Risk Of Prostate Cancer In Men Research Articles

043 Adjusting misclassification of outcome in case-control studies

ObjectiveMisclassification of outcome may cause biased estimation for associations of potential risk factors with important diseases. For example, case-control studies of localised prostate cancer frequently measure blood levels of circulating...

Abstract 924: Possible joint effects between single nucleotide polymorphisms in inflammation genes and serum androgen levels on risk of prostate cancer

Abstract Both inflammation and androgens are likely to be involved in the etiology of prostate cancer. There is evidence for cross-talk between androgen and inflammation pathways, yet little is known about the joint contribution of inflammation and androgens to prostate cancer risk. Thus, we evaluated the joint effects of 9,932 tag single nucleotide polymorphisms (SNPs) in 774 inflammation-related genes and four serum androgen measures (total testosterone [T], bioavailable T, 3α-androstanediol glucuronide [3α diol G], and androstenedione) on risk of prostate cancer in 516 incident cancer cases and 560 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. SNPs included in this study were genotyped as part of the National Cancer Institute Cancer Genetic Markers of Susceptibility genome-wide association study. Likelihood ratio tests (LRT) were used to compare logistic models of prostate cancer regressed on age, center, the androgen (in quartiles), the SNP (additive genetic coding) and the SNP x hormone interaction term to logistic models of prostate cancer regressed on age, center, and the androgen. False discovery rate (FDR) control was used to adjust for multiple testing. Statistically significant LRT P-values were noted for T and three intronic SNPs in linkage disequilibrium (r2>0.7) within the HIPK2 gene on 7q34 (rs10256326, rs7788362, and rs12539357; FDR-adjusted P=0.04 for all SNPs). For each SNP, the minor allele was associated with a reduced prostate cancer risk in men with serum T levels in the lower three quartiles, but was associated with an increased risk among men in the highest quartile of serum T. LRT P-values of borderline statistical significance were also seen for joint effects of these three SNPs and bioavailable T on risk of prostate cancer (FDR-adjusted P=0.07 for all SNPs). There were no significant joint effects for any of the SNPs with 3αdiol G or androstenedione after adjustment for multiple tests. Our preliminary results suggest that T levels could interact with HIPK2 gene variants to influence prostate cancer risk. HIPK2 is an attractive candidate gene for further evaluation because it codes for a serine/threonine kinase involved in transcriptional regulation, particularly involved in p53-dependent and independent regulation of cell cycle control and apoptosis. Future studies are needed to confirm our preliminary findings and to further understand the possible interaction between T and genetic variants in HIPK2, which could contribute to prostate cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 924.

P87 Perceptions of prostate cancer and prostate cancer risk in men of African Caribbean descent; a systematic review

P87 Perceptions of prostate cancer and prostate cancer risk in men of African Caribbean descent; a systematic review

Association between family history of cancers and risk of prostate cancer

Introduction Family history of prostate cancer is an established risk factor for prostate cancer. However, the relationship between family history of cancers other than prostate cancer and prostate cancer risk is inconclusive. This study sought to examine the association between family history of cancers and prostate cancer. Methods A case–control study was conducted in which cases and controls were randomly selected from a large urology clinic in Central Virginia. Cases were 600 histologically confirmed prostate cancer patients who were diagnosed between January 2000 and December 2005, and controls were 686 patients who visited the clinic during the same period and were diagnosed with urological illnesses other than cancers and prostate-related problems. Data on family history of cancers, lifestyle and demographic factors were collected through mail survey utilizing the method suggested by Dillman. Unconditional logistic regression analysis was used to estimate the odds ratios (OR) and the corresponding 95% confidence intervals (CI) after adjustment for potential confounding factors including body mass index (BMI), alcohol intake, physical activity, smoking, diet, history of vasectomy and sexually transmitted disease (STD), age, race, marital history, education, and income. Multiple comparisons adjustments were made using the Bonferroni adjustment. Results Men with a family history of any cancer in first-degree relatives including parents (OR = 2.42, 95% CI = 1.53–3.84) and parents only (OR = 1.90, 95% CI = 1.23– 2.94) were at increased risk of developing prostate cancer. Significant increased risk was also observed with family history of prostate cancer in first-degree relatives (OR = 2.68, 95% CI = 1.53–4.69) and parents only (OR = 3.26, 95% CI = 1.71–6.24). Even after adjustments for multiple comparisons, the significance persisted both in first-degree relatives (OR = 2.68, 95% CI = 1.16–6.21) and parents alone (OR = 3.26, 95% CI = 1.24– 8.63). Conclusion This study demonstrated an increased prostate cancer risk for men with a family history of any cancer or prostate cancer in first-degree relatives and parents alone. Health care providers need to be aware of the potential risk of family history of cancers on prostate cancer.

Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis

Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or selenium-refractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

Association of Colorectal Cancer and Prostate Cancer and Impact of Radiation Therapy

To quantify the risk of prostate cancer after colorectal cancer and the risk of colorectal cancer after prostate cancer and to examine the impact of radiation therapy on subsequent cancer risk, we conducted retrospective cohort studies using data from the Surveillance, Epidemiology and End Results program from 1973 to 2005. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated, adjusting for age, ethnicity, and calendar year. The subsequent risk of developing a prostate cancer was significantly elevated in patients diagnosed with colon cancer before age 50 years (SIR, 1.38; 95% CI, 1.18-1.60). The risk of subsequent prostate cancer was decreased for men with rectal cancer who received radiation therapy (SIR, 0.57; 95% CI, 0.52-0.63). Interestingly, this beneficial effect of radiation therapy was only observed in the prostate-specific antigen (PSA) era (1988+). In addition, the prostate cancer cases developed in the radiation therapy group tended to have higher-grade, later-stage tumors, higher PSA levels, and worse survival than those developed in the nonradiation therapy group. In the cohort of prostate cancer patients, the risk of colon cancer was elevated in patients diagnosed with prostate cancer before age 50 years (SIR, 1.51; 95% CI, 1.03-2.20). In conclusion, a diagnosis of colon or prostate cancer in men of younger ages may be an indication for screening of prostate or colon cancer, respectively. The decreased prostate cancer risk in men who received radiation therapy for rectal cancer may be related to the use of PSA for prostate cancer screening or the cure of occult prostate cancer.

Soy, isoflavones and prostate cancer risk in men: a meta‐analysis

Soy is a major plant source of dietary protein to humans. Epidemiologic studies show that soy consumption may be associated with a reduction in cancer risk in humans. The purpose of this study was to conduct a meta‐analysis on the association between soy and prostate cancer in men. We systematically reviewed studies obtained through a thorough MEDLINE literature search and identified 15 studies on soy consumption and eight on isoflavone intake in relation to prostate cancer risk. We conducted this analysis using a random‐effects model in which studies with smaller standard error of estimate are given greater weight in the summary measure. Our analysis of studies on soy intake yielded an overall risk estimate of 0.74 (95% confidence interval: 0.63, 0.89; P = 0.001). When separately analyzed, studies on non‐fermented soy foods yielded an overall risk estimate of 0.70 (0.56, 0.88; P = 0.002) and those on fermented ones yielded 1.02 (0.73, 1.42; P = 0.922). The analysis of studies on isoflavones yielded an overall risk estimate of 0.88 (0.76, 1.02; P = 0.085). When analyzed on the basis of daily isoflavone intakes, we found an overall risk estimate of 0.63 (0.41, 0.96; P = 0.03) from studies at mg/day and 0.99 (0.85, 1.16; P = 0.909) from those at µg/day, respectively. Results of this analysis suggest that consumption of soy foods is associated with a reduction in prostate cancer risk in men.

Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis

Background: Epidemiologic studies have shown that the consumption of soy foods may be associated with a reduction in cancer risk in humans.Objective: The purpose of this study was to conduct a meta-analysis on the association between soy consumption and prostate cancer risk in men.Design: We systematically reviewed studies obtained through a thorough Medline literature search and identified 15 epidemiologic publications on soy consumption and 9 on isoflavones in association with prostate cancer risk. We extracted the most adjusted relative risks (RRs) and odds ratios (ORs) of the highest and the lowest reported categories of intake from each study and conducted this analysis using a random-effects model in which studies with smaller SEEs are given greater weight in the summary measure.Results: Our analysis of studies on soy intake yielded a combined RR/OR of 0.74 (95% CI: 0.63, 0.89; P = 0.01). When separately analyzed, studies on nonfermented soy foods yielded a combined RR/OR of 0.70 (95% CI: 0.56, 0.88; P = 0.01) and those on fermented soy foods yielded a combined RR/OR of 1.02 (95% CI: 0.73, 1.42; P = 0.92). The analysis of studies on isoflavones yielded a combined RR/OR of 0.88 (95% CI: 0.76, 1.02; P = 0.09). Further separate analyses showed a combined RR/OR of 0.52 (95% CI: 0.34, 0.81; P = 0.01) from studies with Asian populations and 0.99 (95% CI: 0.85, 1.16; P = 0.91) from studies with Western populations.Conclusions: The results of this analysis suggest that consumption of soy foods is associated with a reduction in prostate cancer risk in men. This protection may be associated with the type and quantity of soy foods consumed.

Sexual activity and prostate cancer risk in men diagnosed at a younger age

To examine, in a case-control study, the association between the frequency of sexual activity (intercourse, masturbation, overall) and prostate cancer risk in younger men diagnosed at < or = 60 years old. In all, 431 prostate cancer cases and 409 controls participated and provided information on their sexual activity. In particular, the frequencies of intercourse and masturbation during the participants' different age decades (20s, 30s, 40s, 50s) were collected. Whereas frequent overall sexual activity in younger life (20s) increased the disease risk, it appeared to be protective against the disease when older (50s). Alone, frequent masturbation activity was a marker for increased risk in the 20s and 30s but appeared to be associated with a decreased risk in the 50s, while intercourse activity alone was not associated with the disease. These findings could imply different mechanisms by which sexual activity is involved in the aetiology of prostate cancer at different ages. Alternatively, there is a possibility of reverse causation in explaining part of the protective effect seen for men in their 50s.

Diabetes mellitus and risk of prostate cancer in the health professionals follow‐up study

History of diabetes may be associated with decreased prostate cancer (PCa) risk. Published studies have not always accounted for time since diabetes diagnosis or confounding and effect modification by lifestyle factors. The authors investigated the relationship between diabetes and PCa risk in men in the Health Professionals Follow-Up Study from 1986 to 2004. During that time, 4,511 new PCa cases were identified. Multivariate hazard ratios (HR) were estimated using Cox regression. The HR of PCa comparing men with vs. without diabetes was 0.83 and 95% confidence interval (CI): 0.74, 0.94. PCa risk was not reduced in the first year after diabetes diagnosis (HR: 1.30, CI: 0.97, 1.72), was lower for men diagnosed for 1-6 years (HR: 0.82, CI: 0.66, 1.02), and was even lower for men who had been diagnosed for 6-15 (HR: 0.75, CI: 0.61, 0.93) or >15 years (HR: 0.78, CI: 0.63, 0.96). Reduced PCa risk was stronger in men diagnosed before 1994 (pre-PSA era) vs. after 1994. The authors also demonstrated that obese and diabetic men had a lower HR for PCa than those who were either not obese and diabetic or obese and non-diabetic. Results are consistent with the hypothesis that diabetes is associated with reduced PCa risk. Potential biological mechanisms are discussed.

Percent free prostate‐specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower

Up to 17% of men with a prostate-specific antigen (PSA) level below the accepted prostate biopsy cutoff of 2.5 ng/mL may have prostate cancer. Because identification of these patients represents a difficult task, we assessed the ability of percent free PSA to discriminate between benign and malignant prostate biopsy outcomes in men with PSA < or =2.5 ng/mL. Between 1999 and 2006, 543 men with a PSA < or =2.5 ng/mL were referred for initial prostate biopsy. Age, total PSA, percent free PSA, and digital rectal examination findings represented predictors of prostate cancer at biopsy in logistic regression models. The area under the receiver operating characteristics curve (AUC) quantified the discriminative ability of the predictors. The pathological characteristics of the detected cancers were assessed in individuals treated with radical prostatectomy. Of all, 23% had prostate cancer on biopsy, 16.5% of patients treated with radical prostatectomy had pT3 stage, and 35.6% had a pathological Gleason score of 3 + 4 or higher. The most accurate predictor of prostate cancer on biopsy was percent free PSA (0.68) versus age (0.50), total PSA (0.57), or rectal examination findings (0.58). Of patients with percent free PSA below 14%, 59% had prostate cancer. In multivariate models, percent free PSA (P < .001) and rectal examination findings (P = .001) were the only independent predictors of prostate cancer. The combined AUC of all predictors (0.69) was not significantly (P = .7) higher than that of percentage of free PSA alone (0.68). The risk of prostate cancer is clearly non-negligible in patients with PSA < or =2.5 ng/mL. The percent free PSA can accurately predict the prevalence of prostate cancer at prostate biopsy in these individuals.

Effect of Genetic Variability within 8q24 on Aggressiveness Patterns at Diagnosis and Familial Status of Prostate Cancer

Recently, two independent loci located at 8q24 that contribute to prostate cancer risk in men of European origin were identified. Using Bayesian probability network and logistic regression model, we searched for associations between 34 single-nucleotide polymorphisms (SNP) located at 8q24 and the aggressiveness patterns of prostate adenocarcinoma or familial history of cancers in 823 White Caucasian French men. Probability network according to the Markov chain algorithm separated the SNPs into two main groups: The first one was linked to the locus marked by rs6983267 and the second one was linked to the locus marked by rs1447295. When the patients were stratified according to tumor stage and prostate-specific antigen value, the association between the variant genotypes from six SNPs located in the second network and prostate cancer risk was strongest or confined to the patients from the more aggressive classes. However, the association between prostate cancer risk and the CC genotype of rs7841264, which marked the recombination hotspot at 8q24, was confined to patients with the highest Gleason score (odds ratio, 2.15; 95% confidence interval, 1.27-3.64; P=0.004). Interestingly, the G allele of rs6983267 was associated with familial prostate cancer risk. Our data further support that variability at 8q24 is associated with a high risk of aggressive prostate cancer at diagnosis and is linked with familial history of prostate cancer. These results corroborate that 8q24 SNPs must be evaluated in terms of prostate cancer aggressiveness markers to optimize early diagnosis procedures and management of the disease.

Is the utility of prostate‐specific antigen velocity for prostate cancer detection affected by age?

To determine whether prostate-specific antigen velocity (PSAV) is useful for prostate cancer detection in men from different age groups, and whether the same PSAV thresholds can reasonably be applied to all men aged >or=40 years. From a large prostate cancer screening study, 13,615 men had data on age and a calculable PSAV. We used statistical analysis to examine the ability of PSAV to predict prostate cancer risk in each age decade. For men of all ages, the median PSAV was 0.6-0.7 ng/mL/year in men with prostate cancer, and 0-0.1 ng/mL/year in men with no prostate cancer (P < 0.005 for all). On receiver operating characteristic (ROC) analysis, the area under the curve was 0.800, 0.697, 0.693, and 0.668 for predicting prostate cancer risk using PSAV for men aged 40-49, 50-59, 60-69 and >or=70 years, respectively. In the multivariate model controlling for race, family history, and the total PSA level, both PSA and PSAV were significant independent predictors of prostate cancer risk in men of all ages. The PSAV is significantly higher in men of all ages with prostate cancer compared with men with no prostate cancer; although on ROC analysis it performed the best in young men. Interestingly, the median PSAV in men with prostate cancer was <0.75 ng/mL/year regardless of age, suggesting that this threshold may be too high. Overall, this data confirms that PSAV is a useful tool for prostate cancer detection for men aged >or=40 years.

The association of prostate stem cell antigen (PSCA) mRNA expression and subsequent prostate cancer risk in men with benign prostatic hyperplasia following transurethral resection of the prostate

Prior data showed prostate stem cell antigen (PSCA) mRNA expression in benign prostatic hyperplasia (BPH) tissues. The purpose of the present investigation was to determine whether PSCA mRNA expression in resected BPH samples was associated with the subsequent presence of cancer following transurethral resection of the prostate (TURP). PSCA in situ hybridization was performed on the TURP-resected tissues from 288 patients, who were histopathologically confirmed BPH without cancer. All these patients were continuously followed for 9-70 months postoperatively. Univariate and multivariate cox regression analyses were used to evaluate the predictive performance of PSCA mRNA for subsequent cancer onset following TURP. PSCA mRNA was detected in 93/288 (32.3%) of the resected BPH specimens, with a mean positive-labeling cells of 23.8%, in which 22 patients (23.7%) were identified as having PCa on follow-up. Of 195 patients with negative expression for PSCA mRNA 2 (1.0%) were subsequently found with PCa. PSCA mRNA expression levels were directly proportional to higher Gleason score and clinical T stage. Univariate and multivariate cox regression analyses demonstrated that only PSCA mRNA expression was predictive of the subsequent cancer development after TURP, however, PSA velocity was an univariately significant but not multivariately significant predictor. This prospective study identifies PSCA mRNA in BPH as a significant predictor of cancer development after TURP, suggesting that PSCA may be used to identify patients who are at high risk for subsequent cancer onset following TURP for BPH and the PSCA test may be useful when applied for repeat biopsies.

Risk Factors for Prostate Cancer in Men Aged Less Than 60 Years: A Case–Control Study from Italy

To analyze the relationship between selected risk factors and prostate cancer risk in men younger than 60 years, using data from a large, multicenter, case-control study conducted in Italy. Cases were 219 patients, aged 45 to 59 years, with histologically confirmed prostate cancer, and controls were 431 men of the same age group, admitted in hospital for acute, non-neoplastic diseases. A family history of prostate cancer (odds ratio [OR] = 5.5), brain cancer (OR = 3.7), and leukemia (OR = 6.2) were associated with prostate cancer risk. A significantly increased risk was found for high education level (OR = 3.3 for 12 or more years versus less than 7 years) and a decreased risk for physical activity (OR = 0.5 for active versus inactive). Coffee consumption was directly associated with risk of prostate cancer (OR = 1.9 for the third versus the first tertile). Bread consumption was directly related (OR = 1.6) and consumption of raw and total vegetables inversely related (OR = 0.6) to prostate cancer risk, although these associations were of borderline significance. No association emerged with marital status, body mass index, history of diabetes, alcohol drinking, and other considered foods. This study confirms that some recognized risk factors, including family history of prostate cancer, high level of education, and low physical activity, are associated with prostate cancer risk in middle-aged men.

Advanced but Not Localized Prostate Cancer is Associated With Increased Oxidative Stress

Oxidative damage has been linked to prostate carcinogenesis but its role in disease development and progression remains elusive. We investigated associations between indexes of oxidative stress with localized and advanced prostate cancer. Specifically we assessed the susceptibility of serum lipids to copper induced peroxidation (oxidizability). Serum oxidizability, and levels of alpha-tocopherol, malonyldialdehyde and uric acid were assessed in samples from 79 patients with prostate cancer, including 42 with localized and 37 with metastatic disease receiving androgen deprivation therapy, and 25 control subjects. Oxidizability was assayed by continuous spectroscopic monitoring of the accumulation of peroxidation products. The lag preceding oxidation, that is the delay between the induction and propagation of the reaction, served as a measure of the resistance of serum lipids to oxidation. Compared to control subjects patients with localized prostate cancer had no difference in oxidative stress indexes, whereas those with metastatic disease had a shorter lag preceding oxidation and increased malonyldialdehyde (p <0.05), each reflecting a state of high oxidative stress. In patients with prostate cancer the probability of disease progression from localized to advanced state increased with a shorter lag preceding oxidation (p <0.001), increased malonyldialdehyde (p <0.03) and decreased uric acid (p <0.04). Localized and metastatic disease was associated with increased rather than decreased alpha-tocopherol (p <0.008 and <0.005, respectively). Patients with advanced prostate cancer are subject to high oxidative stress, as determined by increased susceptibility of serum lipids to peroxidation. This association was not detected in patients with localized cancer and it is not attributable to altered levels of alpha-tocopherol.

Clinical trials of natural products as chemopreventive agents for prostate cancer

Epidemiological research on prostate cancer risk in men throughout the world has identified significant correlations between dietary habits and prostate cancer occurrence. These studies served as a catalyst for exploration into the potential of dietary substances to act as chemopreventive agents against this disease, and include green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, curcumin and resveratrol. Before these agents (in the dietary or purified forms) can be recommended as useful chemopreventive strategies for patients, their activity must be confirmed in rigorously designed clinical trials. This review discusses the preclinical and clinical data available for these dietary agents and describes relevant clinical trials currently being conducted.

ICAM gene cluster SNPs and prostate cancer risk in African Americans

Intercellular adhesion molecules (ICAMs) are known to be involved in various human cancers. An ICAM gene cluster lying within a 26 kb region on chromosome 19p13.2, and containing ICAM1, ICAM4, and ICAM5 has recently been identified as harboring a breast and prostate cancer susceptibility locus in two populations of European ancestry from Germany and Australia. The objective of this study was to confirm the ICAM association with prostate cancer in a sample of African American prostate cancer cases (N = 286) and controls (N = 391). Six single nucleotide polymorphisms (SNPs) within the three ICAM genes were genotyped. To control for potential population stratification an ancestry-adjusted association analysis was performed. We found that ICAM1 SNPs, -9A/C (rs5490) and K469E (rs5498) were associated with prostate cancer risk in men with a family history of prostate cancer (P = 0.008). Specifically, increased risk was observed for individuals who possessed the CC genotype of the -9 A/C variant (odds ratio = 2.5; 95% CI = 1.0-6.3) and at least one G allele of non-synonymous K469E variant (odds ratio = 1.8; 95% CI = 1.2-3.1). Strong linkage disequilibrium was observed across the ICAM region (P < 0.001). A common haplotype within the ICAM gene cluster, harboring the -9A/C variant was significantly associated with prostate cancer (P = 0.03), mainly due to men with family history (P = 0.01). Our results replicate previous findings of association of the ICAM gene cluster with prostate cancer and suggest that common genetic variation within ICAM1 and not ICAM5 may be an important risk factor for prostate cancer.

Supplemental and Dietary Vitamin E, β-Carotene, and Vitamin C Intakes and Prostate Cancer Risk

Vitamin E, beta-carotene, and vitamin C are micronutrient antioxidants that protect cells from oxidative damage involved in prostate carcinogenesis. In separate trials, supplemental vitamin E was associated with a decreased risk of prostate cancer among smokers and supplemental beta-carotene was associated with a decreased risk of prostate cancer among men with low baseline plasma beta-carotene levels. We evaluated the association between intake of these micronutrient antioxidants from foods and supplements and the risk of prostate cancer among men in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. At baseline, trial participants completed a 137-item food frequency questionnaire that included detailed questions on 12 individual supplements. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. We identified 1338 cases of prostate cancer among 29 361 men during up to 8 years of follow-up. Overall, there was no association between prostate cancer risk and dietary or supplemental intake of vitamin E, beta-carotene, or vitamin C. However, among current and recent (i.e., within the previous 10 years) smokers, decreasing risks of advanced prostate cancer (i.e., Gleason score > or = 7 or stage III or IV) were associated with increasing dose (RR for > 400 IU/day versus none = 0.29, 95% CI = 0.12 to 0.68; Ptrend = .01) and duration (RR for > or = 10 years of use versus none = 0.30, 95% CI = 0.09 to 0.96; Ptrend = .01) of supplemental vitamin E use. Supplemental beta-carotene intake at a dose level of at least 2000 microg/day was associated with decreased prostate cancer risk in men with low (below the median of 4129 microg/day) dietary beta-carotene intake (RR = 0.52, 95% CI = 0.33 to 0.81). Among smokers, the age-adjusted rate of advanced prostate cancer was 492 per 100,000 person-years in those who did not take supplemental vitamin E, 153 per 100,000 person-years in those who took more than 400 IU/day of supplemental vitamin E, and 157 per 100,000 person-years in those who took supplemental vitamin E for 10 or more years. Among men with low dietary beta-carotene intake, the age-adjusted rate of prostate cancer was 1122 per 100,000 person-years in those who did not take supplemental beta-carotene, and 623 per 100,000 person-years in those who took at least 2000 microg/day of supplemental beta-carotene. Our results do not provide strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, vitamin E supplementation in male smokers and beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease.

Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model

Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.