Risk Of Low-grade Prostate Cancer Research Articles

Interactions of obesity, body shape, diabetes and sex steroids with respect to prostate cancer risk in the UK Biobank cohort.

Obesity and diabetes are associated inversely with low-grade prostate cancer risk and affect steroid hormone synthesis but whether they modify each other's impact on prostate cancer risk remains unknown. We examined the independent associations of diabetes, body mass index (BMI), 'a body shape index' (ABSI), hip index (HI), circulating testosterone, sex hormone binding globulin (SHBG) (per one standard deviation increase) and oestradiol ≥175 pmol/L with total prostate cancer risk using multivariable Cox proportional hazards models for UK Biobank men. We evaluated multiplicative interactions (pMI ) and additive interactions (relative excess risk from interaction (pRERI ), attributable proportion (pAR ), synergy index (pSI )) with obese (BMI ≥30 kg/m2 ) and diabetes. During a mean follow-up of 10.3 years, 9417 incident prostate cancers were diagnosed in 195,813 men. Diabetes and BMI were associated more strongly inversely with prostate cancer risk when occurring together (pMI = 0.0003, pRERI = 0.032, pAP = 0.020, pSI = 0.002). ABSI was associated positively in obese men (HR = 1.081; 95% CI = 1.030-1.135) and men with diabetes (HR = 1.114; 95% CI = 1.021-1.216). The inverse associations with obesity and diabetes were attenuated for high-ABSI ≥79.8 (pMI = 0.022, pRERI = 0.008, pAP = 0.005, pSI <0.0001 obesity; pMI = 0.017, pRERI = 0.047, pAP = 0.025, pSI = 0.0005 diabetes). HI was associated inversely in men overall (HR = 0.967; 95% CI = 0.947-0.988). Free testosterone (FT) was associated most strongly positively in normal weight men (HR = 1.098; 95% CI = 1.045-1.153) and men with diabetes (HR = 1.189; 95% CI = 1.081-1.308). Oestradiol was associated inversely in obese men (HR = 0.805; 95% CI = 0.682-0.951). The inverse association with obesity was stronger for high-FT ≥243 pmol/L (pRERI = 0.040, pAP = 0.031, pSI = 0.002) and high-oestradiol (pRERI = 0.030, pAP = 0.012, pSI <0.0001). The inverse association with diabetes was attenuated for high-FT (pMI = 0.008, pRERI = 0.015, pAP = 0.009, pSI = 0.0006). SHBG was associated inversely in men overall (HR = 0.918; 95% CI = 0.895-0.941), more strongly for high-HI ≥49.1 (pMI = 0.024). Obesity and diabetes showed synergistic inverse associations with prostate cancer risk, likely involving testosterone reduction for diabetes and oestrogen generation for obesity, which were attenuated for high-ABSI. HI and SHBG showed synergistic inverse associations with prostate cancer risk.

Determinants of residential greenness and its association with prostate cancer risk: A case-control study in Singapore

BackgroundExposure to greenness has been shown to be beneficial to health, but few studies have examined the association between residential greenness and prostate cancer (PCa) risk. Our main objectives were to identify the determinants of residential greenness, and to investigate if residential greenness was associated with PCa risk in Singapore. MethodsThe hospital-based case-control study was conducted between April 2007 and May 2009. The Singapore Prostate Cancer Study (SPCS) comprised 240 prostate cancer cases and 268 controls, whose demographics and residential address were collected using questionnaires. Residential greenness was measured by normalized difference vegetation index (NDVI) around the participants’ homes using a buffer size of 1 km. Determinants of NDVI were identified using a multivariable linear regression model. Logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of associations between NDVI and PCa risk, adjusting for potential confounders. ResultsHaving a BMI within the second quartile, as compared to the lowest quartile, was associated with higher levels of NDVI (β-coefficient = 0.263; 95% CI = 0.040–0.485) after adjusting for covariates. Additionally, being widowed or separated, as compared to being married, was associated with lower levels of NDVI (β-coefficient = −0.393; 95% CI = −0.723, −0.063). An interquartile range (IQR) increase in NDVI was positively associated with prostate cancer risk OR = 1.45; 95% CI = 1.02–2.07). Stratified analysis by tumour grade and stage showed that higher NDVI was associated with higher risk of low grade PCa. ConclusionOur findings suggested that residential greenness was associated with higher risk of PCa in Singapore. Future studies on the quality and type of green spaces, as well as other factors of residential greenness, in association with PCa risk should be conducted to better understand this relationship.

Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial.

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Dietary inflammatory index (DII) and risk of prostate cancer in a case-control study among Black and White US Veteran men.

BACKGROUND:We hypothesized a pro-inflammatory diet would be associated with higher prostate cancer (PC) risk.METHODS:We prospectively recruited incident PC cases (n=254) and controls (n=328) at the Durham Veteran Affairs, from 2007–2018. From a self-completed 61-item Food Frequency Questionnaire, we calculated dietary inflammatory index (DII®) scores with and without supplements. We examined the association between DII scores with and without supplements and overall PC risk using logistic regression and risk of low-grade PC (grade group 1) and high-grade PC (grade group 2–5) with multinomial logistic regression.RESULTS:Cases were more likely to be Black (58% vs. 42%), had higher PSA (6.4 vs. 0.8 ng/ml), lower BMI (29.1 vs. 30.6 kg/m2) and were older (64 vs. 62 years) versus controls (all p<0.01). Both black controls and cases had higher DII scores with and without supplements, though the DII scores with supplements in controls was not significant. On multivariable analysis, there were no associations between DII with or without supplements and overall PC risk (p-trend=0.14, p-trend=0.09, respectively) or low-grade PC (p-trend=0.72, p-trend=0.47, respectively). Higher DII scores with (p-trend=0.04) and without supplements (p =0.08) were associated with high-grade PC, though the association for DII without supplements was not significant.CONCLUSIONS:A pro-inflammatory diet was more common among Black men and associated with high-grade PC in our case-control study. The degree to which a pro-inflammatory diet contributes to PC race disparities warrants further study. If confirmed, studies should test whether a low inflammatory diet can prevent high-grade PC, particularly among Black men.

Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study.

BackgroundEpidemiologic 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.MethodsWe conducted a post-hoc analysis of data from 4,974 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.ResultsHigh total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (ORper10mg/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 (ORper10mg/dl 1.08; 95% CI 1.01-1.16; p=0.033) and high-grade prostate cancer (ORper10mg/dl 1.14; 95% CI 1.01-1.28; p=0.034).ConclusionsIn 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.

Metabolic Syndrome and Aggressive Prostate Cancer at Initial Diagnosis.

Links between metabolic syndrome and prostate cancer after androgen deprivation therapy are emerging. The aim of the research was to investigate the association of metabolic syndrome and aggressive prostate malignancy, at initial diagnosis, without the influence of hormonal treatment. Retrospective analysis of 133 patients with prostate tumor diagnosis between 2007 and 2009 was conducted. Patients with prostate cancer were subdivided in 2 groups according to Gleason score: Gleason score≥7 as high-grade prostate tumor (Group 1) and <7 (Group 2) as low-grade prostate tumor. Metabolic syndrome was defined according to International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute definition. Metabolic syndrome was significantly associated with aggressive prostate cancer (OR 1.87, p<0.05) and a reduced risk of low-grade prostate cancer (OR 0.53, p<0.05) at initial diagnosis, without the influence of endocrine therapy. In our study, patients with metabolic syndrome were more likely to present with more aggressive prostate carcinoma vs. patients without metabolic syndrome. Further research should elucidate these relations in larger samples to confirm these associations and to stabilize future prevention and therapeutic strategies.

MP14-03 HIGHER CHOLESTEROL IS LINKED WITH INCREASED RISK OF HIGH-GRADE PROSTATE CANCER: RESULTS FROM THE REDUCE STUDY

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History II1 Apr 2017MP14-03 HIGHER CHOLESTEROL IS LINKED WITH INCREASED RISK OF HIGH-GRADE PROSTATE CANCER: RESULTS FROM THE REDUCE STUDY Juzar Jamnagerwalla, Lauren E. Howard, Adriana C. Vidal, Daniel M. Moreira, Ramiro Castro-Santamaria, Gerald L. Andriole, and Stephen J. Freedland Juzar JamnagerwallaJuzar Jamnagerwalla More articles by this author , Lauren E. HowardLauren E. Howard More articles by this author , Adriana C. VidalAdriana C. Vidal More articles by this author , Daniel M. MoreiraDaniel M. Moreira More articles by this author , Ramiro Castro-SantamariaRamiro Castro-Santamaria More articles by this author , Gerald L. AndrioleGerald L. Andriole More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.467AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Given the prevalence of prostate cancer (PC) and hypercholesterolemia, multiple studies have examined the link between these two conditions with mixed results. These findings may be influenced by studies showing a correlation between higher cholesterol and higher PSA, introducing a bias that may impact the rate of prostate biopsy and cancer detection thereby making high cholesterol appear to be correlated with PC risk. We tested the association between serum lipids and PC in a post-hoc analysis of the REDUCE study, in which subjects underwent study mandated biopsies regardless of PSA, mitigating any bias due to PSA. METHODS REDUCE was a 4 year multi-center study testing the effect of dutasteride on PC risk in men with a PSA of 2.5-10.0 ng/mL and a negative pre-enrollment biopsy. As part of the study protocol subjects were required to undergo study-mandated biopsies. The associations between baseline serum cholesterol, low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) with overall PC risk and disease grade (Gleason 2-6 vs. 7-10) at the 2-year biopsy was examined with logistic and multinomial logistic regression, adjusted for baseline covariates. Continuous lipid levels were presented in 10 mg/dL increments to help interpret hazard ratios. We excluded men taking statins. RESULTS 4,904 subjects not taking statins were included. Elevated serum cholesterol was associated with a higher risk of high-grade PC diagnosis on multivariable analysis (OR 1.23, p=0.008), though no association was seen between overall or low-grade PC risk (p >0.137). No association was seen between serum LDL and overall risk of PC or low- or high-grade disease (p >0.138). In contrast, elevated serum HDL was associated with a higher risk of overall PC risk (OR 1.34, p=0.028) and high-grade PC risk (OR 1.74, p=0.013) on multivariable analysis. CONCLUSIONS In post hoc analysis of REDUCE, both elevated cholesterol and elevated HDL were associated with increased high-grade PC risk. These data support the hypothesis that high cholesterol is linked with aggressive PC. Given recent data questioning the role of HDL as a cardioprotective factor (Ko et al, J Am College of Cardiology, 2016) and a meta-analysis showing drugs that increase HDL do not reduce cardiovascular risk (Keene et al, BMJ 2014), further study is needed to better understand the link between high HDL and increased PC risk. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e163 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Juzar Jamnagerwalla More articles by this author Lauren E. Howard More articles by this author Adriana C. Vidal More articles by this author Daniel M. Moreira More articles by this author Ramiro Castro-Santamaria More articles by this author Gerald L. Andriole More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial.

Finasteride has been found to reduce the risk of low-grade prostate cancer but to have no impact on overall survival. The long-term adverse and beneficial consequences of finasteride have not been examined. We used a linkage between data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims. Patients were examined by randomized study arm (finasteride vs placebo for 7 years) for long-term consequences of the intervention, including cardiac, endocrine, and sexual dysfunction, depression, diabetes, and benign prostatic hyperplasia (BPH)-related events. To examine time to events, we used cumulative incidence and Cox regression, adjusting for covariates. All statistical tests were two-sided. A total of 13 935 of 18 880 participants (73.8%) in the PCPT were linked to Medicare claims, with median Medicare follow-up assessment time of 16 years from trial registration. There were no differences between finasteride and placebo participants with respect to important baseline factors or amount of Medicare follow-up assessment time. Finasteride patients had a 10% higher risk of new claims for depression (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.19, P = .04) and a 6% lower risk of procedures for BPH-related events (primarily lower urinary tract symptoms; HR = 0.94, 95% CI = 0.89 to 1.00, P = .03). No other differences were found in rates of long-term consequences of intervention in the two study arms. Finasteride use is associated with reduced need for procedures for relief of BPH-related events and a modest increase in depression. Overall, there is little need to worry about long-term noncancer consequences of finasteride use in those who use it for treatment of symptomatic BPH, hair growth, or prevention of cancer.

Associations of Obesity with Prostate Cancer Risk Differ Between U.S. African-American and Non-Hispanic White Men: Results from the Selenium and Vitamin E Cancer Prevention Trial

Abstract African-American (AA) men have the highest rates of prostate cancer incidence and mortality in the US. Understanding underlying reasons for this disparity could identify preventive interventions important to AA men. PURPOSE: To determine whether the association of obesity with prostate cancer risk differs between AA and non-Hispanic white (NHW) men and whether obesity modifies the excess risk associated with AA race. METHODS: This is a prospective study among 3398 AA and 22673 NHW men who participated in the Selenium and Vitamin E Cancer Prevention Trial (2001–2011). Using Cox regression, we estimated hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) associated with AA and NHW race and body mass index (BMI) [kg/m2] on total, low- (Gleason score &amp;lt;7), and high-grade (Gleason score ≥7) prostate cancer incidence while adjusting for relevant covariates. RESULTS: There were 270, 148, and 88 cases of total, low-, and high-grade prostate cancers among AA men and a corresponding 1453, 898, and 441 cases in NHW men (median follow-up of 5.6 years). BMI was not associated with risk of total cancer among NHW men, but was positively associated with risk among AA men (BMI &amp;lt; 25 kg/m2 vs. ≥35 kg/m2, HR = 1.49; 95% CI, 0.95–2.34; Ptrend = 0.03). Consequently, the risk associated with AA race increased from 28% (HR = 1.28; 95% CI, 0.91–1.80) among men with BMI &amp;lt; 25 kg/m2 to 103% (HR = 2.03; 95% CI, 1.38–2.98) among AA men with BMI≥35 kg/m2 (Ptrend = 0.03). BMI was inversely associated with low-grade prostate cancer risk among NHW men (BMI &amp;lt; 25 kg/m2 vs. ≥35 kg/m2, HR = 0.80; 95% CI, 0.58–1.09; Ptrend = 0.02), but positively associated with risk among AA men (BMI &amp;lt; 25 kg/m2 vs. ≥35 kg/m2, HR = 1.77; 95% CI, 1.14–2.76; Ptrend = 0.05). BMI was positively associated with risk of high-grade prostate cancer in both NHW (BMI &amp;lt; 25 kg/m2 vs. ≥35 kg/m2, HR = 1.33; 95% CI, 0.90–1.97; Ptrend = 0.01) and AA men (BMI &amp;lt; 25 kg/m2 vs. ≥35 kg/m2, HR = 1.81; 95% CI, 0.79–4.11; Ptrend = 0.02), but associations were not significantly different. CONCLUSION: Obesity is more strongly associated with increased prostate cancer risk among AA than NHW men and reducing obesity among AA men could reduce the racial disparity in cancer incidence. Research is needed to test mechanisms underpinning these associations.

Effect of Finasteride on Serum Androstenedione and Risk of Prostate Cancer Within the Prostate Cancer Prevention Trial: Differential Effect on High- and Low-grade Disease

To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial. We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5α-reductase enzyme. We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease. The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5α-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression.

Obesity increases the risk for high-grade prostate cancer: results from the REDUCE study.

Studies suggest that obesity is associated with lower risk of prostate cancer but more aggressive cancers. As obesity lowers PSA levels, these observations may be influenced by detection bias. We examined the association between obesity and risk of low- and high-grade prostate cancer in REDUCE, in which biopsies were largely independent of PSA. The REDUCE study tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative biopsy. Study participants included 6,729 men who underwent at least one on-study biopsy. The association between baseline body mass index (BMI <25 kg/m(2) normal weight; 25-29.9 kg/m(2) overweight; and ≥30 kg/m(2) obese) and risk of high-grade (Gleason ≥7) or low-grade prostate cancer (Gleason <7) versus no prostate cancer was examined using multinomial logistic regression. Overall, 1,739 men (27%) were normal weight, 3,384 (53%) overweight, and 1,304 (20%) were obese. Obesity was associated with lower risk of low-grade prostate cancer in both univariable (OR, 0.74; P = 0.001) and multivariable analyses (OR, 0.79; P = 0.01). In univariable analysis, obesity was not associated with high-grade prostate cancer (OR, 1.08; P = 0.50). However, in multivariable analysis, obesity was associated with increased risk of high-grade prostate cancer (OR, 1.28; P = 0.042). This analysis was not able to address how obesity may influence prostate cancer progression. Obesity is associated with decreased risk of low-grade and increased risk of high-grade prostate cancer. These data provide further support to the hypothesis that obesity is associated with aggressive prostate cancer. Obesity is linked with aggressive prostate cancer. Avoiding obesity may prevent the risk of developing high-grade prostate cancer.

A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

NKX3.1 is an androgen-regulated prostate tumor suppressor protein. We previously found that antioxidant administration (N-acetylcysteine) in the Nkx3.1 knockout mouse model promoted prostate epithelial proliferation, suggesting that NKX3.1 activity modifies the effect of antioxidant administration on prostate carcinogenesis. Interestingly, administration of the antioxidant vitamin E significantly increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), suggesting that our animal experiments may be relevant to humans. To determine whether NKX3.1 played a role in increased human prostate cancer risk associated with antioxidant administration in SELECT, we investigated the joint risk of antioxidant administration and NKX3.1 genotypes previously found to be associated with decreased NKX3.1 mRNA expression (rs11781886) or DNA-binding activity in vitro (rs2228013) in the SELECT biomarker case-cohort substudy (1,866 cases; 3,135 non-cases). Multivariable COX regression models were developed to determine the joint association of NKX3.1 genotypes with administration of vitamin E, selenium, or the combination, compared with placebo. The CC genotype at rs11781886 combined with selenium administration was associated with increased overall prostate cancer risk [HR, 1.676; 95% confidence interval (CI), 1.011-2.777; P = 0.045] and low-grade prostate cancer risk (HR, 1.811; 95% CI, 1.016-3.228; P = 0.0441). Similarly, the rs11781886 minor allele (CC+CT) combined with vitamin E administration was significantly associated with increased prostate cancer risk (HR, 1.450; 95% CI, 1.117-1.882; P = 0.0052). Our results indicate that variation in NKX3.1 expression combined with selenium or vitamin E treatment modifies the risk of prostate cancer. Genetic background may modulate the effects of antioxidant supplementation thought to act as chemoprevention agents.

Androgens and prostate disease.

A growing body of literature has established the anabolic benefits of testosterone (T) therapy in hypogonadal men. However, there remains a paucity of data regarding the risks of exogenous androgen use in older men and the potential for adverse effects on the prostate gland. Whether T therapy in older, hypogonadal men might worsen lower urinary tract symptoms or exacerbate, unmask, or even incite prostate cancer development has tempered enthusiasm for T therapy, while known prostatic disease has served as a relative contraindication to T therapy. Androgens are necessary for the development and maintenance of the prostate gland. However, epidemiologic studies do not consistently find a positive relationship between endogenous serum androgen concentrations and the risk of prostate disease. Recent data demonstrate that 5α-reductase inhibitors decrease the risk of low-grade prostate cancer, suggesting that modifying androgen metabolism may have beneficial effects on prostate health, yet similar reductions in high-grade disease have not been observed, thereby questioning the true clinical benefits of these agents for chemoprevention. Knowing how to best investigate the relationship between androgens and the development of prostate disease given the lack of large, randomized trials is difficult. Accumulating data challenges the assumption that alterations in serum androgens have parallel effects within the prostate hormonal environment or change androgen-regulated processes within the gland. Long-term intervention studies are needed to truly ascertain the effects of androgen manipulation on prostate tissue and disease risk. However, available data do not support the notion that restoring serum androgens to normal physiologic ranges drives prostate disease.

Agent Orange as a risk factor for high‐grade prostate cancer

Agent Orange (AO) exposure (AOe) is a potential risk factor for the development of prostate cancer (PCa). However, it is unknown whether AOe specifically increases the risk of lethal PCa. The objective of this study was to determine the association between AOe and the risk of detecting high-grade PCa (HGPCa) (Gleason score ≥7) on biopsy in a US Veteran cohort. Risk factors included clinicodemographic and laboratory data from veterans who were referred for an initial prostate biopsy. Outcomes were defined as the presence versus the absence of PCa, HGPCa, or low-grade PCa (LGPCa) (Gleason score ≤6) in biopsy specimens. Risk among AOe veterans relative to unexposed veterans was estimated using multivariate logistic regression. Separate models were used to determine whether AOe was associated with an increased risk of PCa, HGPCa, or LGPCa. Of 2720 veterans who underwent biopsy, PCa was diagnosed in 896 veterans (32.9%), and 459 veterans (16.9%) had HGPCa. AOe was associated with a 52% increase in the overall risk of detecting PCa (adjusted odds ratio, 1.52; 95% confidence interval, 1.07-2.13). AOe did not confer an increase in the risk of LGPCa (adjusted odds ratio, 1.24; 95% confidence interval, 0.81-1.91), although a 75% increase in the risk of HGPCa was observed (adjusted odds ratio, 1.75; 95% confidence interval, 1.12-2.74). AOe was associated with a 2.1-fold increase (95% confidence interval, 1.22-3.62; P < .01) in the risk of detecting PCa with a Gleason score ≥8. The current results indicated that an increased risk of PCa associated with AOe is driven by an increased risk of HGPCa in men who undergo an initial prostate biopsy. These findings may aid in improved PCa screening for Vietnam-era veterans.

Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial

The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16-2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)(n) repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (≥7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05-1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment.

Serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial.

Inflammation may be involved in prostate cancer development and progression. This study examined the associations between inflammation-related phospholipid fatty acids and the 7-year-period prevalence of prostate cancer in a nested case-control analysis of participants, aged 55-84 years, in the Prostate Cancer Prevention Trial during 1994-2003. Cases (n = 1,658) were frequency matched to controls (n = 1,803) on age, treatment, and prostate cancer family history. Phospholipid fatty acids were extracted from serum, and concentrations of ω-3, ω-6, and trans-fatty acids (TFAs) were expressed as proportions of the total. Logistic regression models estimated odds ratios and 95% confidence intervals of associations of fatty acids with prostate cancer by grade. No fatty acids were associated with low-grade prostate cancer risk. Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65); TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). The study findings are contrary to those expected from the pro- and antiinflammatory effects of these fatty acids and suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.

Obesity, Diabetes, and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial

Studies on the relationship between obesity and prostate cancer incidence are inconsistent. In part, this inconsistency may be due to a differential effect of obesity on low-grade and high-grade cancer or confounding of the association of obesity with prostate cancer risk by diabetes. We investigated the associations of obesity and diabetes with low-grade and high-grade prostate cancer risk. Data were from 10,258 participants (1,936 prostate cancers) in the Prostate Cancer Prevention Trial who all had cancer presence or absence determined by prostate biopsy. Multiple logistic regression was used to model the risk of total prostate cancer, and polytomous logistic regression was used to model the risk of low-grade and high-grade prostate cancer. Compared with men with body mass index < 25, obese men (body mass index > or =30) had an 18% [odds ratio (OR), 0.82; 95% confidence interval (95% CI), 0.69-0.98] decreased risk of low-grade prostate cancer (Gleason <7) and a 29% (OR, 1.29; 95% CI, 1.01-1.67) increased risk of high-grade prostate cancer (Gleason > or =7) or, alternatively, a 78% (OR, 1.78; 95% CI, 1.10-2.87) increased risk defining high-grade cancer as Gleason sum 8 to 10. Diabetes was associated with a 47% (OR, 0.53; 95% CI, 0.34-0.83) reduced risk of low-grade prostate cancer and a 28% (OR, 0.72; 95% CI, 0.55-0.94) reduced risk of high-grade prostate cancer. Associations of obesity or diabetes with cancer risk were not substantially changed by mutually statistical controlling for each other. Obesity increases the risk of high-grade but decreases the risk of low-grade prostate cancer, and this relationship is independent of the lower risk for prostate cancer among men with diabetes.