Sociocultural considerations in aging men's health: implications and recommendations for the clinician

http://dx.doi.org/10.1016/j.jomh.2009.07.00

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Risk-based prostate cancer screening

Context: Widespread mass screening of prostate cancer (PCa) is not recommended because the balance between benefits and harms is still not well established. The achieved mortality reduction comes with considerable harm such as unnecessary biopsies, overdiagnoses, and overtreatment. Therefore, patient stratification with regard to PCa risk and aggressiveness is necessary to identify those men who are at risk and may actually benefit from early detection. Objective: This review critically examines the current evidence regarding risk-based PCa screening. Evidence acquisition: A search of the literature was performed using the Medline database. Further studies were selected based on manual searches of reference lists and review articles. Evidence synthesis: Prostate-specific antigen (PSA) has been shown to be the single most significant predictive factor for identifying men at increased risk of developing PCa. Especially in men with no additional risk factors, PSA alone provides an appropriate marker up to 30 yr into the future. After assessment of an early PSA test, the screening frequency may be determined based on individualized risk. A limited list of additional factors such as age, comorbidity, prostate volume, family history, ethnicity, and previous biopsy status have been identified to modify risk and are important for consideration in routine practice. In men with a known PSA, risk calculators may hold the promise of identifying those who are at increased risk of having PCa and are therefore candidates for biopsy. Conclusions: PSA testing may serve as the foundation for a more risk-based assessment. However, the decision to undergo early PSA testing should be a shared one between the patient and his physician based on information balancing its advantages and disadvantages

Maximal Testosterone Suppression In Prostate Cancer - Free Vs Total Testosterone

Testosterone remains a key target in the treatment of advanced prostate cancer. The relationship of free testosterone to prostate cancer treatment and outcomes remains largely unexplored. A consensus of prostate cancer experts was convened in 2013 to review current knowledge surrounding relationship of total and free testosterone to prostate cancer, discuss the free hormone hypothesis, and highlight future avenues for therapeutics. Free testosterone may better reflect prostate cancer tissue androgen levels than serum total testosterone concentration. Free testosterone deserves more research regarding its relation to clinical outcomes. © 2014 Elsevier Inc. All Rights Reserved.83612171222GSK; GlaxoSmithKlineSharifi, R., Bruskewitz, R.C., Gittleman, M.C., Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer (1996) Clin Ther, 18, pp. 647-657Oefelein, M.G., Feng, A., Scolieri, M.J., Reassessment of the definition of castrate levels of testosterone: Implications for clinical decision making (2000) Urology, 56, pp. 1021-1024Nishiyama, T., Serum testosterone levels after medical or surgical androgen deprivation: A comprehensive review of the literature (2014) Urol Oncol, 32, pp. 38e17-38e28Reis, L.O., Variations of serum testosterone levels in prostate cancer patients under LH-releasing hormone therapy: An open question (2012) Endocr Relat Cancer, 19, pp. 93-R98Wilke, T.J., Utley, D.J., Total testosterone, free-androgen index, calculated free testosterone, and free testosterone by analog RIA compared in hirsute women and in otherwise-normal women with altered binding of sex-hormone-binding globulin (1987) Clin Chem, 33, pp. 1372-1375Zlotta, A., Debruyne, F.M.J., Expert opinion on optimal testosterone control in prostate cancer (2005) Eur Urol Suppl, 4, pp. 37-41Morote, J., Esquena, S., Abascal, J.M., Behavior of free testosterone in patients with prostate cancer on androgen deprivation therapy (2005) Int J Biol Markers, 20, pp. 119-122Morote, J., Esquena, S., Abascal, J., Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer (2006) Urologia Int, 77, pp. 135-138Van Der Sluis, T.M., Bui, H.N., Meuleman, E.J.H., Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: New insights attained by mass spectrometry (2012) J Urol, 187, pp. 1601-1606Aschelter, A.M., Giacinti, S., Caporello, P., Marchetti, P., Genomic and epigenomic alterations in prostate cancer (2012) Front Endocrinol (Lausanne), 3, pp. 1-9Rove, K.O., Debruyne, F.M., Djavan, B., Role of testosterone in managing advanced prostate cancer (2012) Urology, 80, pp. 754-762Crawford, E.D., Rove, K.O., Incomplete testosterone suppression in prostate cancer (2010) N Engl J Med, 363, p. 1976Nishiyama, T., Hashimoto, Y., Takahashi, K., The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer (2004) Clin Cancer Res, 10, pp. 7121-7126Mendel, C.M., The free hormone hypothesis: A physiologically based mathematical model (1989) Endocr Rev, 10, pp. 232-274Matsumoto, A.M., Bremner, W.J., Serum testosterone assays - Accuracy matters (2004) J Clin Endocrinol Metab, 89, pp. 520-524Tombal, B., Berges, R., Optimal control of testosterone: A clinical case-based approach of modern androgen-deprivation therapy (2008) Eur Urol Suppl, 7, pp. 15-21Heidenreich, A., Porres, D., Epplen, R., Change of the LHRH analogue in progressive castration-refractory prostate cancer (2012) Urologe A, 51, pp. 1282-1287Silva, É.D., Ferreira, U., Matheus, W., Goserelin versus leuprolide in the chemical castration of patients with prostate cancer (2012) Int Urol Nephrol, 44, pp. 1039-1044Boccafoschi, C., Prostate cancer and androgen deprivation: Optimal castration? Prospects and developments (2011) Arch Ital Urol Androl, 83, pp. 63-66Novara, G., Galfano, A., Secco, S., Impact of surgical and medical castration on serum testosterone level in prostate cancer patients (2009) Urol Int, 82, pp. 249-255Perachino, M., Cavalli, V., Bravi, F., Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: Prognostic significance? (2010) BJU Int, 105, pp. 648-651Pickles, T., Tyldesley, S., (2011) Testosterone Breakthrough during LHRH Agonist Androgen Deprivation with Curative Radiation: Impact on PSA Kinetics and Subsequent Biochemical Outcomes, , Congress of the European Association of Urology Vienna, AustriaBlumberg, J.M., Kwon, E.O., Cheetham, T.C., Early development of castrate resistance varies with different dosing regimens of luteinizing hormone releasing hormone agonist in primary hormonal therapy for prostate cancer (2011) Urology, 77, pp. 412-416Hussain, M., Tangen, C.M., Berry, D.L., Intermittent versus continuous androgen deprivation in prostate cancer (2013) N Engl J Med, 368, pp. 1314-1325Klotz, L., O'Callaghan, C.J., Goldenberg, S.L., (2013) Nadir Testosterone on ADT Predicts for Time to Castrate Resistant Progression: A Secondary Analysis of the PR-7 Intermittent Vs. Continuous ADT Trial, , Canadian Urological Association Annual Meeting Niagra Falls, Ontario, CanadaDreicer, R., Gleave, M., Kibel, A.S., Targeting the androgen receptor - Theory and practice (2011) Urology, 78 (5 SUPPL.), pp. 482-S484Djavan, B., Eastham, J., Gomella, L., Testosterone in prostate cancer: The Bethesda consensus (2012) BJU Int, 110, pp. 344-352Attard, G., Richards, J., De Bono, J.S., New strategies in metastatic prostate cancer: Targeting the androgen receptor signaling pathway (2011) Clin Cancer Res, 17, pp. 1649-1657Scher, H.I., Fizazi, K., Saad, F., Increased survival with enzalutamide in prostate cancer after chemotherapy (2012) N Engl J Med, 367, pp. 1187-1197De Bono, J.S., Logothetis, C.J., Molina, A., Abiraterone and increased survival in metastatic prostate cancer (2011) N Engl J Med, 364, pp. 1995-2005Schulman, C.C., Irani, J., Morote, J., Testosterone measurement in patients with prostate cancer (2010) Eur Urol, 58, pp. 65-74Nelson, P.S., Molecular states underlying androgen receptor activation: A framework for therapeutics targeting androgen signaling in prostate cancer (2012) J Clin Oncol, 30, pp. 644-646Siddiqui, K., Abbas, F., Biyabani, S.R., Role of estrogens in the secondary hormonal manipulation of hormone refractory prostate cancer (2004) J Pak Med Assoc, 54, pp. 445-447Levell, M.J., Siddall, J.K., Rowe, E., Relationship of testosterone, sex hormone binding globulin, and calculated free testosterone to subsequent clinical progress in patients with carcinoma of the prostate treated with bilateral orchidectomy or estrogens (1987) Prostate, 11, pp. 17-21Karr, J.P., Wajsman, Z., Kirdani, R.Y., Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients (1980) J Urol, 124, pp. 232-236Oh, W.K., The evolving role of estrogen therapy in prostate cancer (2002) Clin Prostate Cancer, 1, pp. 81-89Clemons, J., Glode, L.M., Gao, D., Flaig, T.W., Low-dose diethylstilbestrol for the treatment of advanced prostate cancer (2013) Urol Oncol, 31, pp. 198-204Molina, A., Belldegrun, A., Novel therapeutic strategies for castration resistant prostate cancer: Inhibition of persistent androgen production and androgen receptor mediated signaling (2011) J Urol, 185, pp. 787-794Bellmunt, J., Oh, W.K., Castration-resistant prostate cancer: New science and therapeutic prospects (2010) Ther Adv Med Oncol, 2, pp. 189-207Attard, G., Reid, A.H.M., Yap, T., Phase i clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven (2008) J Clin Oncol, 26, pp. 4563-4571Aggarwal, R., Weinberg, V., Small, E.J., The mechanism of action of estrogen in castration-resistant prostate cancer: Clues from hormone levels (2009) Clin Genitourin Cancer, 7, pp. 71-E76Montgomery, B., Nelson, P.S., Vessella, R., Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer (2010) BMC Cancer, 10, p. 244Getzenberg, R.H., Coss, C.C., Hancock, M.L., GTx-758, an ERα agonist, reduces serum free testosterone lower than can be achieved by leuprolide with a significantly lower rate of hot flashes in men with advanced prostate cancer (2013) Eur Urol Suppl, 12, pp. 102-e103Petrylak, D.P., Tangen, C.M., Hussain, M.H., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer (2004) N Engl J Med, 351, pp. 1513-1520Yu, E.Y., Gittelman, M., Keane, T.E., Effect of GTx-758, an ERα agonist, on serum-free testosterone and serum PSA in men with advanced prostate cancer (2013) J Clin Oncol (Meeting Abstracts), 31 (SUPPL. 6). , http://meetinglibrary.asco.org/content/107554-134, Abstract 104. Available at Accessed September 4, 2013Takizawa, I., Nishiyama, T., Hara, N., Serum prostate-specific antigen levels reflect the androgen milieu in patients with localized prostate cancer receiving androgen deprivation therapy: Tumor malignant potential and androgen milieu (2010) Prostate, 70, pp. 1395-1401Dias, E., Mendonça, G., Zani, E., Reis, L.O., (2013) No Equivalence and Sufficiency of Leuprolide and Goserelin Acetates to Suppress Serum Total Testosterone and PSA Levels, , Congress of the Société Internationale d'Urologie Vancouver, CanadaRosner, W., Vesper, H., Toward excellence in testosterone testing: A consensus statement (2010) J Clin Endocrinol Metab, 95, pp. 4542-4548. , on behalf of The Endocrine Society the endorsing organization

Effect of dutasteride on the risk of prostate cancer.

Item does not contain fulltextBACKGROUND: We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. METHODS: In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. RESULTS: Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). CONCLUSIONS: Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.