Prostate ...

[Michael Scally MD]

[OA] [Mice] Testosterone Diminishes Cabazitaxel Efficacy and Intratumoral Accumulation in a Prostate Cancer Xenograft Model
http://www.ebiomedicine.com/article/S2352-3964(17)30505-4/fulltext

Highlights
• Cabazitaxel is highly effective in a castrate setting, while tumor growth inhibition is completely abolished with high AR pathway activity.
• Intratumoral cabazitaxel levels were 3.5 times higher in tumors from castrated mice as compared to tumors from androgen-supplemented animals.

We studied the efficacy of the chemotherapeutic cabazitaxel in castrate mice and mice receiving testosterone. While cabazitaxel was highly effective in castrate mice, it was ineffective in mice receiving testosterone. This was likely caused by higher cabazitaxel levels, as chemotherapeutic levels in tumors from castrate mice were about 3.5 fold higher.

Our study shows that cabazitaxel efficacy might be impacted by androgens and cabazitaxel efficacy is improved in combination with androgen deprivation therapy and possibly androgen receptor targeted therapy.

 

[Michael Scally MD]

Karakiewicz P, Nazzani S. A valuable tool for prediction of repeat biopsy pathology. Nature Reviews Urology 2017. http://dx.doi.org/10.1038/nrurol.2017.216

Multiparametric MRI (mpMRI) findings are not always accurate in patients with a previous negative prostate biopsy. Truong et al. have developed a nomogram to identify patients with previous negative prostate biopsy who are at elevated risk of harbouring benign histology and should undergo repeat biopsy.


Truong M, Wang B, Gordetsky JB, et al. Multi-institutional nomogram predicting benign prostate pathology on magnetic resonance/ultrasound fusion biopsy in men with a prior negative 12-core systematic biopsy. Cancer. Multi‐institutional nomogram predicting benign prostate pathology on magnetic resonance/ultrasound fusion biopsy in men with a prior negative 12‐core systematic biopsy

BACKGROUND: Prostate multiparametric magnetic resonance imaging (mpMRI) may be recommended for patients with a prior negative systematic biopsy (SB). However, a proportion of these patients will continue to have no prostate cancer (PCa) identified on magnetic resonance/ultrasound fusion biopsy (FB) despite abnormal mpMRI findings.

METHODS: In this multi-institutional, retrospective study, clinical and mpMRI parameters were assessed for 285 consecutive patients with at least 1 prior negative biopsy who underwent FB for a Prostate Imaging Reporting and Data System (PI-RADS) score of 3 to 5 at the University of Rochester Medical Center from December 2014 to December 2016, or at the University of Alabama at Birmingham from February 2014 to February 2017. Nomograms were generated for predicting benign prostate pathology on both the targeted biopsy and the concurrent SB.

RESULTS: Benign pathology was found in 132 of 285 patients (46.3%). In a multivariate analysis, the predictors of benign prostate pathology on FB were age, prostate-specific antigen, prostate volume, and PI-RADS score. The predicted probabilities were plotted on a receiver operating characteristic curve, and the area under the curve was 0.825. The nomogram demonstrated excellent calibration and a high net benefit in a decision curve analysis. With a theoretical cutoff probability of ≥0.7 used to recommend deferment of FB, 61 of 285 patients (21.4%) would have avoided an unnecessary biopsy, and only 4 of 285 patients (1.4%) with PCa with a Gleason score ≥ 3 + 4 would have been missed.

CONCLUSIONS: False-positive mpMRI examinations may occur in up to 46.3% of patients with a prior negative biopsy. Thus, a multi-institutional nomogram has been developed and validated for predicting benign pathology after FB in patients with a prior negative biopsy, and this may help to reduce the number of unnecessary biopsies in the setting of abnormal mpMRI findings.

 

[Michael Scally MD]

Scrutiny-Dependent Cancer and Self-fulfilling Risk Factors

Physicists have long understood that the act of observation can affect the phenomenon being observed. Measuring pressure reduces the air pressure in an automobile tire; measuring voltage reduces the amount of voltage in a circuit. Physicians would do well to understand how the act of observation can affect the apparent incidence of cancer—as well as apparent risk factors for this disease.

That the number of cases of cancer diagnosed is sensitive to the degree of scrutiny is a familiar fact in prostate cancer. Consider the remarkable volatility in the reported incidence of prostate cancer in the United States over the past 40 years (Figure). No known tumor biology or carcinogenic process can explain its rapid rise and quick decline.

Instead, the changing incidence is the result of medical practice: the growth of transurethral resection of the prostate as therapy for benign prostatic hyperplasia; the promotion of prostate-specific antigen testing—a “simple blood test” that was frequently offered for free; a period of retrenchment when primary care providers and urologists agreed that screening made no sense in men with limited life expectancy; and, finally, the reaction to recommendations against screening.

Prostate cancer is thus the poster child for scrutiny dependent cancer: When physicians look harder for it, more cases become apparent; when we look less hard, fewer cases become apparent. Indolent prostate cancer is common. Increased scrutiny reveals more cases of cancer, and those revealed are more likely to represent over diagnosis.

Yet, any type of cancer with a substantial disease reservoir of indolent, subclinical forms can be subject to the degree of observer scrutiny—the combined effect of the frequency of diagnostic and screening examinations (including the physical examination, imaging studies, and laboratory testing), their ability to detect small irregularities, and the threshold to label these irregularities as cancer.

…

To avoid such misleading feedback loops, risk factor epidemiology must shift from diagnosis to “harder” outcomes—those more directly related to the disease process. Although late-stage and metastatic disease are potential candidates, DEATH FROM CANCER IS THE MOST MEANINGFUL AND LEAST AMBIGUOUS OUTCOME. As cancer diagnosis becomes increasingly sensitive to observer scrutiny, we hope that those investigating the risk for this disease focus on risk factors for death from cancer, not cancer diagnosis.

Welch H, Brawley OW. Scrutiny-Dependent Cancer and Self-fulfilling Risk Factors. Annals of Internal Medicine 2018. Scrutiny-Dependent Cancer | Annals of Internal Medicine | American College of Physicians

 

[Michael Scally MD]

Chen M, Zhang J, Sampieri K, et al. An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nature Genetics 2018. An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer | Nature Genetics

Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis.

 

[Michael Scally MD]

Jamnagerwalla J, Howard LE, Allott EH, et al. Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study. Prostate Cancer Prostatic Dis 2017. https://www.nature.com/articles/s41391-017-0030-9

BACKGROUND: Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA independent, study-mandated prostate biopsies.

METHODS: We conducted a post hoc analysis of data from 4974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. >/=7), were examined using multivariable logistic regression.

RESULTS: High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (OR per 10 mg/dL 1.05; 95% CI 1.00-1.09; p = 0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values >0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values >0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (OR per 10 mg/dL 1.08; 95% CI 1.01-1.16; p = 0.033) and high-grade prostate cancer (OR per 10 mg/dL 1.14; 95% CI 1.01-1.28; p = 0.034).

CONCLUSIONS: In REDUCE, where all men received PSA independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.

 

[Michael Scally MD]

Ström P, Nordström T, Grönberg H, Eklund M. The Stockholm-3 Model for Prostate Cancer Detection: Algorithm Update, Biomarker Contribution, and Reflex Test Potential. European Urology. Redirecting

Background - It has been shown that the Stockholm-3 model (S3M) outperforms prostate-specific antigen (PSA) as a screening tool for prostate cancer.

Objective - To update the S3M, to give a detailed account of the value of each predictor in the S3M, and to evaluate the S3M as a reflex test for men with PSA ≥3 ng/ml.

Design, setting, and participants - During 2012–2015, the Stockholm-3 study evaluated the S3M relative to PSA as tests for Gleason score ≥7 prostate cancers among men aged 50–69 yr. The participants (n = 59 159) underwent both tests, and biopsy was recommended if at least one was positive. A total of 5073 men had a biopsy because of elevated PSA (≥3 ng/ml).

Outcome measurements and statistical analysis - Logistic regression was used to update the S3M: intact PSA was removed, HOXB13 was included, and the model was fitted to data from the Stockholm-3 training and validation cohorts. To compare S3M with PSA, we fixed the sensitivity for detection of high-grade cancer and evaluated the performance as the number of biopsies needed to achieve that sensitivity for each test.

Results and limitations - The updated S3M slightly improved the area under the receiver operating characteristic curve compared to previously published results (0.75 vs 0.74). When used as a reflex test for men with PSA ≥3 ng/ml, S3M reduced the number of biopsies needed by 34% compared to the use of PSA alone, with equal sensitivity. A limitation is the ethnically homogeneous population.

Conclusions - A major problem with PSA screening—too many unnecessary biopsies—can be mitigated if S3M is used as a reflex test.

Patient summary - To find aggressive prostate cancer with the minimum number of negative biopsies and detection of clinically insignificant cancers, we evaluated the use of a personalized diagnostic prediction model as a second test for men with a positive prostate-specific antigen (PSA) test. We found that this two-step approach could reduce prostate biopsies by a third compared to using PSA alone.

 

[Michael Scally MD]

Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer

Highlights
· Of five HSD17B4 splice forms, only isoform 2 encodes an androgen-inactivating enzyme
· Isoform 2 is the only form that is expressed and lost in CRPC in patients
· Isoform 2 inactivates testosterone and dihydrotestosterone
· Genetic loss of isoform 2 promotes development of CRPC

Castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained testosterone and/or dihydrotestosterone to stimulate progression. 17β-Hydroxysteroid dehydrogenase type 4 (17βHSD4), encoded by HSD17B4, is thought to inactivate testosterone and dihydrotestosterone by converting them to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression increases in CRPC and predicts poor prognosis.

Here, we show that, of five alternative splice forms, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast with other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients.

Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulating androgen receptor (AR) and CRPC development. Our studies specifically implicate HSD17B4 isoform 2 loss in lethal prostate cancer.

Ko H-K, Berk M, Chung Y-M, et al. Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer. Cell Reports;22:809-19. http://dx.doi.org/10.1016/j.celrep.2017.12.081

 

[Michael Scally MD]

The Association of A Number of Risk Factors With Depression in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy

PURPOSE: To identify factors affecting depressive symptoms in patients undergoing androgen-deprivation therapy (ADT) to treat prostate cancer.

MATERIALS AND METHODS: The patients with prostate cancer visiting the psychiatry department without referral because of depressive symptoms while undergoing ADT participated. To assess depressive symptoms, the Beck Depression Inventory (BDI) was used. To identify the risk factors affecting depressive symptoms, univariate regression and multiple linear regression analyses were implemented.

RESULTS: The mean (+/- SD) age, age when initiating ADT, duration of ADT, serum testosterone level and BDI scores of participants (n = 45) were 73.9 +/- 7.9 years, 72 +/- 8.5 years, 33 +/- 31.6 months, 214.9 +/- 219.5 ng/dL and 18 +/- 13.5 points. The androgen dependent and independent were 26 and 9 patients. Eight of these androgen-independent patients underwent concurrent chemotherapy. Twenty-one patients were treated with bicalutamide and 24 with leuprolide. Of the clinical variables affecting BDI scores, the type of ADT drug (P < 0.001), serum testosterone level (P = 0.003), and age at diagnosis (P < 0.001) were significant.

CONCLUSION: Efforts to diagnose and treat depression appropriately, especially if depressive symptoms change in patients undergoing ADT to treat prostate cancer who are using an LHRH agonist (leuprolide), have low testosterone level, or are older at the age when initiating ADT.

Kim CH, Kim KT, Oh JK, et al. The Association of A Number of Risk Factors With Depression in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy. Urology journal 2018. The Association of A Number of Risk Factors With Depression in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy. - PubMed - NCBI

 

[Michael Scally MD]

Claps M, Petrelli F, Caffo O, et al. Testosterone levels and prostate cancer prognosis: A systematic review and meta-analysis. Clinical Genitourinary Cancer. Redirecting

Highlights
· The metanalysis evaluated the relation among testosterone and prostate cancer outcome
· In early stage disease serum testosterone was not prognostic for survival nor relapse
· In advanced stage higher testosterone pre-ADT was associated with prolonged survival
· During ADT lower levels were associated with a reduced risk of death and progression
· In CRPC higher testosterone levels predicted a reduced risk of progression

Introduction - Androgen receptor is the major driver and testosterone the natural growth factor of prostate cancer (PC). Studies exploring the relationship among circulating testosterone levels, PC aggressiveness, and patient prognosis showed contradictory results.

Materials and Methods - We performed a comprehensive literature search for studies reporting the independent relationship between serum testosterone and prognosis of PC patients. Meta-analyses using random effects models were conducted to estimate pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results - We identified 25 articles, that evaluated the prognostic value of testosterone in early stage PC (8 studies), in advanced PC either before (4 studies) or during androgen deprivation therapy (ADT) (5 studies), and in castration-resistant PC (CRPC) (8 studies). In early PC, serum testosterone level was not prognostic in terms of overall survival (OS) (HR 1.03, 95% CI 0.99-1.08; p=0.19) and biochemical recurrence (BCR) (HR 0.99, 95% CI 0.87-1.13; p=0.93). In advanced PC, higher testosterone levels before ADT were associated with a reduced risk of death (HR 0.58, 95% CI 0.45-0.74; p<0.0001). During ADT, lower levels were associated with a reduced risk of death (HR 0.48, 95% CI 0.28-0.81; p=0.006) and progression (HR 0.59, 95% CI 0.46-0.77; p <0.0001). In CRPC patients, higher testosterone levels predicted a reduced risk of progression (HR 0.33, 95% CI 0.11-0.97; p=0.04), but not of death (HR 0.86, 95% CI 0.69-1.07; p=0.18). The heterogeneity of the included studies is a major limitation of this meta-analysis.

Conclusion - The relationship between circulating testosterone and PC prognosis varies in different clinical settings and according to ADT administration.

 

[Michael Scally MD]

Faiena I, Holden S, Cooperberg MR, et al. Prostate Cancer Screening and the Goldilocks Principle: How Much Is Just Right? Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2018:Jco2017764050. http://ascopubs.org/doi/10.1200/JCO.2017.76.4050

As the debate continues on the merits of prostate cancer (PCa) early detection, primary care providers (PCPs), urologists, and specialists are left struggling to balance benefits from early detection and treatment of lethal PCa that justify the inherent risks of overtreatment. The 2012 U.S. Preventive Services Task Force (USPSTF) recommendation against prostate-specific antigen (PSA)–based screening highlighted the limitations in the historical implementation of screening.

Given the low specificity of PSA for clinically significant PCa in the screening setting, it is not surprising in retrospect that population-wide application with a threshold of 4.0 ng/mL defining a positive result led to overdiagnosis and overtreatment as well as many missed cancers when PSA is used alone. The longstanding underuse of active surveillance (AS) in low-risk disease and the associated harms of treatment factored strongly into these recommendations. More recent AS data suggest that the trend has shifted markedly, with increasing evidence now showing that patients can be safely monitored over a long period.

…

In conclusion, the goal of this report is to highlight knowledge gaps that may improve patient outcomes while minimizing potential harms. Although the elimination of overdiagnosis is not feasible, the management of an elevated PSA is changing markedly, with increased use of ancillary testing before biopsy decisions. There is no one-size-fits-all solution. Therefore, individualized screening with SDM is the foundation on which to build a successful program of diagnosis and treatment.

The USPSTF’s recent draft recommendation is a critical step toward finding a more balanced strategy. With an improved understanding of risk stratification and patient management both before and after diagnosis, we are increasingly convinced that a “just right” approach on the basis of personalized SDM is entirely possible. This will ultimately allow us to realize the goal of reduced death and suffering from PCa.

 

[Michael Scally MD]

Prostate Cancer Screening

KEY POINTS

· Prostate cancer (PCa) screening is controversial. PSA-based screening has effected a dramatic stage shift from mostly incurable to mostly curable disease along with a greater than 53% reduction in the US PCa mortality rate; however, concerns have arisen about overdiagnosis and treatment of screen-detected indolent tumors.

· Randomized clinical trials of varying quality and much of their misinterpreted data have created confusion about the benefits versus harms of screening, leading to flawed recommendations in 2008 and 2012 against PSA screening by the US Preventive Services Task Force (USPSTF).

· In the aftermath of the USPSTF recommendations, the widespread rejection of screening by many primary care physicians has had far-reaching consequences, notably, a reversion to more PCa cases being high-grade and advanced at diagnosis.

· A 2017 statistical modeling reanalysis of the large European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trials by the Cancer Intervention and Surveillance Modeling Network of the National Cancer Institute revealed that screening in ERSPC produced a 25% to 31% reduction in PCa mortality versus a 27% to 32% reduction in PLCO.

· The USPSTF has now issued a revised draft recommendation, suggesting shared decision making for screening healthy men 55 years to 69 years of age.

· Consequently, the USPSTF has dropped its total opposition to PCa screening, with a draft recommendation for shared decision making for patients ages 55 years to 69 years old. Further consideration is needed for more intensive screening in men with high-risk factors, such as African ancestry and/or a strong family history of PCa, as well as for healthy men aged greater than or equal to 70 years.

· Further consideration is needed for more intensive screening in men with high-risk factors, such as African ancestry and/or a strong family history of PCa, as well as for healthy men age greater than or equal to 70 years. When correctly interpreted, the data are clear: PSA screening significantly reduces suffering and death from PCa.

Catalona WJ. Prostate Cancer Screening. The Medical clinics of North America 2018;102:199-214. Redirecting

 

[Michael Scally MD]

17beta-Trenbolone Promotes the Proliferation of Human Prostate Cancer Cell Line Through the Akt/AR Signaling Pathway

Highlights

· 17 TB is hydrolyzed form of veterinary drug, Trenbolone acetate.

· 17 TB residues in meat and milk products could cause adverse effects in humans.

· We found mechanism of proliferation of human prostate cancer cell, 22Rv1 by 17 TB.

· 17 TB promotes the proliferation of 22Rv1 line through Akt/AR signaling pathway.

Trenbolone acetate (TBA) is a synthetic anabolic steroidal growth factor that is used for rapid muscle development in cattle. The absorbed TBA is hydrolyzed to the active form, 17beta-trenbolone (17TB; 17beta-hydroxy-estra-4,9,11-trien-3-one) in meat and milk products, which can cause adverse health effects in humans.

Similar to 5alpha-dihydrotestosterone (DHT), 17TB was reported to exhibit endocrine disrupting effects on animals and humans due to its androgenic effect via binding to the androgen receptor. The purpose of this study is to investigate the molecular mechanism of cell proliferation in prostate cancer (PCa) cells treated with 17TB.

We found that 17TB induces AR-dependent cell proliferation in the human prostate cancer cell line, 22Rv1 in a concentration dependent manner. Treatment with 17TB increased the expression of cell cycle regulatory proteins, cyclin D2/CDK-4 and cyclin E/CDK-2, whereas the expression of p27 was down-regulated. Furthermore, phosphorylation of Rb and activation of E2F were also induced, which suggests the activation of cyclin D2/CDK-4 and cyclin E/CDK-2 in the cells.

When 22Rv1 cells were exposed to 30 pM of 17TB, which is the effective concentration (EC50) value required to observe proliferative effects on 22Rv1 cells, the expression levels of the phosphorylated forms of Akt and GSK3beta were increased.

This study demonstrates that 17TB induces AR-dependent proliferation through the modulation of cell cycle-related proteins in the Akt signaling pathway. The present study provides an effective methodology for identifying cell proliferation signaling of veterinary drugs that exert AR agonistic effects.

Lee HS, Jung DW, Han S, et al. Veterinary drug, 17beta-trenbolone promotes the proliferation of human prostate cancer cell line through the Akt/AR signaling pathway. Chemosphere 2018;198:364-9. https://www.sciencedirect.com/science/article/pii/S0045653518301620

 

[Michael Scally MD]

Low circulating free testosterone is associated with reduced incidence of prostate cancer: A pooled analysis of individual participant data from 20 prospective studies.
Low circulating free testosterone is associated with reduced incidence of prostate cancer: A pooled analysis of individual participant data from 20 prospective studies | NCRI Cancer Conference abstracts

Background - Experimental and clinical evidence implicates testosterone in the etiology of prostate cancer, but previous findings from prospective epidemiological studies do not support an association. The androgen saturation model may explain the disparity, hypothesising that the stimulatory effects of androgens increase up to androgen receptor saturation but that above this point any further increase in androgen concentration will not induce a further increase in prostate tissue growth. Because the saturation point is thought to be low, until now there have been insufficient prospective data available to test this theory. We aimed to test the androgen saturation model, hypothesising that men with very low circulating free testosterone concentrations will have a reduced risk of prostate cancer.

Method - We analysed individual participant data from 20 prospective studies, with up to 6,933 prostate cancer cases and 12,088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group. Conditional logistic regression was used to estimate odds ratios for prostate cancer based on study-specific tenths of free testosterone.

Results - Men in the lowest study-specific tenth of free testosterone had a lower risk of prostate cancer (OR=0.79, 95% CI 0.70-0.88; P<0.001) compared with men in the 2nd-10th tenths. There was no evidence of heterogeneity in the association by obesity, age or family history. However, there was heterogeneity by tumour grade (Phet= 0.002), with a decreased risk of low-grade prostate cancer (OR=0.76, 95% CI 0.67-0.88) and an increased risk of high-grade disease (OR=1.65, 95% CI 1.04-2.63) in men with very low levels of free testosterone.

Conclusion - These results support the androgen saturation model in relation to prostate cancer risk. Further large-scale studies which examine co-morbidities and data across a broad range of circulating hormone concentrations are needed to elucidate whether the observed associations are causal or attributable to bias.

 

[Michael Scally MD]

Testosterone Levels and Prostate Cancer Prognosis

Androgen receptor is the major driver of and testosterone the natural growth factor of prostate cancer (PC). Studies exploring the relationship among circulating testosterone levels, PC aggressiveness, and patient prognosis showed contradictory results.

We performed a comprehensive literature search for studies reporting the independent relationship between serum testosterone and prognosis of PC patients. Meta-analyses using random effects models were conducted to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs).

We identified 25 articles that evaluated the prognostic value of testosterone in early-stage PC (8 studies), in advanced PC either before (4 studies) or during androgen deprivation therapy (ADT) (5 studies), and in castration-resistant PC (8 studies).

In early PC, serum testosterone level was not prognostic in terms of overall survival (HR = 1.03; 95% CI, 0.99-1.08; P = .19) and biochemical recurrence (HR = 0.99; 95% CI, 0.87-1.13; P = .93).

In advanced PC, higher testosterone levels before ADT were associated with a reduced risk of death (HR = 0.58; 95% CI, 0.45-0.74; P < .0001).

During ADT, lower levels were associated with a reduced risk of death (HR = 0.48; 95% CI, 0.28-0.81; P = .006) and progression (HR = 0.59; 95% CI, 0.46-0.77; P < .0001).

In castration-resistant PC patients, higher testosterone levels predicted a reduced risk of progression (HR = 0.33; 95% CI, 0.11-0.97; P = .04) but not of death (HR = 0.86; 95% CI, 0.69-1.07; P = .18).

The heterogeneity of the included studies is a major limitation of this meta-analysis. The relationship between circulating testosterone and PC prognosis varies in different clinical settings and according to ADT administration.

Claps M, Petrelli F, Caffo O, et al. Testosterone Levels and Prostate Cancer Prognosis: Systematic Review and Meta-analysis. Clin Genitourin Cancer 2018. http://www.clinical-genitourinary-cancer.com/article/S1558-7673(18)30032-6/abstract

 

[Michael Scally MD]

New NCCN Guidelines Incorporate PCF-Funded Research on Cancer Risk Genes
New NCCN Guidelines Incorporate PCF-Funded Research on Cancer Risk Genes - PCF

These guidelines establish a new standard of care and will pave the way for patients to get better access to genetic testing and counseling and should improve insurance coverage

 

[Michael Scally MD]

Incidence and severity of prostate cancer (PCa) in 792 hypogonadal men with and without long-term testosterone therapy (TTh)

Background: There is no evidence that TTh in hypogonadal men increases PCa incidence or severity. A US-Scandinavian group recently found that men receiving TTh had lower risk of aggressive PCa (Loeb S et al., J Clin Oncol 2017; 35:1430-6).

Methods: 412 men with testosterone ≤350 ng/dL and symptoms received testosterone undecanoate 1000 mg every 3 months for up to 12 years. 380 hypogonadal men (57-74) opted against TTh. Median follow-up: 9 years. Total observation time covered approximately 6,400 patient-years. Prostate volume (PV) and PSA were measured and digital rectal examination/transrectal ultrasound performed before treatment/observation initiation and then every 3-6 months (T-group) or once or twice per year (CTRL). Biopsies were performed when indicated according to EAU guidelines.

Results: In the T-group, 11 men (2.7%) were diagnosed with PCa. In CTRL, 34 (8.9%) were diagnosed with PCa. The incidence per 10,000 years was 33 in the T-group and 108 in CTRL. The mean baseline age of PCa patients was 65.2 years in the T-group and 64.3 in CTRL.

All PCa diagnoses in the T-group were made within the first 18 months of treatment initiation. In CTRL, PCa was diagnosed at any time during the observation time.

In the T-group, radical prostatectomy was performed in all men. All but 1 patient had a Gleason score (GS) ≤6, and all but 1 a predominant GS of 3. Tumor grade was G2 in all 11 (100%), tumor stage T2a in 7 (64%), T2b in 3 (27%), and T2c in 1 (9%) patient(s).

In CTRL, radical prostatectomy was performed in all but 6 patients. GS was > 6 in all 34 patients. 7 men had a GS of 7, 17 a GS of 8, and 10 a GS of 9. 2 men had a predominant Gleason score of 3, 22 had 4, and 10 had 5. Tumor grade was G2 in 6 (17.6%) and G3 in 28 (82.4%) patients, tumor stage T2c in 1 (0.3%), T3a in 3 (8.8%), T3b in 13 (38.2%) and T3c in 17 (50%) patients.

In CTRL, biochemical recurrence occurred in 8 (23.5%) patients. These patients received androgen deprivation therapy (ADT). 10 (29.4%) patients died of whom 5 were on ADT. In the T-group, there were no biochemical recurrences or deaths during the observation time.

Conclusions: In hypogonadal men, TTh may decrease PCa incidence compared to CTRL. PCa was less severe in the T-group.

Haider A, Haider KS. Incidence and severity of prostate cancer (PCa) in 792 hypogonadal men with and without long-term testosterone therapy (TTh): Results from a controlled registry study. Journal of Clinical Oncology 2018;36:167-. https://doi.org/10.1200/JCO.2018.36.6_suppl.167

 

[Michael Scally MD]

Key Points

Question Is there a difference in prostate cancer–specific mortality and distant metastasis associated with extremely dose-escalated radiotherapy, external beam radiotherapy, or radical prostatectomy in patients with Gleason score 9-10 prostate cancer?

Findings In this retrospective cohort study that included 1809 men with biopsy Gleason score 9-10 prostate cancer, external beam radiotherapy with a brachytherapy boost and androgen deprivation therapy was associated with significantly better prostate cancer–specific survival and longer time to distant metastasis compared with external beam radiotherapy and androgen deprivation therapy (hazard ratios, 0.41 and 0.30, respectively) or with radical prostatectomy (hazard ratios, 0.38 and 0.27, respectively).

Meaning Extremely dose-escalated radiotherapy combined with androgen deprivation therapy was associated with better clinical outcomes.

Kishan AU, Cook RR, Ciezki JP, et al. Radical prostatectomy, external beam radiotherapy, or external beam radiotherapy with brachytherapy boost and disease progression and mortality in patients with gleason score 9-10 prostate cancer. JAMA 2018;319:896-905. Disease Progression and Mortality in Gleason 9-10 Prostate Cancer After Definitive Treatment

Importance The optimal treatment for Gleason score 9-10 prostate cancer is unknown.

Objective To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment.

Design, Setting, and Participants Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013.

Exposures Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy.

Main Outcomes and Measures The primary outcome was prostate cancer–specific mortality; distant metastasis-free survival and overall survival were secondary outcomes.

Results Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer–specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer–specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer–specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]).

Conclusions and Relevance Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer–specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

 

[Michael Scally MD]

There is a new PSA screening trial out today in @JAMA_current
Care for a brief TWEETORIAL?
[And some polls inside!]
Unrolled thread from @VinayPrasad82

 

[Michael Scally MD]

Naji L, Randhawa H, Sohani Z, et al. Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis. The Annals of Family Medicine 2018;16:149-54. Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis

PURPOSE Although the digital rectal examination (DRE) is commonly performed to screen for prostate cancer, there is limited data to support its use in primary care. This review and meta-analysis aims to evaluate the diagnostic accuracy of DRE in screening for prostate cancer in primary care settings.

METHODS We searched MEDLINE, Embase, DARE (Database of Abstracts of Reviews of Effects), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) from their inception to June 2016. Six reviewers, in pairs, independently screened citations for eligibility and extracted data. Pooled estimates were calculated for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DRE in primary care settings using an inverse-variance meta-analysis. We used QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) and GRADE (Grades of Recommendation Assessment, Development, and Evaluation) guidelines to assess study risk of bias and quality. RESULTS Our search yielded 8,217 studies, of which 7 studies with 9,241 patients were included after the screening process. All patients analyzed underwent both DRE and biopsy. Pooled sensitivity of DRE performed by primary care clinicians was 0.51 (95% CI, 0.36–0.67; I2 = 98.4%) and pooled specificity was 0.59 (95% CI, 0.41–0.76; I2 = 99.4%). Pooled PPV was 0.41 (95% CI, 0.31–0.52; I2 = 97.2%), and pooled NPV was 0.64 (95% CI, 0.58–0.70; I2 = 95.0%). The quality of evidence as assessed with GRADE was very low.

CONCLUSION Given the considerable lack of evidence supporting its efficacy, we recommend against routine performance of DRE to screen for prostate cancer in the primary care setting.

 

[MR10X]

doc checked mine and said it was small and no lumps...but after a PSA it was 11.2....after biopsy it came back gleason 8.did seed implants and ext radiation 5 years ago and PSA was 0.02 at last check...