Prostate ...

[Michael Scally MD]

[OA] MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.

BACKGROUND - Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited.

METHODS - In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography–guided biopsy.

Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12–core, transrectal ultrasonography–guided biopsy.

The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer.

RESULTS - A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy.

Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005).

MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy.

Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, −13 percentage points; 95% CI, −19 to −7; P<0.001).

CONCLUSIONS - The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography–guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027.)

Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. New England Journal of Medicine 2018. NEJM - Error

 

[Michael Scally MD]

Single PSA screening and futile overdiagnosis

This is one of the most important studies ever done in British primary care. The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) was designed 18 years ago to determine the effects of a low-intensity, single invitation PSA test and standardized diagnostic pathway on prostate cancer–specific and all-cause mortality, while aiming to minimize overdetection and overtreatment.

Now, after a median of 10 years follow-up, it shows no significant difference in prostate cancer mortality between screened and unscreened symptomless men (over 400,000 in the two arms).

Yet there was a nearly 5-fold difference in the diagnosis of prostate cancer between groups in the first 18 months: 10.42 per 1000 person-years in the intervention group compared with 2.18 per 1000 person-years in the control group.

Over subsequent years, the difference waned, but the headline message is clear: the harms of single PSA testing greatly outweigh any possible benefits, because it grossly over-detects harmless early neoplasia. PSA has Perfectly Stupid Attributes as a population screening tool. Researchers who work to timescales like this to resolve real clinical questions are true heroes.

 

[Michael Scally MD]

[OA] A Brief History of Intracrine Androgen Metabolism by Castration-Recurrent Prostate Cancer

This mini-review describes the evolution of the concept of intracrine androgen metabolism by prostate cancer during androgen deprivation therapy. Persistence of androgen receptor protein in the face of castrate circulating levels of testosterone could not be explained fully by hypersensitization or mutation of the androgen receptor.

The hypothesis that castration-recurrent prostate cancer produced its own testosterone was proven using radioimmunoassay and mass spectrometry methods adopted for use in prostate tissue. Intracrine synthesis of testicular androgens led to FDA approval of abiraterone, an inhibitor of androgen metabolism.

Further understanding of intracrine androgen metabolism may allow the development of more targeted agents that perform better and do not require co-administration of prednisone that may extend survival and diminish side effects from treatment of advanced prostate cancer.

Mohler JL. A brief history of intracrine androgen metabolism by castration-recurrent prostate cancer. American journal of clinical and experimental urology 2018;6:101-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902728/

 

[Michael Scally MD]

[OA] Androgen Action in Prostate Function and Disease

Benign prostatic hyperplasia (BPH) is an enlargement of the prostate gland that is frequently found in aging men. Androgens are essential for the development and differentiated function of the prostate, as well as for proliferation and survival of prostatic cells.

In man, dog and rodent, there are age-related decreases in serum testosterone. Despite the lower serum testosterone levels, benign prostatic hyperplasia increases with age in men and dogs, while age-dependent prostatic hyperplasia develops in the dorsal and lateral lobes of the rat prostate.

The possible mechanisms that lead to prostate hyperplasia have been extensively studied over many years. It is clear that androgens, estrogens and growth factors contribute to the condition, but the exact etiology remains unknown.


Prostate cancer (CaP) represents a significant cause of death among males worldwide. As is the case of BPH, it is clear that androgens (testosterone and dihydrotestosterone) and their metabolites play important roles in the disease, but cause-effect relationships have not been established. Androgen deprivation therapy has been used for decades, primarily in the metastatic stage, to inhibit androgen-dependent prostate cancer cell growth. Androgen deprivation, which can be achieved by targeting hormone biosynthesis or androgen receptor activation, results in symptom amelioration.

However, most patients will develop hormone refractory cancer or castration-resistant prostate cancer (CRPC). Prostatic epithelial cells demonstrate enormous plasticity in response to androgen ablation. This characteristic of prostatic epithelial cells may give rise to different populations of cells, some of which may not be dependent on androgen.

Consequently, androgen receptor positive and negative cells might co-exist within CRPC. A clear understanding of this possible cellular heterogeneity and plasticity of prostate epithelial cells is necessary to develop an optimal strategy to treat or prevent CRPC.

Banerjee PP, Banerjee S, Brown TR, Zirkin BR. Androgen action in prostate function and disease. American journal of clinical and experimental urology 2018;6:62-77. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902724/

 

[Michael Scally MD]

[OA] Resolving the Coffey Paradox: what does the androgen receptor do in normal vs. malignant prostate epithelial cells?

Donald Straley Coffey completed his 85 year life's journey on November 9, 2017. In his wake, he left a legion of inspired and loyal students, fellows, and faculty colleagues from all over the world to carry on his passion both for life in general and his 50 year quest to conquer cancer.

Early in his career, Dr. Coffey developed a series of animal models to study how androgen regulates the growth of both normal and abnormal prostatic epithelium. As part of these early studies, Dr. Coffey uncovered a paradox in that anti-androgen treatment given at the "wrong" time paradoxically enhanced, not inhibited, normal prostate growth.

Advances over the last several years concerning the paracrine-dependent stem cell organization of the prostate provide a mechanistic explanation for this "Coffey Paradox". This is based upon the realization that the normal function of the Androgen Receptor (AR) in the paracrine-dependent stem cell organization of the prostate is to induce terminal differentiation of normal prostate epithelial cells while suppressing their growth, despite the presence of high levels of stromal cell-derived paracrine growth factors.

Such growth suppression involves ligand-dependent AR binding to the Tcf-4/beta-catenin 3'c-Myc enhancer in prostate epithelial cells, which inhibits c-Myc transcription needed for proliferation. Therefore, if anti-androgen is given at the wrong time, it prevents such AR-dependent c-Myc down regulation, and thus paradoxically enhances epithelial regrowth (i.e. the Coffey Paradox) induced by exogenous androgen replacement in the castration regressed prostate.

In contrast to the normal prostate epithelium, in prostate cancer cells retaining AR expression, androgen-induced AR signaling no longer reduces c-Myc transcription but instead up-regulates c-Myc translation and protein stability to stimulate malignant growth.

Thus, in these AR expressing prostate cancer cells, AR signaling is converted from a growth suppressor to an oncogene, which involves a gain of function to upregulate c-Myc protein expression. Such a gain of function "addicts" these prostate cancer cells to AR signaling for their proliferation and survival, which provides the rationale for therapy targeted at inhibiting such AR signaling.

While therapies targeted at maximally decreasing the level of androgen ligand are the most commonly used, recent studies have documented that a subset of patients progressing on such androgen ablation (i.e. castration-resistant disease) due to their adaptive increase in AR protein expression respond positively to rapid cycling between pharmacologically high and castration low levels of circulating androgen. [i.e. Bipolar Androgen Therapy (BAT)].

Isaacs JT. Resolving the Coffey Paradox: what does the androgen receptor do in normal vs. malignant prostate epithelial cells? American journal of clinical and experimental urology 2018;6:55-61. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902723/

 

[Michael Scally MD]

Persisting Adverse Body Composition Changes 2 Years After Cessation of Androgen Deprivation Therapy for Localised Prostate Cancer

Objective: Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT.

Design: Prospective case-control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age 67.6 years [interquartile range 64.6, 72.0]) and 29 age-matched (70.6 years [65.3, 72.9]) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median 4.4 years).

Methods: Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MAD [95% CI]) between groups from baseline to study end are reported.

Results: Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (IQR 1.8, 3.1).

Two years after cessation of ADT, total testosterone remained lower (MAD -3.4nmol/L [-6.3, -0.5], p<0.022), fat mass (2214g [490, 3933], p=0.025) and insulin resistance (HOMA2-IR 0.69 [0.31, 1.07], p<0.001) remained higher in cases whereas lean mass (-1450g [-2259, -640], p<0.001) and physical component of QoL remained lower than controls (-11.9 [-16.4, -7.4], p<0.001).

Conclusion: Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted.

This may be related to incomplete testosterone recovery.

Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment.

Cheung AS, Tinson A, Milevski S, Hoermann R, Zajac J, Grossmann M. Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer. European journal of endocrinology 2018. Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer

 

[anonymous_475692]

PSA is produced by both cancerous and non-cancerous prostate cells. Non-cancerous conditions can therefore cause elevated serum PSA levels that must be investigated, resulting in unnecessary medical procedures and patient anxiety.

I really like this and if I may ask from your knowledge what would be the best method of finding out if my PSA is high for my age? because my prostate is swollen an is giving me discomfort, do you have any recommendations?.

I know this is your first message on your thread but I would like to start to learn from that & I hope you’re having a good day today an thank you ahead of time for reading my post

 

[Michael Scally MD]

 

[anonymous_475692]

View attachment 90926

So it’s best to stop steroids and if you do can the prostate decrease in size? An be better?

 

[Michael Scally MD]

Circulating Selenium and Prostate Cancer Risk: A Mendelian Randomization Analysis

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 mug/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies.

We constructed a genetic instrument comprising 11 single nucleotide polymorphisms robustly (P < 5 x 10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72 729 men in the PRACTICAL Consortium (44 825 case subjects, 27 904 control subjects), 114 mug/L higher genetically elevated circulating selenium was not associated with prostate cancer (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.89 to 1.13).

In concordance with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR = 1.21, 95% CI = 0.98 to 1.49) and type 2 diabetes (OR = 1.18, 95% CI = 0.97 to 1.43; in a type 2 diabetes genome-wide association study meta-analysis with up to 49 266 case subjects and 249 906 control subjects).

Our Mendelian randomization analyses do not support a role for selenium supplementation in prostate cancer prevention and suggest that supplementation could have adverse effects on risks of advanced prostate cancer and type 2 diabetes.

Yarmolinsky J, Bonilla C, Haycock PC, et al. Circulating Selenium and Prostate Cancer Risk: A Mendelian Randomization Analysis. Journal of the National Cancer Institute 2018. Circulating Selenium and Prostate Cancer Risk: A Mendelian Randomization Analysis | JNCI: Journal of the National Cancer Institute | Oxford Academic

 

[Michael Scally MD]

[OA] The pendulum swings back: Screening for prostate cancer in 2018

Since the advent of PSA testing in the early 1990s, allowing early detection and treatment of prostate cancer, deaths from this disease have been falling. Subsequently, the US Preventive Services Task Force recommended against PSA testing, a decision that led to declines in prostate cancer screening and detection.

After more than a decade of declining deaths from prostate cancer, research in this issue of Cancer has discovered that rates of metastatic prostate cancer are now increasing.

This finding should prompt physicians to renew their discussions of PSA testing with their patients and, at a national level, calls for an increased focus on clinical trials incorporating new methods of early diagnosis of this disease.

Thompson IM, Jr. The pendulum swings back: Screening for prostate cancer in 2018. Cancer 2018. https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31555

 

[Michael Scally MD]

Recurrence Rates Following Testosterone Therapy in A Large Clinical Cohort of Men with Prostate Cancer

INTRODUCTION AND OBJECTIVES - There is a limited evidence regarding the safety of testosterone (T) therapy (TTh) in men with a history of prostate cancer (PCa). We present here a large single-center experience of TTh in men after a variety of PCa treatments to help guide further clinical decision-making.

METHODS - The electronic medical record database at a men's health center affiliated with an academic hospital was queried to identify men who received TTh for testosterone deficiency after diagnosis and/or treatment of PCa over the previous 5y. Testosterone was delivered via transdermal gels/liquids, short- and long-acting injections, and/or pellets.

Biochemical recurrence (BCR) was operationally defined as PSA 0.3 ng/ml or higher after radical prostatectomy (RP), and PSA nadir plus 2 ng/ml after primary radiation treatment (external beam, brachytherapy). For men on active surveillance (AS) progression was defined as any biopsy showing higher Gleason score than initial diagnosis.

RESULTS - We identified 320 men with a diagnosis of both PCa and T deficiency. Of these, 222 men received TTh. We excluded from analysis men with <3 mo follow-up and men with advanced disease. Mean age for the remaining 199 men was 68y (41-88), and mean follow-up was 50.5 mo.

PCa treatments included RP in 92 men, radiotherapy in 50 men, HIFU in 3 men, and active surveillance in 57 men. BCR was observed in 6 men after RP (6.5%), in 1 man after XRT (2.0%), and in 2 after HIFU. Progression was noted in 2 men on AS (3.5%).

CONCLUSIONS - To our knowledge, this is the largest series to date of TTh in a group of men with PCa. Recurrence rates were consistent with published recurrence/progression rates for the various forms of PCa treatments and for AS. These results provide valuable and reassuring information for clinicians and patients considering TTh for symptomatic men with testosterone deficiency and a history of PCa.

Morgentaler A, Magauran D, Neel D, et al. Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. Data presented in poster format at the American Urological Association 2018 annual meeting in San Francisco, May 18–21. MP17-03. https://www.jurology.com/article/S0022-5347(18)39868-9/fulltext

 

[Michael Scally MD]

Testosterone Supplementation Therapy Does Not Increase the Risk of Prostate Cancer Progression but Might Alter Patient Choice for Definitive Treatment During Active Surveillance

INTRODUCTION AND OBJECTIVES - The AUA Guidelines on Early Detection of Prostate Cancer provide no specific recommendations for prostate cancer screening among men receiving testosterone supplementation therapy (TST). Data has shown that while TST can cause fluctuations in PSA, it does not confer an increased risk of prostate cancer.

As such, concurrent TST in individuals after definitive treatment for prostate cancer is not uncommon. With increasing implementation of active surveillance (AS) protocols, the effect of TST in men with low-risk, untreated prostate cancer warrants more thorough exploration.

METHODS - A retrospective analysis was performed of a single institution database containing men diagnosed with prostate cancer between 2007-2015. The cohort was further subdivided into those with and without concurrent TST. Comparative analysis was performed on diagnostic characteristics and treatment outcomes between the two groups. Statistical analysis consisted of paired t-test with significance determined by p-value < 0.05.

RESULTS - A total of 123 men were included in the analysis: 61 of whom were men on TST with a matched group of 62 non-TST men. Thirty-one percent of the entire cohort was on AS (19 men each in the TST and non-TST groups). There were equivalent rates of individuals with a positive family history (15.7% vs 16.7%).

Overall, men on TST were diagnosed at lower PSA values (3.1 vs 5.3, p = 0.02), 3 years younger at diagnosis (p = 0.34), and on AS for 36 months longer (p = 0.15) as compared to the non-TST patients.

Eleven men demonstrated progression on repeat biopsy during AS (5 in the TST, 6 in the non-TST group). All 5 patients in the TST group and only 1 patient in the non-TST group underwent definitive treatment due to pathologic progression. The remaining non-TST patients with progression chose to continue AS despite recommendations for treatment.

CONCLUSIONS - Without specific guideline-based recommendations, providers are enrolling men in AS who are concurrently on TST. Men on TST were subjected to a more rigorous protocol, as they were biopsied at younger ages and on AS for a longer period of time; however, prostate cancer detection rates were equivalent in this study.

Our data suggests that aggressive screening or treatment is not indicated for men undergoing TST but TST might alter patient choice of definitive therapy during AS protocol. Future studies are needed to further explore the relationship between AS and prostate cancer outcomes for men receiving TST.

Nseyo U, Unterberg S, Hsieh M. Testosterone supplementation does not increase the risk of prostate cancer progression but might alter patient choice for definitive treatment during active surveillance. Data presented in poster format at the American Urological Association 2018 annual meeting in San Francisco, May 18–21. MP17-09. https://www.jurology.com/article/S0022-5347(18)39874-4/fulltext

 

[Michael Scally MD]

Adopting a diet heavy with vegetables did not slow prostate cancer progression among men with low-risk disease who were on active surveillance, according to final, 2-year results from a novel US study presented here at the American Urological Association (AUA) 2018 Annual Meeting.

Parsons and his team had high hopes that helping men learn how to buy, prepare, and consume seven servings of vegetables a day might "substantially inform clinical care of prostate cancer patients."

But those hopes were not realized, at least in the short term.

"There was no significant effect on 2-year clinical progression in active surveillance," Parsons told a packed audience at the plenary session.

Specifically, disease progression — the study's primary outcome — was roughly the same for the men in the intervention arm (n = 226) as for the men in control arm (n = 217) (hazard ratio, 0.96; P = .76).
Medscape: Medscape Access


The Men’s Eating and Living (Meal) Study: A Randomized Clinical Trial of A Diet Intervention In Men On Active Surveillance For Prostate Cancer
https://www.jurology.com/article/S0022-5347(18)42733-4/fulltext

INTRODUCTION AND OBJECTIVES - Diet modifies the risks of prostate cancer incidence and progression. We tested the efficacy of a high-vegetable diet to prevent clinical progression in prostate cancer patients on active surveillance

METHODS - In the Men′s Eating and Living (MEAL) Study (CALGB 70807 [Alliance]), we randomized (1:1) eligible participants to a telephone-based, validated diet counseling intervention promoting vegetable intake or to a control condition for 2 years.

Eligibility criteria included age 50 to 80 years; biopsy-proven adenocarcinoma of the prostate; diagnosis ≤ 24 months prior to presentation with ≥ 10-core prostate biopsy in which < 25% of the total number of cores and ≤ 50% of any single core contained cancer; Gleason sum ≤ 6 for men ≤ 70 years and Gleason sum ≤ (3 + 4) = 7 for men > 70 years; clinical stage ≤ T2a; and serum PSA < 10 ng/mL. Randomization was stratified by age (> 70 years vs. ≥ 70 years), race (African American vs. Other) and time since diagnostic biopsy (0-12 months vs. > 12 and ≤ 24 months).

The primary outcome was clinical progression defined as serum prostate-specific antigen (PSA) ≥ 10 ng/mL, PSA doubling time (PSADT) < 3 years, or pathological progression on follow-up biopsy. The primary endpoint was time to progression (TTP), defined as the length of time from the date of random assignment to clinical progression; patients who died from any cause without experiencing progression were censored at the time of death and patients who elected to pursue treatment despite not meeting the criteria for progression were censored at the time of withdrawal.

The primary analysis will be based on all randomized patients, but exclude those patients who later became ineligible by centralized pathology review of their baseline tissue specimens. Secondary outcomes included the incidence of definitive treatment for prostate cancer.

RESULTS - From 2011 to 2015, 478 (103%) of a targeted 464 patients were randomized at 91 study sites. Final results for the primary and secondary outcomes comparing intervention to control will be presented.

CONCLUSIONS - The MEAL Study is the first national, multi-institutional phase III clinical trial of a diet intervention for prostate cancer. These results may substantially inform clinical care of prostate cancer patients.

 

[Michael Scally MD]

[OA] Recent Changes in Prostate Cancer Trends and Disease Characteristics

BACKGROUND - Temporal trends in prostate cancer incidence and death rates have been attributed to changing patterns of screening and improved treatment (mortality only), among other factors.

This study evaluated contemporary national‐level trends and their relations with prostate‐specific antigen (PSA) testing prevalence and explored trends in incidence according to disease characteristics with stage‐specific, delay‐adjusted rates.

METHODS - Joinpoint regression was used to examine changes in delay‐adjusted prostate cancer incidence rates from population‐based US cancer registries from 2000 to 2014 by age categories, race, and disease characteristics, including stage, PSA, Gleason score, and clinical extension.

In addition, the analysis included trends for prostate cancer mortality between 1975 and 2015 by race and the estimation of PSA testing prevalence between 1987 and 2005. The annual percent change was calculated for periods defined by significant trend change points.

RESULTS - For all age groups, overall prostate cancer incidence rates declined approximately 6.5% per year from 2007. However, the incidence of distant‐stage disease increased from 2010 to 2014. The incidence of disease according to higher PSA levels or Gleason scores at diagnosis did not increase. After years of significant decline (from 1993 to 2013), the overall prostate cancer mortality trend stabilized from 2013 to 2015.

CONCLUSIONS - After a decline in PSA test usage, there has been an increased burden of late‐stage disease, and the decline in prostate cancer mortality has leveled off.

Negoita S, Feuer Eric J, Mariotto A, et al. Annual Report to the Nation on the Status of Cancer, part II: Recent changes in prostate cancer trends and disease characteristics. Cancer 2018. https://doi.org/10.1002/cncr.31549

 

[Michael Scally MD]

Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: Not Yet.

Prostate cancer (PCa) is a heterogeneous disease. After almost a decade of contradictory screening recommendations made by expert and advisory panels (1), prostate cancer has risen again as the second leading cause of cancer death in American males (2).

…

Low-testosterone could be a normal age-related event or a pathological process associated with certain medical conditions. Contrarily to what proponents of TST believe, neither TST efficacy nor its safety have been undoubtedly proved by an unbiased long-term RCT, even in a healthy population.

There is a complex interaction between testosterone and normal/malignant prostate cells and PCa has distinct androgen stimulation pathways that are still not completely elucidated.

Until nowadays, only results of small observational retrospective studies evaluating TST in patients treated with radical prostatectomy are available and there is no definitive data that the prescription of TST in this scenario is safe and does not lead to BCR or clinical progression, mainly in an era when more aggressive PCa are being treated by surgery.

Discussions on TST should start with what we know regarding benefits and risks of this treatment. Categorical statements about TST safety should be evidence-based. At present, clinicians must inform their patients that oncological outcomes of TST on patients after RP are still unknown.

Wroclawski ML, Heldwein FL. Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: Not Yet. International braz j urol : official journal of the Brazilian Society of Urology 2018;44:8-13. Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: Not Yet

 

[Michael Scally MD]

Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: YES.

Testosterone Replacement Therapy (TRT) was – during the last 7 to 8 decades - associated with triggering or worsening of a prostate cancer. A meta-analysis in 2005 of 19 randomized controlled trials showed no statistically significant difference in the diagnosis of prostate cancer in men using TRT or placebo (1).

A pooled-analysis of 18 population-based longitudinal studies comprising 3886 men with prostate cancer (PCa) and 6438 matched controls showed no association between endogenous androgen levels and the risk of developing PCa (2).

However, more controversial is the use of TRT in men after the treatment of a prostate cancer. But, during the last years more and more studies are showing that we can use – at least in a selected group – TRT after radical prostatectomy (RP) in symptomatic hypogonadal men with no impact in the oncologic outcomes. We conducted a Medline search to find publications on TRT after RP and we summarized what we have found in literature.

…

The analysis of all these data raises two questions:

1. Do we have good evidence to conclude that testosterone hormone therapy after radical prostatectomy is safe ?

2. Is there any evidence that it is safe to initiate TRT one year after radical prostatectomy?

…

In conclusion: “Do we have enough evidences to safely treat a man with hypogonadism one year after radical prostatectomy for prostate cancer ?” YES !!

This revision reassures us that selected hypogonadal symptomatic men after curative treatment for prostate cancer with radical prostatectomy can safely receive testosterone replacement therapy, since biochemical recurrence rate of the tumor is very low.

“Do we have enough evidences to safely treat a man with hypogonadism one year after radical prostatectomy for prostate cancer ? YES !

The data above showed us that it is also safe to offer TRT earlier – just three months after surgery ! And the inclusion criteria for the FDA approved Clinical Trial on TRT after RP is three months after surgery with two undetectable PSAs. So why one year after treatment would not be safe ?

Torres LO. Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: YES. International braz j urol : official journal of the Brazilian Society of Urology 2018;44:4-7. Do we have enough evidences that make you safe to treat a man with hypogonadism one year after a radical prostatectomy for prostate cancer? | Opinion: YES

 

[Michael Scally MD]

Schumacher FR, Al Olama AA, Berndt SI, et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature Genetics 2018. https://doi.org/10.1038/s41588-018-0142-8

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry.

Our analysis identified 62 novel loci associated (P < 5.0 × 10−8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10−9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10−9; T>G, p.Val109Gly) in CDKN1B.

The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55–2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04–6.48) risk stratum compared with the population average.

These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .


Dadaev T, Saunders EJ, Newcombe PJ, et al. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nature Communications 2018;9:2256. https://doi.org/10.1038/s41467-018-04109-8

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.

 

[Michael Scally MD]

Persisting Adverse Body Composition Changes 2 Years After Cessation Of Androgen Deprivation Therapy

OBJECTIVE: Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT.

DESIGN: Prospective case-control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age: 67.6 years (interquartile range: 64.6-72.0)) and 29 age-matched (70.6 years (65.3-72.9)) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median: 4.4 years).

METHODS: Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MADs (95% CI)) between groups from baseline to study end are reported.

RESULTS: Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (interquartile range: 1.8-3.1).

Two years after cessation of ADT, total testosterone remained lower (MAD: -3.4 nmol/L (-6.3 to -0.5), P < 0.022), fat mass (2214 g (490-3933), P = 0.025) and insulin resistance (homeostasis model assessment of insulin resistance: 0.69 (0.31-1.07), P < 0.001) remained higher in cases, whereas lean mass (-1450 g (-2259 to -640), P < 0.001) and physical component of QoL remained lower than controls (-11.9 (-16.4 to -7.4), P < 0.001).

CONCLUSION: Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted. This may be related to incomplete testosterone recovery. Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment.

Cheung AS, Tinson AJ, Milevski SV, Hoermann R, Zajac JD, Grossmann M. Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer. European journal of endocrinology 2018;179:21-9. Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer

 

[Michael Scally MD]

[OA] Walsh TJ, Shores MM, Krakauer CA, et al. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels. PloS one 2018;13:e0199194. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels

Purpose - Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP.

Materials and Methods - Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively.

Results - Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49–0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48–0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70–1.13) or any CaP (HR 0.90; 95% CI 0.81–1.01). No association between cumulative testosterone dose or formulation and CaP was observed.

Conclusions - Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.