Prostate ...

[Michael Scally MD]

[Open Access] Testosterone Replacement Therapy and Prostate Cancer Incidence

While early studies demonstrated a positive association between testosterone and prostate cancer, evidence on the nature of the relationship has evolved with time and newer data.

Studies examining links between baseline testosterone levels as well as testosterone therapy and incident prostate cancer, reveal a more complex relationship.

Moreover, investigators have reported their initial experiences with supplementing testosterone in men with a history of both treated and untreated prostate cancer.

Eisenberg ML. Testosterone Replacement Therapy and Prostate Cancer Incidence. World J Mens Health 2015;33(3):125-9. Testosterone Replacement Therapy and Prostate Cancer Incidence

 

[Michael Scally MD]

Study of Testosterone-Guided Androgen Deprivation Therapy in Management of Prostate Cancer

BACKGROUND: Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval.

METHODS: We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for >/=1 year and had castrate serum testosterone [<1.75 nmol/l (approx. 50 ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted.

Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC).

RESULTS: Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was >1 year.

In univariable analysis, lower baseline testosterone [</=1 vs. >1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (>5 vs. </=5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200).

CONCLUSIONS: Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers.

Niraula S, Templeton AJ, Vera-Badillo FE, et al. Study of testosterone-guided androgen deprivation therapy in management of prostate cancer. Prostate 2016;76(2):235-42. Study of testosterone-guided androgen deprivation therapy in management of prostate cancer - Niraula - 2015 - The Prostate - Wiley Online Library

 

[Michael Scally MD]

Endogenous and Exogenous Testosterone and The Risk of Prostate Cancer and Increased Prostate Specific Antigen (PSA)

OBJECTIVE: To review and quantify the association between endogenous and exogenous testosterone and prostate specific antigen (PSA) and prostate cancer.

METHODS: Literature searches were performed following the PRISMA guidelines. Prospective cohort studies that reported data on the associations between endogenous testosterone and prostate cancer, and placebo controlled randomised trials of testosterone replacement therapy (TRT) that reported data on PSA and/or prostate cancer cases were retained. Meta-analyses were performed using random-effects models with tests for publication bias and heterogeneity.

RESULTS: Twenty estimates were included in a meta-analysis which produced a summary relative risk of prostate cancer for an increase of 5 nmol/L of testosterone of 0.99 (95% CI (0.96, 1.02)) without heterogeneity (I(2) = 0%). Based on 26 trials, the overall difference in PSA levels following onset of use of TRT was 0.10 ng/mL (-0.28, 0.48). Results were similar when conducting heterogeneity analyses by mode of administration, region, age at baseline, baseline testosterone, trial duration, type of patients and type of testosterone replacement therapy. The summary relative risk of prostate cancer as an adverse effect from 11 TRT trials was 0.87 (0.30; 2.50). Results were consistent across studies.

CONCLUSIONS: PROSTATE CANCER APPEARS TO BE UNRELATED TO ENDOGENOUS TESTOSTERONE LEVELS. TESTOSTERONE REPLACEMENT THERAPY FOR SYMPTOMATIC HYPOGONADISM DOES NOT APPEAR TO INCREASE PSA LEVELS NOR THE RISK OF PROSTATE CANCER DEVELOPMENT.

The current data are reassuring although some care is essential until multiple studies with longer follow-up are available.

Boyle P, Koechlin A, Bota M, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate specific antigen (PSA): a meta-analysis. BJU Int. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate specific antigen (PSA): a meta-analysis - Boyle - BJU International - Wiley Online Library

 

[Michael Scally MD]

[Open Access] Challenges To Treat Hypogonadism In Prostate Cancer Patients

The literature suggests that the serum testosterone level required for maximum androgen receptor (AR) binding may be in the range of nanomolar and above this range of concentrations; this sexual hormone may not significantly affect tumour biology.

This assumption is supported by clinical studies showing that cell proliferation markers did not change when serum T levels increased after exogenous T treatment in comparison to subjects treated with placebo.

However, a considerable part of the global scientific community remains sceptical regarding the use of testosterone replacement therapy (TRT) in men suffering from hypogonadism and prostate cancer (Pca).

The negative attitudes with respect to testosterone supplementation in men with hypogonadism and Pca may be justified by the relatively low number of clinical and preclinical studies that specifically dealt with how androgens affect Pca biology.

More controversial still is the use of TRT in men in active surveillance or at intermediate or high risk of recurrence and treated by curative radiotherapy.

In these clinical scenarios, clinicians should be aware that safety data regarding TRT are scanty limiting our ability to draw definitive conclusions on this important topic.

In this review we critically discuss the newest scientific evidence concerning the new challenges in the treatment of men with hypogonadal condition and Pca providing new insights in the pharmacological and psychological approaches.

Gravina GL, Di Sante S, Limoncin E, et al. Challenges to treat hypogonadism in prostate cancer patients: implications for endocrinologists, urologists and radiotherapists. Transl Androl Urol 2015;4(2):139-47. Challenges to treat hypogonadism in prostate cancer patients: implications for endocrinologists, urologists and radiotherapists - Gravina - Translational Andrology and Urology

 

[Michael Scally MD]

[Open Access] Racial Differences in Age-Related Variations of Testosterone Levels Among US Males: Potential Implications for Prostate Cancer and Personalized Medication

AIM: The magnitude of the age-related declines in testosterone rather than levels measured at single point in time may be related to the genesis of prostate cancer (PCa). We examined age-related variations of testosterone levels among black and white males, which may provide important insights into racial disparities in PCa incidence and mortality.

METHOD: We analyzed data from the 1999-2004 National Health and Nutritional Examination Survey to compare age-related variations in the testosterone levels of 355 black and 631 white males.

RESULT: Overall, between the ages of 12 and 15, black males had lower testosterone levels than white males. Testosterone levels increased rapidly with age and reached higher and earlier peak levels in black males compared to white males at 20-30 years of age.

After reaching a peak level, testosterone levels declined earlier in blacks than in whites. Further analyses showed that black males had considerably higher levels of testosterone compared to white males aged 20-39 years after adjusting for covariates, including age, body mass index, cigarette smoking, physical activity, and waist circumference; however, no statistically significant differences were observed between the groups at any other age.

CONCLUSION: Our study revealed that testosterone levels in black males decrease substantially with increasing age compared to those in white males. This rapid drop in testosterone levels may contribute to racial disparities in PCa. Our findings also suggest that personalized medication for hormone replacement therapy may be necessary to avoid sudden drops in testosterone levels, particularly for black males.


Hu H, Odedina FT, Reams RR, Lissaker CT, Xu X. Racial Differences in Age-Related Variations of Testosterone Levels Among US Males: Potential Implications for Prostate Cancer and Personalized Medication. J Racial Ethn Health Disparities 2016;2(1):69-76. Racial Differences in Age-Related Variations of Testosterone Levels Among US Males: Potential Implications for Prostate Cancer and Personalized Medication - Springer

 

[Michael Scally MD]

Efesoy O, Apa D, Tek M, Cayan S. The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism. Aging Male. An Error Occurred Setting Your User Cookie

OBJECTIVES: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

METHODS: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4 ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

RESULTS: The mean serum total testosterone significantly increased from 178.04 +/- 51.92 to 496.28 +/- 103.73 ng/dl (p = 0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

CONCLUSIONS: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.

 

[Michael Scally MD]

[Open Access] Current Status of Primary Pharmacotherapy and Future Perspectives Toward Upfront Therapy for Metastatic Hormone-Sensitive Prostate Cancer

Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking.

However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades.

Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy.

The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field.

Shiota M, Eto M. Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer. International Journal of Urology. Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer - Shiota - 2016 - International Journal of Urology - Wiley Online Library

 

[Michael Scally MD]

Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. Testosterone Therapy In Patients With Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. The Journal of Urology. Testosterone Therapy In Patients With Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes

Purpose - Both testosterone deficiency (TD) and prostate cancer (CaP) have increasing prevalence with age. However, because of the relationship between CaP and androgen receptor activation, testosterone therapy (TT) among patients with known CaP has been approached with caution.

Materials and Methods - We identified a cohort of 82 hypogonadal men with CaP who were treated with TT. These included 50 men treated with Radiation Therapy (XRT), 22 with Radical Prostatectomy (RP), 8 managed with Active Surveillance (AS), 1 with Cryotherapy and 1 with High-Intensity Focused Ultrasound. We monitored prostate specific antigen (PSA), testosterone, hemoglobin, biochemical recurrence (BCR) and PSA Velocity (PSAV).

Results - Median patient age was 75.5 years and median follow up was 41 months. We found an increase in both testosterone (p<0.001) and PSA (p=0.001) levels in the entire cohort. PSA increased in the AS patients, however no patients were upgraded to higher Gleason Score on subsequent biopsies, and none have yet gone on to definitive treatment. We did not have any cases of BCR amongst RP patients, but 3 XRT patients (6%) experienced BCR. It is unclear whether these were related to TT or reflected the natural biology of their disease. We calculated the mean PSAV to be 0.001, 0.12, and 1.1 ug/L/yr for the RP, XRT, and AS groups, respectively.

Conclusions - In the absence of randomized placebo controlled trials, our study supports the hypothesis that TT may be oncologically safe in hypogonadal men following definitive treatment or active surveillance for CaP.

 

[Michael Scally MD]

Novel Dual-Binding Selective Degraders of Full Length and Splice Variant Androgen Receptors for the Treatment of Castration-Resistant Prostate Cancer
http://www.aua2016.org/abstracts/abstractprint.cfm?id=LB-S&T-06

Introduction and Objectives - The clinical success of new androgen receptor (AR)-targeted therapies in patients with castration-resistant prostate cancer (CRPC) emphasizes the continued importance of the AR signaling axis in the disease. Despite the use of this new generation of therapies, some men with CRPC do not respond and resistance to these therapies typically develops for those that do.

Mechanisms attributed to the emergence of this non-responsive CRPC include the expression of ligand binding domain (LBD)-null constitutively active splice variants of the AR (AR-SV), hyperactive AR, and others. These AR-SV expressing CRPCs require alternate approaches to inhibit both the full length and AR-SVs.

The objective of this work is to develop selective androgen receptor degraders (SARDs) that degrade all forms of the AR and provide advanced treatment options to men with CRPC.

Methods - AR ligand binding, transactivation, fluorescence polarization, and Western blot assays were performed to screen novel SARDs. Prostate cancer cell line gene expression, proliferation, cell line and patient-derived xenografts (PDX) were performed to evaluate the efficacy of SARDs. Molecular mechanistic studies were performed to understand the mechanism of action.

Results - A novel series of highly potent SARDs with unique pharmacology have been discovered. These compounds selectively bind to the LBD, inhibit, and degrade the AR at nanomolar concentrations. The SARDs degrade AR-V7 and other variants that lack the LBD and inhibit the proliferation of AR- and AR-SV- dependent PCa cells with potencies better than that of comparators.

SARDs robustly inhibit the growth of the LNCaP androgen-dependent prostate cancer (PCa) xenograft, the 22RV1 CRPC xenograft, and AR- and AR-SV- positive CRPC patient-derived xenografts (PDX). 22RV1 and PDX Pr-3001 are dependent on AR-SV expression and the observed inhibition of growth is indicative of the SARDs&[prime] ability to inhibit the AR-SV activity in vivo.

Quenching of the steady-state fluorescence spectrum supports an interaction between the SARDs and the AR activation function domain (AF-1), making these molecules first-in-class dual-interacting AR antagonists and degraders. Ongoing studies are revealing the mechanism of action for these SARDs.

Conclusions - Novel highly potent SARDs that interact with both the AF-1 and LBD of the AR were discovered and characterized as a potential next-generation treatment option for CRPC.

 

[Michael Scally MD]

Geifman N, Butte AJ. A patient-level data meta-analysis of standard-of-care treatments from eight prostate cancer clinical trials. Sci Data 2016;3:160027. A patient-level data meta-analysis of standard-of-care treatments from eight prostate cancer clinical trials : Scientific Data

Open clinical trial data offer many opportunities for the scientific community to independently verify published results, evaluate new hypotheses and conduct meta-analyses. These data provide valuable opportunities for scientific advances in medical research.

Herein we present the comparative meta-analysis of different standard of care treatments from newly available comparator arm data from several prostate cancer clinical trials.

Comparison of survival rates following treatment with mitoxantrone or docetaxel in combination with prednisone as well as prednisone alone, validated the previously demonstrated superiority of treatment with docetaxel.

Additionally, comparison of four testosterone suppression treatments in hormone-refractory prostate cancer revealed that subjects who had undergone surgical castration had significantly lower survival rates than those treated with LHRH, anti-androgen or LHRH plus anti-androgen, suggesting that this treatment option is less optimal.

This study illustrates how the use of patient-level clinical trial data enables meta-analyses that can provide new insights into clinical outcomes of standard of care treatments and thus, once validated, has the potential to help optimize healthcare delivery.

 

[Michael Scally MD]

Dihydrotestosterone (DHT) Sensitizes Prostate Cell Death

Androgen receptor (AR) signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology.

Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5alpha-dihydrotestosterone (DHT) treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS), TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself.

We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP) in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes.

Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2) were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1) were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins, such that androgen signaling sensitizes mitochondria to apoptotic signaling, thus rendering HPr-1AR more vulnerable to cell death signals. Our study offers insight into AR-mediated regulation of prostate epithelial cell death signaling.

Chen C, Dienhart JA, Bolton EC. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells. PLoS One 2016;11(5):e0156145. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells

 

[Michael Scally MD]

Flawed Study of Advanced Prostate Cancer Spreads False Alarm
http://www.nytimes.com/2016/07/21/health/advanced-prostate-cancer-false-alarm.html

Bad news for men popped up in news media all over the country this week, based on a study from Northwestern University reporting that cases of advanced, aggressive prostate cancer had risen sharply from 2004 to 2013.

Newsweek, NBC, CBS, Fox News and United Press International were among the organizations that covered the study. The reports suggested that recent medical advice against routine screening might be to blame for the apparent increase in advanced cases, by leading to delays in diagnosis until the cancer reached a late stage. Another factor cited was the possibility that prostate cancer had somehow become more aggressive.

But the frightening news appears to be a false alarm — the product of a study questioned by other researchers but promoted with an incendiary news release and initially reported by some news media with little or no analysis from outside experts.

The claim of an increase in advanced cases does not hold up, according to the American Cancer Society, which posted a statement on its website challenging the findings. The main concern is that the study’s methods do not pass muster with statistics experts, so the increase may not be real.

In an interview, the cancer society’s chief medical officer, Dr. Otis W. Brawley, called the study “misguided epidemiology” and said its authors “don’t know that they don’t know.”

The episode began late last week when Northwestern University emailed an attention-grabbing news release to reporters. “Metastatic Prostate Cancer Cases Skyrocket,” it said, and described a study published Tuesday in the journal Prostate Cancer and Prostatic Diseases.

The study’s authors wrote that routine use of blood tests to screen for prostate cancer had declined, and that they wanted to find out if the decline had led to changes in the incidence of advanced disease at the time of diagnosis.

Prostate screening has long been a subject of intense debate, with advocates insisting it saves lives and detractors saying it leads to too much unnecessary treatment of tumors that would never have progressed. The operation can leave men incontinent and impotent. In recent years, expert groups have advised against routine screening, saying the risks outweigh the benefits. But some doctors worry that the drop in screening will leave some men with disease that is found too late to be easily cured.

The senior author of the study, Dr. Edward Schaeffer, a prostate cancer oncologist and the chairman of urology at Northwestern, said in an interview that he believed screening saved lives.

In the study, the doctors examined the records of 767,550 men with prostate cancer diagnosed from 2004 to 2013. Using the number of cases of metastatic disease in 2004 (1,685) and 2013 (2,890), they reported an alarming increase of 72 percent.

But for the United States population, that percentage could be meaningless. On the cancer society website, Dr. Brawley said that to measure whether a disease was becoming more common, researchers could not rely on just the absolute number of cases. They need to calculate rates, meaning the number of cases per a certain number of people.

“Epidemiologists learned long ago that you can’t simply look at raw numbers,” he wrote. “A rising number of cases can be due simply to a growing and aging population among other factors.”

Another expert expressed similar doubts. Dr. Christopher Filson, an assistant professor of urology at Emory University School of Medicine, said: “I don’t want to claim their results are wrong. They may be true, but the way they looked at the question brings in too many possible alternative explanations.”

The authors acknowledged in their report that the lack of rates was a “limitation.” But they said that because the number of patients was large, their findings probably reflected national patterns.

Dr. Schaeffer emphasized that the researchers did not claim a link between their findings and the advisories against screening; they noted that advanced cases started rising even before those.

Most of the initial news articles about the study reported the supposed increase without caveats, and few quoted the cancer society or outside experts. In some cases, online versions of the articles were amended to tone down the message and add comments from Dr. Brawley.

Maggie Fox, a reporter for NBC, said she reported on the study because “prostate cancer is a huge issue in this country, and the question of screening has been greatly controversial.” Dr. Schaeffer, she said, is influential. “What he says will make waves, and we felt it was important to report and include criticism of the study.”

Dr. Brawley said that even if further analysis found an increase in advanced cases, it would probably be from improvements in magnetic resonance imaging scanning. In other words, rather than reflecting more cases of advanced disease, the increase would mean doctors had become better at finding it.



Weiner AB, Matulewicz RS, Eggener SE, Schaeffer EM. Increasing incidence of metastatic prostate cancer in the United States (2004-2013). Prostate Cancer Prostatic Dis. Prostate Cancer and Prostatic Diseases - Increasing incidence of metastatic prostate cancer in the United States (2004-2013)

Background: Changes in prostate cancer screening practices in the United States have led to recent declines in overall incidence, but it is unknown whether relaxed screening has led to changes in the incidence of advanced and metastatic prostate cancer at diagnosis.

Methods: We identified all men diagnosed with prostate cancer in the National Cancer Data Base (2004–2013) at 1089 different health-care facilities in the United States. Joinpoint regressions were used to model annual percentage changes (APCs) in the incidence of prostate cancer based on stage relative to that of 2004.

Results: The annual incidence of metastatic prostate cancer increased from 2007 to 2013 (Joinpoint regression: APC: 7.1%, P<0.05) and in 2013 was 72% more than that of 2004. The incidence of low-risk prostate cancer decreased from years 2007 to 2013 (APC: −9.3%, P<0.05) to 37% less than that of 2004. The greatest increase in metastatic prostate cancer was seen in men aged 55–69 years (92% increase from 2004 to 2013).

Conclusions: Beginning in 2007, the incidence of metastatic prostate cancer has increased especially among men in the age group thought most likely to benefit from definitive treatment for prostate cancer. These data highlight the continued need for nationwide refinements in prostate cancer screening and treatment.

 

[Michael Scally MD]

Prostate Cancer Isn’t Colorblind
http://www.nytimes.com/2016/07/27/opinion/prostate-cancer-isnt-colorblind.html

ST. LOUIS — In 1966, the Rev. Dr. Martin Luther King Jr. said, “Of all the forms of inequality, injustice in health care is the most shocking and inhuman.” While major advances have been made in health care, ethnic and racial disparities remain in the prevention, diagnosis and treatment of many illnesses, particularly prostate cancer.

The risks facing African-Americans are shocking: They have the highest incidence of prostate cancer and the highest mortality rate from the disease of any ethnic or racial group in the United States. One in six African-American men will develop prostate cancer in his lifetime, and one in 23 will die from it. The mortality rate is 2.4 times higher than that of the overall population. Indeed, the racial disparity related to prostate cancer is greater than for almost all other solid tumors.

Beginning in the 1990s, doctors began administering the prostate-specific antigen test, the most significant advancement in the diagnosis of prostate cancer. PSA is a protein secreted by prostate tissue and is easily measured with a simple blood test, allowing for early detection of prostate cancer.

Before the widespread use of PSA screening, advanced or metastatic prostate cancers constituted 25 percent of newly diagnosed cases in white men, and 50 percent in African-American men. These advanced-stage cancers remain difficult to treat and incurable. The most effective therapy includes lifelong testosterone-lowering drugs or castration, with all its grave side effects. Thankfully, with the widespread use of PSA screening, fewer than 5 percent of men with newly diagnosed cases are found to have metastatic prostate cancer.

Unfortunately, PSA is an imperfect screening tool. While an elevated PSA level may indicate prostate cancer, an abnormal blood test may occur for reasons unrelated to the disease and can also lead to the detection of prostate cancers that are unlikely to be life-threatening.

Guidelines from most medical organizations acknowledge these shortcomings and recommend that men weigh the benefits and limitations of PSA screening before deciding whether it is right for them.

Four years ago, however, the United States Preventive Services Task Force went further, recommending against routine PSA screenings for all men. This recommendation was based largely on the findings of two clinical studies that enrolled more than 250,000 men. The problem is that neither of these trials had enough black subjects to accurately assess the impact of screening in this high-risk population. This low rate of participation runs counter to a National Cancer Institute directive requiring adequate representation of minorities in clinical trials.

The government guidelines stunned doctors who recognize the greater dangers of prostate cancer in African-American men. Many believe that the disadvantages of routine PSA screening are outweighed when it comes to high-risk populations, and they worry that the guidelines will lead to less screening for men who might benefit the most from it. Their concerns have been borne out: Recent studies note a decrease in PSA screening for all populations, including African-American men.

Current screening techniques may have flaws, but that doesn’t mean they should be scrapped altogether, particularly for African-American men who develop prostate cancer at an earlier age. For them, the disease can be more aggressive, with double the mortality rate. Thanks to the routine use of PSA screening and improved therapies over the past 25 years, all racial and ethnic groups have experienced a decrease in mortality from the disease.

What’s needed, instead, is a smarter approach that incorporates the American Cancer Society’s recommendation that doctors and patients discuss the risks and benefits of PSA tests beginning at age 45 for African-American men, and at younger ages for men with a strong family history of prostate cancer.

The discussion should acknowledge that African-American men are at a higher risk of developing and dying from prostate cancer, that they have an increased risk for aggressive disease at diagnosis, that there are significant advancements in the detection and staging of prostate cancer, that the PSA test is just one of many available to help make an educated decision, and that the importance of seeking high-quality cancer care with supportive services and clinical trial opportunities are paramount.

In 2010 the Centers for Disease Control and Prevention began its Healthy People 2020 program, which among other things calls for a reduction of prostate cancer mortality by 10 percent, to 21.8 deaths per 100,000 men. But without a smarter approach to screening, this goal is unachievable for African-American men.

Amid our renewed national conversation about racial discrimination and equality, injustice in health care must be addressed directly. We can start by rethinking how we talk about and test for prostate cancer.

 

[Michael Scally MD]

Testosterone Therapy Among Prostate Cancer Survivors

INTRODUCTION: The use of testosterone in men with a history of prostate cancer remains controversial in light of established findings linking androgens to prostate cancer growth. However, hypogonadism significantly affects quality of life and has negative sequelae, and the risks and benefits of testosterone therapy might be worthwhile to consider in all men, even those with a history of high-risk prostate cancer.

AIM: To discuss the effects of testosterone on the prostate and the use of testosterone therapy in hypogonadal men with a history of prostate cancer.

METHODS: Review of the literature examining the effects of testosterone on the prostate and the efficacy and safety of exogenous testosterone in men with a history of prostate cancer.

MAIN OUTCOME MEASURES: Summary of effects of exogenous and endogenous testosterone on prostate tissue in vitro and in vivo, with a focus on effects in men with a history of prostate cancer.

RESULTS: Testosterone therapy ameliorates the symptoms of hypogonadism, decreases the risk for its negative sequelae, and can significantly improve quality of life. Recent studies do not support an increased risk for de novo prostate cancer, progression of the disease, or biochemical recurrence in hypogonadal men with a history of non-high-risk prostate cancer treated with testosterone therapy. Evidence supporting the use of testosterone in the setting of high-risk prostate cancer is less clear.

CONCLUSION: Despite the historical reluctance toward the use of testosterone therapy in men with a history of prostate cancer, modern evidence suggests that testosterone replacement is a safe and effective treatment option for hypogonadal men with non-high-risk prostate cancer. Additional work to definitively demonstrate the efficacy and safety of testosterone therapy in men with prostate cancer is needed, and persistent vigilance and surveillance of treated men remains necessary.

Nguyen TM, Pastuszak AW. Testosterone Therapy Among Prostate Cancer Survivors. Sex Med Rev. Testosterone Therapy Among Prostate Cancer Survivors

 

[Michael Scally MD]

Gnanapragasam VJ, Lophatananon A, Wright KA, Muir KR, Gavin A, Greenberg DC. Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study. PLoS Med 2016;13(8):e1002063. Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study

Why Was This Study Done?

· Prostate cancer incidence is rising worldwide, and, with improved detection, increasing proportions of men are presenting with non-metastatic disease (over 80%). Amongst these men, the disease is heterogeneous, and different management options are possible.
· Risk stratification is the primary method of deciding which treatment is appropriate for an individual. However, the current method of risk stratification is based on historical data and was not originally validated against prostate cancer mortality as an outcome. Moreover, no current risk stratification system has been developed first in an unscreened population, which represents the vast majority of men presenting with prostate cancer worldwide.
· Current risk models therefore require improvement to be more relevant for the management of prostate cancer in patients. In this study, we sought to improve clinical risk stratification by refining the attributes that make up the current risk stratification system and incorporating the latest pathological grading system for prostate cancer from the International Society of Urological Pathology.


What Did the Researchers Do and Find?

· We studied a large dataset from a cohort of UK patients. Data from 10,139 men were available, and the cohort was split into a training group and a testing group for analysis.
· Clinico-pathological characteristics at diagnosis (including clinical stage, biopsy grade, and prostate-specific antigen [PSA] concentration) were used first to categorise patients according to the standard three-stratum risk stratification system (from the UK NICE guidelines). These same three individual characteristics were then used to sub-stratify within each risk group. In addition, we incorporated the new pathological prognostic grading system (score 1–5) recently adopted by the International Society of Urological Pathology.
· We found that the new risk model (with five subgroups) was significantly better at identifying patient populations with very different outcomes in terms of prostate-cancer-specific mortality. The model performance held true even when other competing risks of death were included. Most importantly, the model demonstrated improved prognostic power in comparison to the NICE stratification system, both in our primary cohort and in a separate external validation cohort.


What Do These Findings Mean?

· To our knowledge, this study is the first to test the standard three-stratum risk stratification system in an unscreened first diagnosis population and to measure this system’s ability to predict prostate-cancer-specific mortality. We show that this model has a poor concordance for predicting mortality outcome at the point of diagnosis and is probably of little value in this context.
· Our new model performs much better and not only improves prediction of mortality but also provides better distinction of patient subgroups to inform clinical decision making. Moreover, the cohorts used for our study are more representative of real-world practice, where screening for prostate cancer is uncommon.
· These findings do need further validation in independent external cohorts, and our study is limited by its reliance on cancer registry records and relatively short follow-up.
· Nevertheless, the large sample size and the consistency of our findings in external validation suggest that these findings are robust and ready for clinical use. The new model does not require any additional variables other than those routinely collected at diagnosis in any clinic setting worldwide and will therefore be simple to adopt internationally.

 

[Michael Scally MD]

Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. Testosterone Therapy in Patients with Treated and Untreated Prostate Cancer: Impact on Oncologic Outcomes. The Journal of Urology 2016;196(4):1082-9. http://www.jurology.com/article/S0022-5347(16)30307-X/fulltext

Purpose - Testosterone deficiency and prostate cancer have an increasing prevalence with age. However, because of the relationship between prostate cancer and androgen receptor activation, testosterone therapy among patients with known prostate cancer has been approached with caution.

Materials and Methods - We identified a cohort of 82 hypogonadal men with prostate cancer who were treated with testosterone therapy. They included 50 men treated with radiation therapy, 22 treated with radical prostatectomy, 8 on active surveillance, 1 treated with cryotherapy and 1 who underwent high intensity focused ultrasound. We monitored prostate specific antigen, testosterone, hemoglobin, biochemical recurrence and prostate specific antigen velocity.

Results - Median patient age was 75.5 years and median followup was 41 months. We found an increase in testosterone (p <0.001) and prostate specific antigen (p = 0.001) in the entire cohort. Prostate specific antigen increased in patients on active surveillance. However, no patients were upgraded to higher Gleason score on subsequent biopsies and none have yet gone on to definitive treatment.

We did not note any biochemical recurrence among patients treated with radical prostatectomy but 3 (6%) treated with radiation therapy experienced biochemical recurrence. It is unclear whether these cases were related to testosterone therapy or reflected the natural biology of the disease. We calculated mean prostate specific antigen velocity as 0.001, 0.12 and 1.1 μg/l per year in the radical prostatectomy, radiation therapy and active surveillance groups, respectively.

Conclusions - In the absence of randomized, placebo controlled trials our study supports the hypothesis that testosterone therapy may be oncologically safe in hypogonadal men after definitive treatment or in those on active surveillance for prostate cancer.

 

[Michael Scally MD]

Prostate Magnetic Resonance Imaging Findings in Patients Treated for Testosterone Deficiency While On Active Surveillance for Low-Risk Prostate Cancer

Highlights

• We investigated the mpMRI findings in patients treated with TRT.
• The PI-RADSv2 scores increased after TRT in 2/12 patients.
• Both patients experienced Gleason score upgrade on follow-up biopsy.

OBJECTIVE: To investigate the multiparametric prostate magnetic resonance imaging (mpMRI) findings in patients treated with testosterone replacement therapy (TRT) while on active surveillance for low-risk prostate cancer.

METHODS: We retrospectively reviewed 12 patients who underwent mpMRI before and after TRT while on active surveillance. Changes in serum testosterone level, prostate-specific antigen (PSA), prostate biopsy findings, prostate volume, and Prostate Imaging Reporting and Data System Version 2 (PI-RADSv2) score before and after TRT were summarized.

RESULTS: After TRT, there was a significant increase in serum testosterone (516.5ng/dl vs. 203.0ng/dl), PSA (4.2ng/ml vs. 3.3ng/ml), and prostate volume (55.2cm3 vs. 39.4cm3). In total, 2 patients had biopsy progression during the study period. The PI-RADSv2 scores before and after TRT were unchanged in 10/12 patients; none of these demonstrated biopsy progression on post-TRT. The PI-RADSv2 scores increased after TRT in 2/12 patients; both showed Gleason score upgrade on follow-up biopsy. Of these 2 patients, 1 patient underwent radical treatment due to clinical progression. The area under the curve for detecting biopsy progression calculated from PI-RADSv2 score after TRT was 0.90, which was better than that calculated from post-TRT PSA level (0.48).

CONCLUSIONS: After TRT, mpMRI findings remained stable in patients without biopsy progression, whereas PI-RADSv2 score increase was identified in patients with Gleason score upgrade on follow-up biopsy.

Hashimoto T, Rahul K, Takeda T, et al. Prostate magnetic resonance imaging findings in patients treated for testosterone deficiency while on active surveillance for low-risk prostate cancer. Urol Oncol. http://www.urologiconcology.org/article/S1078-1439(16)30167-3/abstract

 

[Michael Scally MD]

Fiamegos A, Varkarakis J, Kontraros M, et al. Serum testosterone as a biomarker for second prostatic biopsy in men with negative first biopsy for prostatic cancer and PSA>4ng/mL, or with PIN biopsy result. Int Braz J Urol 2016;42(5):925-31. Serum testosterone as a biomarker for second prostatic biopsy in men with negative first biopsy for prostatic cancer and PSA>4ng/mL, or with PIN biopsy result

INTRODUCTION: Data from animal, clinical and prevention studies support the role of androgens in prostate cancer growth, proliferation and progression. Results of serum based epidemiologic studies in humans, however, have been inconclusive. The present study aims to define whether serum testosterone can be used as a predictor of a posi nottive second biopsy in males considered for re-biopsy.

MATERIAL AND METHODS: The study included 320 men who underwent a prostatic biopsy in our department from October 2011 until June 2012. Total testosterone, free testos notterone, bioavailable testosterone and prostate pathology were evaluated in all cases. Patients undergoing a second biopsy were identified and biopsy results were statistically analyzed.

RESULTS: Forty men (12.5%) were assessed with a second biopsy. The diagnosis of the second biopsy was High Grade Intraepithelial Neoplasia in 14 patients (35%) and Prostate Cancer in 12 patients (30%). The comparison of prostatic volume, total testosterone, sex hormone binding globulin, free testosterone, bioavailable testosterone and albumin showed that patients with cancer of the prostate had significantly greater levels of free testosterone (p=0.043) and bioavailable T (p=0.049).

CONCLUSION: In our study, higher free testosterone and bioavailable testosterone levels were associated with a cancer diagnosis at re-biopsy. Our results indicate a possible role for free and bioavailable testosterone in predicting the presence of prostate cancer in patients considered for re-biopsy.

 

[Michael Scally MD]

Schiff JP, Lewis BE, Ledet EM, Sartor O. Prostate-specific Antigen Response and Eradication of Androgen Receptor Amplification with High-dose Testosterone in Prostate Cancer. Eur Urol. https://www.sciencedirect.com/science/article/pii/S0302283816309125

Metastatic castrate-resistant prostate cancer (CRPC) has been studied from a tissue-based molecular perspective and much has been learned. Alterations in the androgen receptor (AR) are common, as are a multiplicity of other genetic changes.

More recent studies indicate that plasma cell-free DNA (cfDNA) may be used to assess the molecular genetics of tumors, and potentially direct therapy. Resistance to newer hormonal agents such as abiraterone and enzalutamide can be predicted by cfDNA changes, including both AR amplification and select AR mutations.

Here we describe a case involving a heavily pretreated patient for whom high-dose testosterone (HDT) eradicated AR amplification and restored sensitivity to abiraterone after prior resistance. The effect of HDT therapy on patients with progressive metastatic CRPC has been described, but no effects on AR or MYC amplification have been reported. We hypothesize that these cfDNA findings are of mechanistic importance in terms of understanding the subsequent restoration of abiraterone sensitivity.

This case demonstrates eradication of AR and MYC amplification, PSA declines, and clinical improvement with HDT therapy. After the PSA response and the subsequent PSA progression on HDT, reintroduction of abiraterone resulted in a PSA response even though the patient had previously experienced clear progression on abiraterone therapy. We believe that this concept should be further explored in the context of prospective clinical trials such as the TRANSFORMER trial.

 

[Michael Scally MD]

[Podcast] Testosterone Treatment for Prostate Cancer
Testosterone Treatment for Prostate Cancer

Dr. Samuel Denmeade led the research team at Johns Hopkins University to explore the effects of testosterone on prostate cancer. Prostate cancer patients were deprived of testosterone and then treated with the hormone. In some cases, the cancer cells died completely. About one-third of the patients in the study responded very well to the testosterone treatment.

Listen as Dr. Denmeade joins Dr. Susanne Bennett to share the results of the study and the potential future for testosterone treatment of prostate cancer.