Risk Of Total Prostate Cancer Research Articles

MP50-07 CURRENT EVIDENCE DOES NOT SUPPORT THE HYPOTHESIS THAT STATIN USE REDUCES THE RISK OF PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2016MP50-07 CURRENT EVIDENCE DOES NOT SUPPORT THE HYPOTHESIS THAT STATIN USE REDUCES THE RISK OF PROSTATE CANCER Ping Tan, Lu Yang, Shiyou Wei, Liang Gao, Zhuang Tang, and Qiang Wei Ping TanPing Tan More articles by this author , Lu YangLu Yang More articles by this author , Shiyou WeiShiyou Wei More articles by this author , Liang GaoLiang Gao More articles by this author , Zhuang TangZhuang Tang More articles by this author , and Qiang WeiQiang Wei More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.441AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the most widely used drugs for lowering cholesterol. Recently, there has been increasingly great interest in the anti-tumor effects of statins, which have been shown to promote cancer cell apoptosis, inhibiting inflammation, tumor growth and invasion/metastasis. However, clinical studies have not yet shown a consensus. In this abstract, we aim to investigate the effects of statins use on prostate cancer (PCa) risk. METHODS We performed a literature search without language restrictions using the databases of PubMed, MEDLINE, EMBASE, The Cochrane Library, Web of Science, and ClinicalTrials.gov. Data from each study were independently extracted by two reviewers (TP and WSY). Odds Ratio (ORs) and their 95% CIs were used to assess the strength of association between statin use and the risk of PCa. Statistic heterogeneity scores were assessed with the standard Cochran's Q test. Publication bias was detected using the Egger's tests. Statistical significance was determined using the two-tailed test, where P < 0.05 was considered significant. STATA version 10 (Stata corporation, college station, TX) was employed to conduct all statistical analyses. RESULTS 8633 articles were identified initially, and after employing exclusion criteria, 42 studies were included in the meta-analysis. The pooled result suggested that statins had a neutral effect on total PCa (OR = 0.92 95% CI: 0.82-1.03). In addition, results showed that long-term statins use (n=14) (defined as ≥5 years of use) had no effect on the risk of PCa (OR = 0.86, 95% CI: 0.63-1.09). However, a 12% reduction in total PCa risk among in short-term statins users (n=14) (defined as <5 years of use) as compared to non-users was observed (OR = 0.88, 95% CI: 0.78-0.98). Furthermore, a plausible link was found between a decreased risk of advanced PCa (n=11) (defined by the stage of the disease as ′regional′ or ′distant′ or the TNM stage within T3-4, N1-3 and M1) and statins use (OR = 0.83, 95% CI: 0.75-0.92), which was the same as that in high-grade PCa (n=15) (defined as Gleason sum ≥ 7) (OR = 0.83, 95% CI: 0.66-0.99). However, the pooled results showed that use of any statin had a neutral influence on the occurrence of both low-grade PCa (defined as Gleason sum < 7) (OR = 0.95, 95% CI: 0.88-1.02) and localized PCa(defined by the stage of the disease as ′localized′ or the TNM stage as T1-2, N0/x and M0/x.) (OR = 0.98, 95% CI: 0.91-1.06). There was no publication bias observed (Egger's test, p=0.298) CONCLUSIONS The evidence determined by the analyses does not support the hypothesis that statins use are protective against the development of total prostate cancer, localized PCa and low-grade PCa. In addition, results show that long-term statins use has no effect on the risk of PCa. Instead, Statins use are associated with a protective effect for advanced prostate cancer and high-grade prostate cancer, however, which should be evaluated with caution, given the detection bias in these observational studies. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e675 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Ping Tan More articles by this author Lu Yang More articles by this author Shiyou Wei More articles by this author Liang Gao More articles by this author Zhuang Tang More articles by this author Qiang Wei More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Selenium status and risk of prostate cancer in a Danish population.

Low-Se status may be associated with a higher risk of notably advanced prostate cancer. In a Danish population with a relatively low Se intake, we investigated the association between pre-diagnostic Se status and (1) the risk of total, advanced and high-grade prostate cancer and (2) all-cause and prostate cancer-specific mortality among men with prostate cancer. Within the Danish 'Diet, Cancer and Health' cohort, including 27 179 men, we identified 784 cases with incident prostate cancer through 2007. Each case was risk set-matched to one control. Two-thirds (n 525) of the cases had advanced disease at the time of diagnosis, and among these 170 had high-grade disease; 305 cases died (n 212 from prostate cancer) during follow-up through 2012. Plasma Se was not associated with total or advanced prostate cancer risk, but higher Se levels were associated with a lower risk of high-grade disease (HR 0·77; 95 % CI 0·64, 0·94; P=0·009). In survival analyses, a higher level of plasma Se was associated with a lower risk of all-cause (HR 0·92; 95 % CI 0·85, 1·00; P=0·04), but not prostate cancer-specific mortality. Higher levels of selenoprotein P were associated with a lower risk of high-grade disease (HR 0·85; 95 % CI 0·74, 0·97; P=0·01), but not with the risk of or mortality from advanced prostate cancer. In conclusion, levels of plasma Se and selenoprotein P were not associated with the risk of total and advanced prostate cancer, but higher levels of these two biomarkers were associated with a lower risk of high-grade disease.

Abstract C41: Serum vitamin D and risk of prostate cancer among black men in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial

Abstract Introduction: Cohort studies and meta-analyses suggest higher circulating 25-hydroxyvitmain D (25(OH)D) is associated with increased prostate cancer risk. The association has largely been defined in non-Hispanic white populations. Using data from the PLCO Trial, we prospectively examined the association between circulating 25(OH)D and prostate cancer risk in black men, a group with lower circulating vitamin D and higher prostate cancer rates relative to other racial/ethnic groups. Methods: This nested case-control analysis included 226 black prostate cancer cases and 452 controls matched 2:1 based on age at randomization (+/- 5 years), date of blood draw (+/- 30 days), and calendar-year of entry into the cohort. Serum 25(OH)D was measured using liquid chromatography-mass spectrometry (LC/MS), and we estimated odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer by quartiles and clinically defined cut-points (&amp;lt;25, 25-50, and 75+, with 50-&amp;lt;75 nmol/L as the referent group) of baseline 25(OH)D from multivariable conditional logistic regression models. Two methods were used to adjust for seasonal variation in 25(OH)D: 1) quartiles created for sunnier (May-October) and darker (November-April) months were combined to create season-specific quartiles; 2) 25(OH)D was regressed on week of blood draw and the residuals were used to create season-standardized quartiles. Risk of total, aggressive (clinical stage III or IV or Gleason score ≥7) and non-aggressive (clinical stage I or II and Gleason score &amp;lt;7) disease were determined. Results: We found statistically non-significant associations between circulating 25(OH)D and risk of total prostate cancer in black men (season-specific Q4 vs. Q1 OR=0.83, 95% CI:0.42-1.67, P for trend = 0.41). For non-aggressive disease, the association was inverse (global P-value = 0.025), particularly in the 3rd quartile: Q3 vs. Q1 OR= 0.17, 95% CI: 0.06-0.55, Q4 vs. Q1 OR= 0.62, 95% CI: 0.23-1.71, P for trend =0.10). In contrast, the association with aggressive disease, while non-significant, appeared positive (Q4 vs. Q1 OR=1.18, 95% CI: 0.38-3.62, P for trend = 0.77). Similar results were obtained for total, non-aggressive, and aggressive prostate cancer using season-standardized quartiles of 25(OH)D. There was no evidence of an association with total prostate cancer using clinically defined cut-points, although categories above and below the referent category appeared to be inversely associated with risk of aggressive disease, while positively associated with risk of non-aggressive disease. We found no evidence of a difference in our findings for total prostate cancer and 25(OH)D when stratified by median total vitamin D intake, family history of prostate cancer, smoking status, physical activity, aspirin use, or body mass index. Conclusions: Our analysis of circulating 25(OH)D and prostate cancer risk among black men indicates a possible modest inverse association with total prostate cancer risk. This was reflective of the association with non-aggressive disease, where circulating 25(OH)D had a protective effect, but not for aggressive disease. Our finding of potential variability in the vitamin D-prostate cancer risk association by disease aggressiveness may be related to differences in pathogenesis and prognosis of indolent and aggressive prostate cancers. Our study adds to the limited prospective research addressing this relationship in a high risk population. Additional studies of the vitamin D-prostate cancer risk association in black men are needed. Citation Format: Tracy M. Layne, Stephanie Weinstein, Xiaomei Ma, Barry I. Graubard, Susan T. Mayne, Demetrius Albanes. Serum vitamin D and risk of prostate cancer among black men in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C41.

Obesity and Prostate Cancer.

Prostate cancer is a complex, heterogeneous disease. Factors related to detection, particularly PSA screening, further increase heterogeneity in the manifestation of the disease. It is thus not possible to provide a simple summary of the relationship between obesity and prostate cancer. Findings on obesity, often defined using body mass index (BMI), and total prostate cancer risk have been mixed; however, obesity is relatively consistently associated with ahigher risk of aggressive prostate cancer, with aggressiveness defined in various ways (e.g., advanced stage, fatal, poorer prognosis in men with prostate cancer). Many methodologic issues (e.g., influence of PSA screening, detection bias and treatment) need to be thoroughly considered in both existing and future etiologic and prognostic research. Biological mechanisms supporting the link are under investigation, but may involve insulin and IGF axis, sex steroid hormones and alterations in metabolism. Some promising data suggest that molecular sub-types of prostate cancer may offer insights into etiology, but further study is required. A full evaluation of body fatness and weight change over the life course would not only provide insights to the underlying mechanisms but also allow more effective interventions.

Abstract PR04: Aspirin, NSAIDs, and risk of prostate cancer: Results from the REDUCE study

Abstract Background: A recent meta-analysis showed aspirin was associated with a reduced risk of total prostate cancer (PC) however the effect of non-aspirin NSAIDs on PC appeared to vary by geographic region. In North America non-aspirin NSAIDs were null to protective while studies from Europe found either null or positive associations between PC and any NSAIDs use. However, as anti-inflammatory medications can alter PSA levels, which is the chief driver of PC detection, whether these findings reflect reduced detection of PC or truly a biological link with lower PC risk is unknown. We tested the association between aspirin and non-aspirin NSAIDs on PC diagnosis among men with an elevated PSA and negative pre-study biopsy in the REDUCE study where all men received biopsies at 2- and 4-years regardless of PSA levels. Methods: The REDUCE study tested dutasteride for PC risk reduction in men with a PSA of 2.5-10.0 ng/mL and a negative pre-study biopsy. Study participants for this analysis included 6,427 men who underwent at least one on-study biopsy. The association between use of aspirin, NSAIDs or both, and risk of total and low-grade (Gleason &amp;lt;7) or high-grade (Gleason ≥7) PC vs. no PC was examined using multinomial logistic regression as well as stratified analysis by geographic region (Europe vs. North America) and treatment arm. Results: Overall, 3,189 men (50%) were non-users, 1,377 (21%) aspirin users, 1,181 (18%) NSAIDs users, and 680 (11%) used both aspirin and NSAIDs. In univariable analysis, aspirin use was associated with lower risk of total PC (OR=0.85, p=0.04), but no associations were found for NSAIDs use (OR=0.74, p=0.08). In multivariable analyses, aspirin use and NSAIDs use was not associated with total, low- or high-grade PC (all p&amp;gt;0.09). However, as the multivariable ORs for both aspirin, NSAIDs, and the combination group were very similar for all outcomes and all suggestive of a slightly lower risk (OR 0.84-0.95), we combined these groups creating a dichotomous variable of aspirin/NSAID user vs. not. When this was done, the use of aspirin and/or NSAIDs was linked with lower risk of total (OR=0.86, p=0.01) and high-grade PC (OR=0.82, p=0.05) in unadjusted analysis. After adjusting for key covariates, the use of aspirin and/or NSAIDs remained associated with decreased risk of total PC (OR=0.87, p=0.02) but not with low- (OR=0.91, p=0.22) or high-grade PC (OR=0.85, p=0.14), though the ORs for low- and high-grade PC were similar to the OR for overall PC. When analyses were stratified by geographic region the association between intake of aspirin, NSAIDs, both, or either (i.e. the dichotomous variable of any aspirin and/or NSAID) and reduced risk of PC was similar in Europe and North America (p-interaction&amp;gt;0.41). Results were similar in placebo and dutasteride treated men. Conclusions: Among men in the REDUCE study the use of either aspirin and/or NSAIDs was associated with decreased risk of total PC. These data provide further support to the hypothesis that anti-inflammatory drugs may help reduce the risk of PC. Prospective clinical trials to test this hypothesis are warranted. Citation Format: Adriana C. Vidal, Lauren E Howard, Daniel M Moreira, Ramiro Castro-Santamaria, Gerald L Andriole, Stephen J Freedland. Aspirin, NSAIDs, and risk of prostate cancer: Results from the REDUCE study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PR04.

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.

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.

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.

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.

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.

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.

Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial , , ,

Recent posttrial analysis of a completed randomized trial found an increased risk of prostate cancer among healthy men taking high-dose vitamin E supplements. Trials that examined the effect of vitamin C supplements on cancer risk are few. We examined whether vitamin E or vitamin C supplementation affects the risk of cancer events during posttrial follow-up of the Physicians' Health Study II. Beginning in 1997, a total of 14,641 US male physicians aged ≥50 y were randomly assigned to receive 400 IU of vitamin E every other day, 500 mg of vitamin C daily, or their respective placebos. The vitamin E and vitamin C treatment ended in 2007, and observational follow-up continued through June 2011. This study included an additional 356 cases of incident prostate cancer and 771 total cancers that developed during a mean (maximum) of 2.8 (3.8) y of posttrial observation. During an overall mean of 10.3 (13.8) y, there were a total of 1373 incident prostate cancers and 2669 total cancers documented. In comparison with placebo, vitamin E supplementation had no effect on the incidence of prostate cancer (HR: 0.99; 95% CI: 0.89, 1.10) or total cancers (HR: 1.02; 95% CI: 0.95, 1.10). There was also no effect of vitamin C supplementation on total cancers (HR: 1.02; 95% CI: 0.94, 1.10) or incident prostate cancer (HR: 1.03; 95% CI: 0.93, 1.15). Neither vitamin E nor vitamin C supplementation had effects on other site-specific cancers overall. Stratification by known cancer risk factors, history of cancer, other randomized treatment, and follow-up time showed no significant interactions. In this large-scale randomized trial in men, vitamin E and C supplementation had no immediate or long-term effects on the risk of total cancers, prostate cancer, or other site-specific cancers.

Serum phytanic and pristanic acid levels and prostate cancer risk in Finnish smokers.

Phytanic acid is a saturated branched-chain fatty acid found predominantly in red meat and dairy products, and may contribute to the elevated risks of prostate cancer associated with higher consumption of these foods. Pristanic acid is formed during peroxisomal oxidation of phytanic acid, and is the direct substrate of α-Methyl-CoA-Racemase (AMACR)—an enzyme that is consistently overexpressed in prostate tumors relative to benign tissue. We measured phytanic and pristanic acids as percentages of total fatty acids by gas chromatography-mass spectrometry in prediagnostic blood samples from 300 prostate cancer cases and 300 matched controls, all of whom were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study supplementation trial and follow-up cohort. In addition to providing a fasting blood sample at baseline, all men completed extensive diet, lifestyle, and medical history questionnaires. Among controls, the strongest dietary correlates of serum phytanic and pristanic acids were saturated fat, dairy fat, and butter (r = 0.50 and 0.40, 0.46 and 0.38, and 0.40 and 0.37, respectively; all P-values <0.001). There was no association between serum phytanic acid and risk of total or aggressive prostate cancer in multivariate logistic regression models (for increasing quartiles, odds ratios (OR) and 95% confidence intervals (CI) for aggressive cancer were 1.0 (referent), 1.62 (0.97–2.68), 1.12 (0.66–1.90), and 1.14 (0.67–1.94), Ptrend = 0.87). Pristanic acid was strongly correlated with phytanic acid levels (r = 0.73, P < 0.0001), and was similarly unrelated to prostate cancer risk. Significant interactions between phytanic and pristanic acids and baseline circulating β-carotene concentrations were noted in relation to total and aggressive disease among participants who did not receive β-carotene supplements as part of the original ATBC intervention trial. In summary, we observed no overall association between serum phytanic and pristanic acid levels and prostate cancer risk. Findings indicating that the direction and magnitude of these associations depended upon serum levels of the antioxidant β-carotene among men not taking β-carotene supplements should be interpreted cautiously, as they are likely due to chance.

Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial.

Epidemiologic studies have reported inconsistent associations of vitamin D and prostate cancer risk; however, few have adequately controlled for detection bias related to prostate-specific antigen (PSA) screening, and the results of many studies may be affected by occult prostate cancers among controls. Data for this nested case-control analysis (n = 1,695 cases/1,682 controls) are from the Prostate Cancer Prevention Trial. Baseline serum was analyzed for 25-hydroxyvitamin D [25(OH)D]. The presence or absence of cancer was subsequently determined by prostate biopsy. Polytomous logistic regression models were used to estimate associations of 25(OH)D with risk of total, Gleason 2-6, Gleason 7, and Gleason 8-10 prostate cancer. Results are presented for placebo and finasteride arms separately and combined. There were no associations of serum 25(OH)D with total prostate cancer risk. For Gleason 2-6 cancers, results were inconsistent across treatment arms with a suggestion of increased risk in the placebo arm only; however, there was no dose-response relationship. For Gleason 8-10 prostate cancers, 25(OH)D concentrations were associated with a linear decrease in risk among combined treatment arms [quartile 4 vs. 1: OR, 0.55; 95% confidence interval (CI), 0.32-0.94; P(trend) = 0.04]. These findings were somewhat stronger among men ≥65 versus 55-64 years at baseline (quartile 4 vs. 1: OR, 0.40; 95% CI, 0.18-0.88 vs. OR, 0.73; 95% CI, 0.35-1.52, respectively; P(interaction) = 0.52). Higher serum 25(OH)D may modestly increase risk of Gleason 2-6 disease and more substantially reduce risk of Gleason 8-10 prostate cancer. Vitamin D may have different effects for different stages of prostate cancers.