in patients having a complete response was 524 +/- 18.04 ng. per dl. The mean in the progression group was 279.4 +/- 110.1 ng. per dl. This difference was not statistically significant owing to the large standard deviation in the progression group. However, of the 15 patients who had a pre-treatment serum testosterone level of more than 500 ng. per dl. only 1 (7 per cent) had progression. None of the patients whose pre-treatment testosterone level was less than 200 ng. per dl. had objective tumor regression. Our study suggests that pre-treatment serum testosterone levels may predict the probability of a satisfactory response to androgen deprivation therapy.