Total Prostate Cancer Research Articles

Serum Retinol and Carotenoid Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial.

Findings from epidemiologic studies examining associations of serum retinol and carotenoids with prostate cancer risk have been inconsistent. This case-control study nested in the Prostate Cancer Prevention Trial evaluated associations of serum retinol and carotenoids with total, low-, and high-grade prostate cancer risk in a highly screened study population. We used logistic regression adjusting for age, family history of prostate cancer, race, body mass index, and serum cholesterol to estimate ORs and 95% confidence intervals (CI) of prostate cancer by quartiles of serum retinol and carotenoids, separately in the placebo (975 cases/1,009 frequency-matched controls) and finasteride (708 cases/743 frequency-matched controls) arms of the trial. Serum retinol concentrations were associated with increased risk of total prostate cancer [OR (95% CI) comparing the highest quartile of serum retinol with the lowest: 1.30 (1.00-1.68)] and high-grade prostate cancer [OR (95% CI), 1.74 (1.14-2.68)] in the placebo arm of the trial only. Also in the placebo arm, there was a moderate positive association of α-carotene with risk of total prostate cancer [OR (95% CI), 1.32 (1.01-1.73)]. None of the other carotenoids was associated with prostate cancer risk in the placebo arm. No associations were observed for retinol and carotenoids in the finasteride arm. In the placebo arm of this prospective study, high serum retinol and α-carotene concentrations were associated with increased risk of total and high-grade prostate cancers. Men with higher levels of serum retinol and α-carotene may be at increased risk for prostate cancer.

Highlights of This Issue

Because both smoking and excess body weight are major preventable risk factors for premature death, Meyer and colleagues analyzed the single and combined associations with site-specific cancer mortality. The study population comprised 35,784 men and women who participated in population-based health surveys in Switzerland. Heavy smoking (≥20 cigarettes/day) was associated with increased mortality due to cancer of the lung, upper aerodigestive tract, pancreas, bladder, liver, and the total of remaining sites. Obesity was associated with higher risk of dying from cancer of the liver and the female genital tract. Smoking was a much stronger risk factor for cancer than was excess body weight. This study supports recommendations for obese persons to quit smoking despite potential postcessation weight gain.Katz and colleagues performed cross-sectional telephone interviews to evaluate if women living in Appalachia were completing three cancer screening tests (mammography, Pap test, and colorectal cancer test). The authors report that fewer than 10% of women ages 51–75 were within guidelines for three cancer screening tests. Participants with higher incomes and conditions requiring regular medical visits were more likely to be within guidelines for all three screening tests. The low participation rate for cancer test uptake among women in Appalachia Ohio illustrates the need for innovative interventions to improve these rates.Global trends in female breast cancer incidence and mortality estimates were obtained from GLOBOCAN 2012. DeSantis and colleagues analyzed trends from 1993 onward using incidence data from 39 countries from the International Agency for Research on Cancer and mortality data from 57 countries from the World Health Organization. The authors report that in nine countries, mainly in Northern/Western Europe, breast cancer incidence increased and breast cancer mortality decreased. In contrast, incidence and death rates both increased in Colombia, Ecuador, and Japan and death rates increased in Brazil, Egypt, Guatemala, Kuwait, Mauritius, and Moldova. Awareness about the benefits of early breast cancer detection and improved access to treatment must be prioritized in order to successfully implement breast cancer control programs.Findings from studies examining associations of serum retinol and carotenoids with prostate cancer risk have been inconsistent. In this case–control study nested in the Prostate Cancer Prevention Trial, Nash and colleagues evaluated associations of serum retinol and carotenoids with total, low-, and high-grade prostate cancer risk. Serum retinol concentrations were associated with increased risk of total prostate cancer and high-grade prostate cancer in the placebo arm of the trial only. Also in the placebo arm, there was a moderate positive association of α-carotene with risk of total prostate cancer. Men with higher levels of serum retinol and α-carotene may be at increased risk for prostate cancer.

Intake of Meat Mutagens and Risk of Prostate Cancer in a Cohort of U.S. Health Professionals.

Evidence relating heterocyclic aromatic amines (HCA), associated with high-temperature cooking methods, to prostate cancer risk is inconsistent. In a large U.S. cohort study, intakes of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and a meat-derived mutagenicity (MDM) index were assessed using a cooking method questionnaire administered in 1996. Until 2010, 2,770 prostate cancer cases were observed among 26,030 participants. Intake of PhIP from red meat was statistically significantly associated with total prostate cancer risk (top vs. bottom quintile HR, 1.18; 95% confidence intervals; CI, 1.03-1.35), but not other HCAs (MeIQx, 1.12; 0.98-1.27, PhIP from white meat, 1.08; 0.95-1.22, DiMeIQx, 1.09; 0.97-1.21) or MDM (1.13; 1.00-1.28). For high-grade (Gleason sum 7 with pattern 4+3 and Gleason sum 8-10, n = 483 cases) and advanced cancers (n = 281), we only observed positive associations for PhIP from red meat (top vs. bottom quintile: high grade: HR, 1.44; 95% CI, 1.04-1.98, Ptrend = 0.03; advanced: HR, 1.50; 95% CI, 0.99-2.26; Ptrend = 0.12), but associations for advanced cancers did not reach statistical significance. Observed associations remained similar after adjustment for total, unprocessed, or processed red meat intake. Observed positive associations between PhIP intake from red meat and prostate cancer, particularly high-grade and possibly also advanced prostate cancer, need to be confirmed in other studies. Results do not provide strong evidence that HCAs increase risk of prostate cancers.

Body size across the life course and prostate cancer in the Health Professionals Follow-up Study.

Current evidence of an association between body size and prostate cancer is conflicting, possibly due to differential effects of body size across the lifespan and the heterogeneity of the disease. We therefore examined childhood and adult body size in relation to total incident prostate cancer and prognostic subtypes in a prospective cohort of 47,491 US men in the Health Professionals Follow-up Study. We assessed adult height, body mass index (BMI) in early and middle-to-late adulthood, adult waist circumference, and body shape at age 10. With follow-up from 1986 to 2010, we estimated the relative risk (RR) of prostate cancer using Cox proportional hazards models. We identified 6,183 incident cases. Tallness was associated with increased risk of advanced-stage tumors, particularly fatal disease (RR = 1.66, 95% CI 1.23-2.23, highest vs. lowest quintile, ptrend < 0.001). High BMI at age 21 was inversely associated with total prostate cancer (RR = 0.89, 95% CI 0.80-0.98, BMI ≥ 26 vs. 20-21.9, ptrend = 0.01) and with fatal and advanced disease. The association for late adult BMI differed by age (pinteraction < 0.001); high BMI was inversely associated with total prostate cancer (RR = 0.64, 95% CI 0.51-0.78, BMI ≥ 30 vs. 21-22.9, ptrend <0.001) and with non-advanced and less aggressive tumors among men ≤ 65 years, whereas no association was seen among men >65 years. Adult waist circumference was weakly inversely associated with less aggressive disease. Childhood obesity was unclearly related to risk. Our study confirms tall men to be at increased risk of fatal and advanced prostate cancer. The influence of adiposity varies by prognostic disease subtype and by age. The relationship between body size and prostate cancer is complex. Body size changes progressively throughout life and consequent effects on prostate cancer risk may be associated with related changes in hormonal and metabolic pathways. This large prospective study examined potential associations between the risk of various prostate cancer subtypes and multiple anthropometric measures at different ages in men. Tallness was confirmed to be associated with an elevated risk of advanced prostate cancer, particularly fatal disease. The extent to which body weight influenced risk varied according to factors such as age and disease subtype.

Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies.

Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose-response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose-response meta-analysis to summarise the dose-response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95% CI were estimated using a random-effects model. For breast cancer, the linear dose-response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95% CI 0·99, 1·11, n 16,023 cases). Evidence for non-linearity was not statistically significant (P non-linearity= 0·50, n 15,415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95% CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95% CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95% CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95% CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out.

Abstract 1884: Dietary intake of phytoestrogens and the risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Prostate cancer is the most common non-cutaneous cancer and second leading cause of cancer death among men in the U.S. Although ecologic and migrant studies suggest that diet plays a role in the etiology of prostate cancer, few specific nutrients that alter its occurrence have been identified in case-control and cohort studies. Phytoestrogens are a family of bioactive compounds that are abundant in soy products and some other food groups (e.g. legumes and chick peas). Experimental studies revealed that phytoestrogen intake may modulate the risk of prostate cancer due to their structural similarity to 17β-estradiol and the resulting competitive binding to estrogen receptors. Despite biological plausibility, it still remains elusive whether phytoestrogen intake influences prostate cancer risk in human populations. Therefore, the objective of the present study was to investigate the associations between dietary intake of phytoestrogens and the risk of total and advanced prostate cancer among 30,097 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). A total of 3628 cases of prostate cancer (including 396 advanced cases) have been documented during a median follow up of 11.5 years. Advanced prostate cancer were defined as stage II cancer with a Gleason score of ≥8, or stage III or stage IV cancer. Dietary intake of phytoestrogens was assessed with a validated food frequency questionnaire. Cox proportional hazards regression was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for dietary intake of phytoestrogens in relation to prostate cancer risk. After adjustment for confounders, an increased risk of advanced prostate cancer was found for the higher dietary intake of isoflavones (HR: 1.58; 95% CI: 1.11, 2.24), genistein (HR: 1.42; 95% CI: 1.02, 1.98), daidzein (HR: 1.62; 95% CI: 1.13, 2.32), and glycitein (HR: 1.53; 95% CI: 1.09, 2.15). Conversely, it appears that the higher dietary intake of genistein was associated with a reduced risk of non-advanced prostate cancer (HR: 0.88; 95% CI: 0.78, 0.99) and total prostate cancer (HR: 0.90; 95% CI: 0.81, 1.00). The risk estimates presented above were obtained for comparisons between the quintile 5 and quintile 1 of respective phytoestrogen intake. In summary, our analysis of this national prospective cohort study suggests that dietary intake of phytoestrogens modulated the risk of prostate cancer and that some of these effects may differ by the aggressiveness of the disease. Citation Format: Michael Reger, Terrell Zollinger, Ziyue Liu, Josette Jones, Jianjun Zhang. Dietary intake of phytoestrogens and the risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1884. doi:10.1158/1538-7445.AM2015-1884

Abstract 4605: Variation in genes involved in the immune response and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial

Abstract Background: We previously found that inflammation in benign prostate tissue is associated with increased odds of prostate cancer especially higher-grade disease. To understand this link, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial (PCPT). Men were screened yearly and if not diagnosed with prostate cancer during the trial, underwent an end-of-study biopsy. Thus, in a subanalysis, we were able to study associations in men with low PSA; i.e., men in whom bias due to any link between inflammation and elevated PSA, an indication for biopsy, is reduced. Methods: We genotyped 16 candidate SNPs in IL1b, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and 7 tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum &amp;lt;7; N = 674) and higher (7-10; N = 172) grade. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. Results: The minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95% CI 1.10-1.53; P-trend = 0.0017) and lower-grade (OR = 1.36, 95% CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95% CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95% CI: 0.75-0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95% CI 1.03-1.66, P-trend = 0.03) were associated with prostate cancer risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were generally similar among men with prostate specific antigen (PSA)&amp;lt;2 ng/mL at biopsy. Conclusion: Our study suggests that variation in some immune response genes possibly may be associated with prostate cancer risk. These associations were not fully explained by PSA-associated detection bias as they remained in men with low PSA. Our findings provide some support to inflammation's role in the etiology of prostate cancer. Funding: P01 CA108964, U10 CA37429, UM1 CA182883, T32 CA009314. *A SWOG-Coordinated Study S9217 Citation Format: Danyelle A. Winchester, Cathee Till, Phyllis J. Goodman, Catherine M. Tangen, Regina M. Santella, Teresa L. Johnson-Pais, Robin J. Leach, Jianfeng Xu, S. Lilly Zheng, Ian M. Thompson, M. Scott Lucia, Scott M. Lippmann, Howard L. Parnes, Paul J. Dluzniewski, William B. Isaacs, Angelo M. De Marzo, Charles G. Drake, Elizabeth A. Platz. Variation in genes involved in the immune response and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4605. doi:10.1158/1538-7445.AM2015-4605

Variation in genes involved in the immune response and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial.

We previously found that inflammation in benign prostate tissue is associated with an increased odds of prostate cancer, especially higher-grade disease. Since part of this link may be due to genetics, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. We genotyped 16 candidate SNPs in IL1β, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and seven tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum <7; N = 674) and higher (7-10; N = 172) grade, and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. The minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95%CI 1.10-1.53; P-trend = 0.0017) and lower-grade (OR = 1.36, 95%CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95%CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95%CI: 0.75-0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95%CI 1.03-1.66, P-trend = 0.03) were associated with risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were similar among men with PSA <2 ng/ml at biopsy. Variation in some immune response genes may be associated with prostate cancer risk. These associations were not fully explained by PSA-associated detection bias. Our findings generally support the role of inflammation in the etiology of prostate cancer.

Magnetic Resonance Imaging/Transrectal Ultrasonography Fusion Prostate Biopsy Significantly Outperforms Systematic 12-Core Biopsy for Prediction of Total Magnetic Resonance Imaging Tumor Volume in Active Surveillance Patients.

To correlate the highest percentage core involvement (HPCI) and corresponding tumor length (CTL) on systematic 12-core biopsy (SBx) and targeted magnetic resonance imaging/transrectal ultrasonography (MRI/TRUS) fusion biopsy (TBx), with total MRI prostate cancer (PCa) tumor volume (TV). Fifty patients meeting criteria for active surveillance (AS) based on outside SBx, who underwent 3.0T multiparametric prostate MRI (MP-MRI), followed by SBx and TBx during the same session at our institution were examined. PCa TVs were calculated using MP-MRI and then correlated using bivariate analysis with the HPCI and CTL for SBx and TBx. For TBx, HPCI and CTL showed a positive correlation (R(2)=0.31, P<0.0001 and R(2)=0.37, P<0.0001, respectively) with total MRI PCa TV, whereas for SBx, these parameters showed a poor correlation (R(2)=0.00006, P=0.96 and R(2)=0.0004, P=0.89, respectively). For detection of patients with clinically significant MRI derived tumor burden greater than 500 mm(3), SBx was 25% sensitive, 90.9% specific (falsely elevated because of missed tumors and extremely low sensitivity), and 54% accurate in comparison with TBx, which was 53.6% sensitive, 86.4% specific, and 68% accurate. HPCI and CTL on TBx positively correlates with total MRI PCa TV, whereas there was no correlation seen with SBx. TBx is superior to SBx for detecting tumor burden greater than 500 mm(3). When using biopsy positive MRI derived TVs, TBx better reflects overall disease burden, improving risk stratification among candidates for active surveillance.

Serum Carotenoid Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial

Epidemiologic studies examining associations of circulating concentrations of retinol and carotenoids with prostate cancer risk have been mixed. This study examined associations with serum retinol and carotenoids in a case‐control study nested within the Prostate Cancer Prevention Trial (n = 1752 controls, 1687 cases). Presence or absence of cancer was determined by prostate biopsy, recommended during the trial due to elevated prostate specific antigen (PSA) or abnormal digital rectal examination (DRE), and offered to all men at trial end. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age, race, BMI, family history of prostate cancer, and serum cholesterol. In the placebo arm, men in the highest quartile of serum retinol had a 30% (OR (95% CI): 1.30 (1.00, 1.68), P‐trend = 0.04) and 74% (OR (95% CI): 1.74 (1.14, 2.68), P‐trend = 0.02) increased odds of total and high‐grade prostate cancer, respectively, relative to those in the lowest. The highest quartile of serum α‐carotene was associated with a 32% (OR (95% CI): 1.32 (1.01, 1.73), P‐trend = 0.03) increased odds of total prostate cancer, relative to the lowest. Associations with retinol were strongest in men who used vitamin A supplements, or who were diagnosed due to abnormal PSA or DRE. There were no associations with serum retinol and α‐carotene in the finasteride arm, or with β‐carotene and β‐cryptoxanthan in either treatment arm. This study was supported by the National Cancer Institute: P01 CA108964, U01 CA37429.

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.

MP14-13 WEIGHING IN ON ACTIVE SURVEILLANCE: IMPACT OF OBESITY ON PATIENT COUNSELING

INTRODUCTION AND OBJECTIVES: The association between body mass index (BMI) and prostate cancer (PC) risk is mixed. Some have speculated that this relates to the fact that BMI is only a moderate measure of adiposity and that perhaps better measures (total percent body fat) or that central adiposity (waist circumference) may better correlate with PC risk. We tested multiple measures of adiposity and PC risk using prospectively collected and measured data from men undergoing prostate biopsies in a Veterans Affairs hospital. We hypothesized that on the aggregate level, BMI, total percent body fat and waist circumference would be highly correlated and that all would be associated with aggressive PC, but not overall incidence. METHODS: We used data from a case-control study among veterans between 2007 and 2012 undergoing prostate biopsy at the Durham Veterans Affairs. The sample consisted of 323 (46%) with biopsy-positive PC (cases) and 375 (54%) biopsy negative (controls). We abstracted Gleason score and race from the records. Weight, height, and waist circumference were measured by trained personnel. Body fat was measured using bio-impedance. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to test the association between adiposity measures and PC risk. Multinomial logistic regression was used to examined high-grade PC (Gleason 7e10) vs. low-grade (2e6) vs. no-PC. RESULTS: BMI was strongly related to percent body fat (Spearman, r1⁄40.81) and waist circumference (r1⁄40.87). Men with higher BMI had significantly higher TRUSprostate volumes, percent body fat, and waist circumference. In both adjusted and unadjusted logistic regression analyses, all three adiposity measures were unrelated to total PC risk (all p>1⁄40.14). However, when stratified by Gleason score, all adiposity measures were associated with a significantly increased risk of high-grade disease (all p 1⁄40.35). CONCLUSIONS: BMI, body fat and waist circumference are all highly correlated with each other and all were significantly associated with aggressive PC, but not overall PC risk. Despite individual differences in these measures, this study supports the continued use of BMI in epidemiological studies of obesity and PC.

Molecular profiling of ETS and non-ETS aberrations in prostate cancer patients from northern India.

BACKGROUNDMolecular stratification of prostate cancer (PCa) based on genetic aberrations including ETS or RAF gene‐rearrangements, PTEN deletion, and SPINK1 over‐expression show clear prognostic and diagnostic utility. Gene rearrangements involving ETS transcription factors are frequent pathogenetic somatic events observed in PCa. Incidence of ETS rearrangements in Caucasian PCa patients has been reported, however, occurrence in Indian population is largely unknown. The aim of this study was to determine the prevalence of the ETS and RAF kinase gene rearrangements, SPINK1 over‐expression, and PTEN deletion in this cohort.METHODSIn this multi‐center study, formalin‐fixed paraffin embedded (FFPE) PCa specimens (n = 121) were procured from four major medical institutions in India. The tissues were sectioned and molecular profiling was done using immunohistochemistry (IHC), RNA in situ hybridization (RNA‐ISH) and/or fluorescence in situ hybridization (FISH).RESULTS ERG over‐expression was detected in 48.9% (46/94) PCa specimens by IHC, which was confirmed in a subset of cases by FISH. Among other ETS family members, while ETV1 transcript was detected in one case by RNA‐ISH, no alteration in ETV4 was observed. SPINK1 over‐expression was observed in 12.5% (12/96) and PTEN deletion in 21.52% (17/79) of the total PCa cases. Interestingly, PTEN deletion was found in 30% of the ERG‐positive cases (P = 0.017) but in only one case with SPINK1 over‐expression (P = 0.67). BRAF and RAF1 gene rearrangements were detected in ∼1% and ∼4.5% of the PCa cases, respectively.CONCLUSIONSThis is the first report on comprehensive molecular profiling of the major spectrum of the causal aberrations in Indian men with PCa. Our findings suggest that ETS gene rearrangement and SPINK1 over‐expression patterns in North Indian population largely resembled those observed in Caucasian population but differed from Japanese and Chinese PCa patients. The molecular profiling data presented in this study could help in clinical decision‐making for the pursuit of surgery, diagnosis, and in selection of therapeutic intervention. Prostate 75:1051–1062, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Cholesterol metabolism and prostate cancer-specific mortality.

12 Background: Cholesterol is needed in prostate cancer cells for cell proliferation and for androgen biosynthesis. Cholesterol-lowering statin drug use is associated with a lower risk of total and advanced prostate cancer and lower prostate cancer-specific mortality (PCSM). We hypothesized that tumor expression of cholesterol synthesis enzymes, transporters and regulators is associated with PCSM. Methods: We studied mRNA expression of 43 cholesterol metabolism genes in surgical specimens from 249 participants in the Health Professionals' Follow-up Study diagnosed with prostate cancer between 1986 and 2004. We included 81 cases of lethal prostate cancer and 168 indolent cases who survived &gt;8 years without metastases. After multivariate dimensionality reduction for the synthesis, transport and regulator pathways using principal components analysis, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We adjusted for age, year of diagnosis, body mass index, smoking status, family history, multivitamin use, high serum cholesterol and cholesterol-lowering drug use. Results: Reflecting the impact of the synthesis pathway and of the regulator pathway, respectively, the expression of squalene epoxidase (SQLE) and low-density lipoprotein receptor (LDLR) were significantly associated with lethal cancer in opposing directions. Compared to men with the mean level of SQLE expression, men with SQLE expression &gt;1 standard deviation (SD) above the mean were 15.4 times more likely to have lethal cancer (95% CI: 3.31–71.53). For LDLR, expression &gt;1 SD above the mean was associated with 96% lower odds of lethal cancer (95% CI: 0.01–0.70). Higher SQLE expression and lower LDLR expression were associated with higher Gleason grades (Fisher's test, p &lt; 0.001 and p = 0.036, respectively) and were also predictive of PCSM independently from grade and tumor stage. Conclusions: These results suggest that the local cholesterol metabolism of the prostate tumor is tightly linked with mortality. Lethal cancers have higher activity of the second rate-controlling enzyme of cholesterol synthesis and are less dependent on cholesterol uptake.

Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study.

A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease. Overall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were <1 (all P ≥ 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms. Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted.

Do environmental factors modify the genetic risk of prostate cancer?

Many SNPs influence prostate cancer risk. To what extent genetic risk can be reduced by environmental factors is unknown. We evaluated effect modification by environmental factors of the association between susceptibility SNPs and prostate cancer in 1,230 incident prostate cancer cases and 1,361 controls, all white and similar ages, nested in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Trial. Genetic risk scores were calculated as number of risk alleles for 20 validated SNPs. We estimated the association between higher genetic risk (≥12 SNPs) and prostate cancer within environmental factor strata and tested for interaction. Men with ≥12 risk alleles had 1.98, 2.04, and 1.91 times the odds of total, advanced, and nonadvanced prostate cancer, respectively. These associations were attenuated with the use of selenium supplements, aspirin, ibuprofen, and higher vegetable intake. For selenium, the attenuation was most striking for advanced prostate cancer: compared with <12 alleles and no selenium, the OR for ≥12 alleles was 2.06 [95% confidence interval (CI), 1.67-2.55] in nonusers and 0.99 (0.38-2.58) in users (Pinteraction = 0.031). Aspirin had the most marked attenuation for nonadvanced prostate cancer: compared with <12 alleles and nonusers, the OR for ≥12 alleles was 2.25 (1.69-3.00) in nonusers and 1.70 (1.25-2.32) in users (Pinteraction = 0.009). This pattern was similar for ibuprofen (Pinteraction = 0.023) and vegetables (Pinteraction = 0.010). This study suggests that selenium supplements may reduce genetic risk of advanced prostate cancer, whereas aspirin, ibuprofen, and vegetables may reduce genetic risk of nonadvanced prostate cancer. The effect of genetic factors on prostate cancer risk may vary by lifestyle interventions.

Fiber intake and risk of subsequent prostate cancer in Japanese men

Dietary fiber may reduce the risk of prostate cancer, possibly by increasing circulating concentrations of sex hormone-binding globulin and improving insulin sensitivity. However, results from previous epidemiologic studies of fiber intake and prostate cancer are inconsistent, and to our knowledge, no study has comprehensively evaluated the effects of soluble and insoluble fiber on prostate cancer in Asia. The objective was to examine the association between fiber intake and prostate cancer in Japanese men. We conducted a population-based prospective study in 43,435 Japanese men aged 45-74 y. Participants responded to a validated questionnaire, which included 138 food items. Follow-up was from 1995 through 2009. HRs and 95% CIs of incidence were calculated according to quartiles of fiber intake. During the 11.6-y follow-up, of the 825 men newly diagnosed with prostate cancer, 213 had advanced-stage cancer, 582 had organ-localized disease, and 30 had an undetermined stage of disease. Among them, 217 cases were detected by subjective symptoms. Total fiber was not associated with total or advanced prostate cancer, with respective multivariable HRs for the highest and lowest quartiles of 1.00 (95% CI: 0.77, 1.29; P-trend = 0.97) and 0.67 (95% CI: 0.42, 1.07; P-trend = 0.30). Total fiber and insoluble fiber intake were associated with a decreased risk of advanced cancers detected by subjective symptoms, with multivariate HRs (95% CIs) across increasing quartiles of 1.00, 0.58, 0.62, and 0.44 (0.21, 0.92; P-trend = 0.05) for total fiber and 1.00, 0.60, 0.52, and 0.46 (0.22, 0.93; P-trend = 0.04) for insoluble fiber. Soluble fiber intake showed no association with prostate cancer. Dietary fiber is inversely associated with advanced prostate cancer detected by subjective symptoms even among populations with relatively low intake, such as Japanese. These results suggest that a very low intake of dietary fiber is associated with an increased risk of prostate cancer.

Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies

Dairy product and calcium intakes have been associated with increased prostate cancer risk, but whether specific dairy products or calcium sources are associated with risk is unclear. In the Continuous Update Project, we conducted a meta-analysis of prospective studies on intakes of dairy products and calcium and prostate cancer risk. PubMed and several other databases were searched up to April 2013. Summary RRs were estimated by using a random-effects model. Thirty-two studies were included. Intakes of total dairy products [summary RR: 1.07 (95% CI: 1.02, 1.12; n = 15) per 400 g/d], total milk [summary RR: 1.03 (95% CI: 1.00, 1.07; n = 14) per 200 g/d], low-fat milk [summary RR: 1.06 (95% CI: 1.01, 1.11; n = 6) per 200 g/d], cheese [summary RR: 1.09 (95% CI: 1.02, 1.18; n = 11) per 50 g/d], and dietary calcium [summary RR: 1.05 (95% CI: 1.02, 1.09; n = 15) per 400 mg/d] were associated with increased total prostate cancer risk. Total calcium and dairy calcium intakes, but not nondairy calcium or supplemental calcium intakes, were also positively associated with total prostate cancer risk. Supplemental calcium was associated with increased risk of fatal prostate cancer. High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk. The diverging results for types of dairy products and sources of calcium suggest that other components of dairy rather than fat and calcium may increase prostate cancer risk. Any additional studies should report detailed results for subtypes of prostate cancer.

Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study

High calcium intake has been associated with an increased risk of advanced-stage and high-grade prostate cancer. Several studies have found a positive association between phosphorus intake and prostate cancer risk. We investigated the joint association between calcium and phosphorus and risk of prostate cancer in the Health Professionals Follow-Up Study, with a focus on lethal and high-grade disease. In total, 47,885 men in the cohort reported diet data in 1986 and every 4 y thereafter. From 1986 to 2010, 5861 cases of prostate cancer were identified, including 789 lethal cancers (fatal or metastatic). We used Cox proportional hazards models to assess the association between calcium and phosphorus intake and prostate cancer, with adjustment for potential confounding. Calcium intakes >2000 mg/d were associated with greater risk of total prostate cancer and lethal and high-grade cancers. These associations were attenuated and no longer statistically significant when phosphorus intake was adjusted for. Phosphorus intake was associated with greater risk of total, lethal, and high-grade cancers, independent of calcium and intakes of red meat, white meat, dairy, and fish. In latency analysis, calcium and phosphorus had independent effects for different time periods between exposure and diagnosis. Calcium intake was associated with an increased risk of advanced-stage and high-grade disease 12-16 y after exposure, whereas high phosphorus was associated with increased risk of advanced-stage and high-grade disease 0-8 y after exposure. Phosphorus is independently associated with risk of lethal and high-grade prostate cancer. Calcium may not have a strong independent effect on prostate cancer risk except with long latency periods.

Does cumulative prostate cancer length (CCL) in prostate biopsies improve prediction of clinically insignificant cancer at radical prostatectomy in patients eligible for active surveillance?

To evaluate if cumulative prostate cancer length (CCL) on prostate needle biopsy divided by the number of biopsy cores (CCL/core) could improve prediction of insignificant cancer on radical prostatectomy (RP) in patients with prostate cancer eligible for active surveillance (AS). Patients diagnosed with prostate cancer on extended (≥10 cores) biopsy with an initial prostate-specific antigen (iPSA) level of <15 ng/mL, clinical stage (cT) ≤ 2a, and highest biopsy Gleason score 3 + 3 = 6 or 3 + 4 = 7 with <3 positive cores who underwent RP were included in the study. The CCL/core and presence of insignificant cancer (organ-confined, volume <0.5 mL, Gleason score at RP ≤6) were recorded. pT2 prostate cancer with RP Gleason score ≤3 + 4 = 7 and volume <0.5 mL were categorised as low-tumour-volume organ-confined disease (LV-OCD). In all, 221 patients met the inclusion criteria: the mean age was 59 years and the median iPSA level was 4.5 ng/mL. The clinical stage was cT1 in 86% of patients; biopsy Gleason score was 3 + 3 = 6 in 67% (group 1) and 3 + 4 = 7 in 33% of patients (group 2). The maximum percentage of biopsy core involvement was <50 in 85%; the median CCL/core was 0.15 mm. Insignificant cancer was found in 27% and LV-OCD in 44% of patients. Group 2 was associated with higher number of positive cores, maximum percentage core involvement, total prostate cancer length, and CCL/core. Group 1 was more likely to have insignificant cancer (39%) or LV-OCD (54%) than group 2 (3% and 23%, respectively). Group 2 had significantly higher RP Gleason score and pathological stage. Univariate analysis of group 1 showed that the iPSA level, maximum percentage core involvement, prostate cancer length, and CCL/core were all significantly associated with insignificant cancer and LV-OCD. For group 2, the number of positive cores (1 vs 2) was also significantly associated with LV-OCD. On multivariate logistic regression analysis, maximum percentage core involvement of <50, and number of positive cores (1 vs 2) were independent predictors of insignificant cancer in group 1; biopsy Gleason score, maximum percentage core involvement of <50 and prostate cancer length of <3 mm or CCL/core of <0.2 mm were all independent predictors of LV-OCD in the whole population. The maximum percentage of core involvement of <50 and prostate cancer length of <3 mm or CCL/core of <0.2 mm were also independent predictors of LV-OCD in group 1 patients. In patients eligible for AS, a CCL/core of <0.20 mm was significantly associated with insignificant cancer and LV-OCD. However, when parameters of cancer burden were considered, CCL/core did not independently add any additional value for predicting insignificant cancer in patients with biopsy Gleason score 6. The CCL/core was an independent predictor of LV-OCD in the whole population and in group 1 patients, although the model including prostate cancer length showed slightly higher area under the receiver operating characteristic curve.