Abstract 3618: Peripheral cytokine profiles and prostate cancer risk in CLUE II.

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

MP09-20 THE COMBINATION OF HISTOLOGICAL PROSTATE ATROPHY AND INFLAMMATION IS ASSOCIATED WITH LOWER RISK OF PROSTATE CANCER

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAID), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in previous epidemiologic studies. Acetaminophen, a commonly used pain reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects. Few studies have examined the association between long-term acetaminophen use and prostate cancer incidence. We examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated by using follow-up questionnaires in 1997 and every two years thereafter. Relative risks (RR) were estimated by using proportional hazards regression models. All models were adjusted for age, race, education, body mass index, diabetes, NSAID use, and history of prostate-specific antigen testing. During follow-up from 1992 through 2007, 8,092 incident prostate cancer cases were identified. Current regular use of acetaminophen (30 or more pills per month) for 5 or more years was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI: 0.44-0.87) and aggressive prostate cancer (RR = 0.49, 95% CI: 0.27-0.88). Current regular use of less than 5 years duration was not associated with prostate cancer risk. These results suggest that long-term regular acetaminophen use may be associated with lower prostate cancer risk. If the association between acetaminophen use and lower risk of prostate cancer is confirmed, it could provide clues about biological mechanisms that are important in prostate carcinogenesis.

Background: Thyroid hormones are hypothesized to be associated with risk of cancer because of their important role in cell differentiation, growth, and metabolism. They have also been shown to increase the proliferation of prostate cancer cells in vitro. Only one previous prospective epidemiologic study has examined circulating thyroid hormones and risk of prostate cancer, and this study provided support for the hypothesized relationship. Thus, we undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Within the ATBC Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and α-carotene supplements on cancer incidence in male smokers, 402 prostate cancer cases were randomly sampled. Controls were matched 2:1 to cases based on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer by quintiles of total and free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-binding globulin (TBG), as well as by categories of thyroid status (i.e., hypothyroid, hyperthyroid, and euthyroid). Multivariable models were adjusted for the following factors: BMI, serum retinol, total cholesterol, α-tocopherol, and α-carotene, cigarettes per day, years smoked, family history of prostate cancer, physical activity, education, marital status, urban residence, intake of energy, dietary vitamin D, fruit, vegetables, red meat, alcohol, and supplemental calcium. Results: After multivariable adjustment, we observed that men with TSH ≤ 2.2 αIU/mL had a statistically significantly decreased risk of prostate cancer compared to men with TSH < 2.2 αIU/mL (OR=0.70, 95% CI: 0.51 - 0.97, p = 0.03). This finding was similar in relation to aggressive disease. When the T4 and TSH measurements were combined to define men as clinically or sub-clinically hypothyroid or hyperthyroid, we observed that hypothyroid men had a statistically significant lower risk of overall prostate cancer compared to men who had normal thyroid function (OR=0.48, 95% CI=0.28 - 0.81; p = 0.006). We observed no association between hyperthyroid status and risk of prostate cancer, although the number of cases in this category was small (n=9). There were too few aggressive cases who were hypothyroid or hyperthyroid to examine the association between thyroid status and disease aggressiveness. Conclusions: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethic groups, and should be large enough to evaluate the association between thyroid status and aggressive disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4472. doi:1538-7445.AM2012-4472

TH1 cytokines, such as IFNγ and TNFα, and potentially innate cytokines, such as IL6, can potentiate the immune response to tumor. Cytokines, such as IL1β, IL8, and IL10, may suppress anticancer immunity. Thus, we prospectively evaluated the association between peripheral-cytokine concentrations and prostate cancer. We conducted an age-race matched case-control study (268 pairs) of incident prostate cancer in CLUE-II. We measured plasma IFNγ, IL10, IL12p70, IL1β, IL6, IL8, and TNFα concentrations using an ultrasensitive multiplex kit. ORs and 95% confidence intervals (CI) were calculated using conditional logistic regression. The OR of prostate cancer decreased across quartiles of IFNγ (highest vs. lowest quartiles: OR, 0.49; 95% CI, 0.30-0.81; Ptrend = 0.006), TNFα (OR, 0.56; 95% CI, 0.33-0.96; Ptrend = 0.01), and IL6 (OR, 0.46; 95% CI, 0.26-0.79; Ptrend = 0.007). Higher TNFα (OR, 0.28; 95% CI, 0.09-0.85; Ptrend = 0.01) and IL6 (OR, 0.20; 95% CI, 0.06-0.67; Ptrend = 0.003) concentrations were associated with lower Gleason sum ≥7 disease risk. Other cytokines were not as clearly associated with risk. Men with a prediagnostic circulating TH1 profile and higher IL6 may have a lower risk of prostate cancer, including aggressive disease. Whether this profile reflects (i) an intraprostatic immune environment in benign tissue that protects against prostate cancer, (ii) the immune milieu in response to a prostate adenocarcinoma that inhibits tumor growth and detectability, and/or (iii) a systemic immune profile that mediates the influence of modifiable factors on risk, warrants additional study. Identifying specific inflammatory cytokines associated with prostate cancer may lead to improved prevention and treatment strategies.

Research on the association between physical activity and the risk of prostate cancer is inconsistent. The aim of this study was to investigate whether the timing, intensity, and type of recreational physical activity influence prostate cancer risk. A population-based case-control study was conducted in Western Australia in 2001-2002. Data were collected on lifetime recreational physical activity from a self-reported questionnaire. The estimated effects of recreational physical activity on prostate cancer risk were analyzed using logistic regression, adjusting for demographic and lifestyle factors. This analysis included 569 incident cases and 443 controls. There was a significant, inverse dose-response relationship between vigorous-intensity recreational physical activity between the ages 19 and 34years and the risk of prostate cancer (pTrend = 0.013). Participants in the most active quartile of vigorous-intensity physical activity in this age period had a 33% lower risk of prostate cancer than participants in the least active quartile (Adjusted Odds Ratio = 0.67, 95% confidence interval = 0.45-1.01). Moderate-intensity recreational physical activity was not associated with the risk of prostate cancer. Recreational physical activity performed over the lifetime showed no association with prostate cancer risk. Weight training performed from early adulthood onwards showed a non-significant but consistent inverse association with prostate cancer risk. There was no strong evidence that physical activity was differentially associated with the risks of low-grade and medium-to-high grade prostate cancers. A high level of vigorous recreational physical activity in early adulthood may be required to reduce the risk of prostate cancer.

Background - There is suggestive evidence of familial clustering of breast and prostate cancer in first-degree relatives; women with a family history of prostate cancer are at increased risk of breast cancer. Few studies have investigated joint family history of breast and prostate cancer and prostate cancer risk, and no study to date has examined lethal prostate cancer. Methods - We studied 42,672 from the Health Professionals Follow-up Study between 1996 to 2012. During follow-up, 4,258 prostate cancer cases were diagnosed, of whom 380 were lethal disease. Men self-reported family history of breast and prostate cancer, including in siblings or parents. Using cause-specific hazards regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) of the association between family history and prostate cancer risk and progression. Results - About 8% of men had a family history of prostate cancer, 8.7% had a family history of breast cancer, and 1.4% of men had a family history of both breast and prostate cancer. A family history of prostate cancer was significantly associated with an increased risk of prostate cancer (HR: 1.69; 95% CI: 1.54-1.85). Increased risk was higher for men with a father diagnosed with prostate cancer (HR: 1.64 95% CI: 1.49-1.80) than for men with a diagnosis in a brother(s) (HR: 1.51 95% CI: 1.27-1.80). A positive family history of breast cancer was associated with a small, but significant 22% increased risk (HR: 1.22; 95% CI: 1.11-1.35). Familial breast cancer in a sister (HR: 1.22 95% CI: 1.06-1.41) increased risk more than familial breast cancer in a mother (HR: 1.12; 95% CI: 0.99-1.25). Men with a family history of both prostate and breast cancer had a 52% (HR: 1.52; 95%CI: 1.23-1.88) increased risk of prostate cancer compared to men with no family history of either cancer. Risk of lethal prostate cancer was also significantly increased for men with a positive family history of prostate cancer (HR: 1.64; 95% CI: 1.20-2.24), as well as for men with a family history of breast cancer (HR: 1.47; 95% CI: 1.07-2.01). Conclusions - These results support the findings of familial aggregation of breast and prostate cancer, and for the first time suggest an association between familial breast cancer and lethal prostate cancer. Data from this prospective study have translational relevance for family counseling of cancer patients. Citation Format: Lauren E. Barber, Travis A. Gerke, Sarah C. Markt, Giovanni Parmigiani, Lorelei A. Mucci. A family affair: Prostate cancer risk and family history of breast or prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2543.

Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculator for Initial Prostate Biopsy by Incorporating the 2014 International Society of Urological Pathology Gleason Grading and Cribriform growth

Background: Prostate cancer incidence rates vary 25-fold worldwide. Differences in PSA screening are largely, but not entirely, responsible. We examined geographic differences in prevalence of histologic prostate inflammation and subsequent prostate cancer risk.Methods: Seven thousand nonHispanic white men were enrolled in the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial from Europe (n = 4,644), North America (n = 1,746), South America (n = 466), and Australia/New Zealand (n = 144). Histologic inflammation in baseline negative prostate biopsies was classified as chronic (lymphocytes/macrophages) or acute (neutrophils). Multivariable logistic regression was used to examine associations between region and prostate inflammation, and between region and prostate cancer risk at 2-year biopsy.Results: Prevalence of prostate inflammation varied across region, with broadly similar patterns for acute and chronic inflammation. Relative to Europe, prevalence of acute inflammation was higher in North America [odds ratio (OR), 1.77; 95% confidence interval (CI), 1.51-2.08] and Australia/New Zealand (OR, 2.07; 95% CI, 1.40-3.06). Men from these regions had lower prostate cancer risk than Europeans at biopsy. Among North Americans, prevalence of acute inflammation was higher in Canada versus the United States (OR, 1.40; 95% CI, 1.07-1.83), but prostate cancer risk did not differ between these regions. Among Europeans, prevalence of acute inflammation was lower in Northern and Eastern (OR, 0.79; 95% CI, 0.65-0.97 and OR 0.62; 95% CI, 0.45-0.87, respectively), relative to Western Europe, and these men had higher prostate cancer risk at biopsy.Conclusions: Prevalence of histologic prostate inflammation varied by region. Geographic differences in prostate inflammation tracked inversely with geographic differences in prostate cancer risk.Impact: Characterization of premalignant prostate biology and the relationship with subsequent prostate cancer risk could inform prostate cancer prevention efforts. Cancer Epidemiol Biomarkers Prev; 27(7); 783-9. ©2018 AACR.

Prostate cancer and obesity are common diseases among men in the United States. A link between obesity and prostate cancer risk has potential implications in understanding prostate cancer genesis and screening strategies. We conducted a population-based case-control study examining the relationship between body mass index (BMI) and prostate cancer risk. Incident cases of prostate cancer were identified in King County, Washington, using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Interviews were completed with 753 men ages 40-64 that were diagnosed with prostate cancer between 1993 and 1996. Interviews were also completed with 703 age-matched controls identified from the same population through random digit dialing. Logistic regression was performed to generate odds ratios and 95% confidence intervals while controlling for age, race, education, smoking, family history, prostate cancer screening, dietary fat, and caloric intake. BMI was inversely related to prostate cancer risk (P for trend=0.04). Men with a BMI > 29 kg/m2 had the lowest risk of prostate cancer (odds ratio=0.77; 95% confidence interval=0.56, 1.06). Weight was also inversely associated with prostate cancer risk (P for trend=0.03), however, height was not. The results of this study support the hypothesis that obesity is inversely associated with prostate cancer risk in middle-aged men.

Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

Physical activity and body mass index (BMI) are involved in prostate cancer etiology; possible biologic mechanisms include their effects on hormonal levels. Our aim was to investigate the relationship between physical activity, obesity, and prostate cancer. We followed a cohort of 13,109 Swedish men for 13 years and investigated the association of self-reported physical activity and BMI at baseline with prostate cancer incidence. We further analyzed whether BMI could modulate effects of physical activity. Occupational, recreational, and total physical activity were analyzed in relation to overall, localized, and advanced prostate cancer. During the study follow-up, we observed a total of 904 cases of prostate cancer (429 localized, 407 advanced, and 68 unclassified). High levels of occupational physical activity were associated with a nonsignificantly decreased risk of overall (HR 0.81, 95 % CI 0.61-1.07), localized (HR 0.75, 95 % CI 0.51-1.12), and advanced (HR 0.85, 95 % CI 0.55-1.31) prostate cancer. We found no association between high BMI and risk of prostate cancer incidence: We observed, however, a significant interaction between BMI and leisure physical activity. No association was confirmed between total physical activity and localized or advanced prostate cancer. The highest, relative to the lowest, level of occupational physical activity tended to be linked to a lower risk of prostate cancer, with a suggested dose-response relationship. We found no association between high BMI and risk of prostate cancer incidence; however, our analyses suggested an interaction between BMI and physical activity during recreational time that merits further investigation in future studies.

An association between the Pro/Pro genotype of p53 codon 72 and a lower risk of prostate cancer in Caucasians was recently reported. However, the association of this polymorphism with prostate cancer risk in a Japanese population has not been clarified. We performed a case-control study consisting of 114 prostate cancer patients and 105 noncancer controls. Sixty-nine percent (79 of 114) of the patients had a positive family history. The genotypic frequencies in the controls were 39.0% for Arg/Arg, 54.3% for Arg/Pro and 6.7% for Pro/Pro; they were in Hardy-Weinberg equilibrium. When a comparison of the distribution of the p53 codon 72 polymorphism was made between patients with a first-degree family history and all control subjects, the adjusted odds ratios (ORs) for prostate cancer associated with the Arg/Arg, Arg/Pro and Pro/Pro genotypes were 1.00, 0.99 [95% confidence interval (CI) 0.53-1.88] and 2.80 (95% CI 1.04-7.53), respectively. When stratification of cases was performed based on clinical stage (localized or metastatic cancer) and pathological grade (a Gleason score of <7 or > or =7), there tended to be a greater number of patients with localized cancers among those patients with the Arg/Pro genotype than among those with the Arg/Arg genotype (overall cases: age-adjusted OR 0.36, 95% CI 0.13-1.00, p = 0.049; positive family history cases: age-adjusted OR 0.25, 95% CI 0.075-0.84, p = 0.025). In addition, there tended to be a greater number of patients with low-grade cancers among those with the Pro/Pro genotype than among those with other genotypes (overall cases: age-adjusted OR 0.41, 95% CI 0.13-1.30, p = 0.13; positive family history cases: age-adjusted OR 0.20, 95% CI 0.004-0.89, p = 0.035). The present findings suggest that the Pro/Pro genotype of p53 codon 72 played a role in prostate cancer susceptibility in a Japanese population. However, the Pro allele did not appear to worsen such clinical parameters as clinical stage or pathological grade.

PLASMA SELENIUM LEVEL BEFORE DIAGNOSIS AND THE RISK OF PROSTATE CANCER DEVELOPMENT

Insulin‐like growth factor‐I (IGF‐I) and testosterone may be related to prostate cancer risk. Acromegaly is associated with clinically high IGF‐I concentrations. Klinefelter's syndrome, testicular hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnosis with these conditions was associated with subsequent prostate cancer diagnosis and mortality. We used linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 to construct and follow‐up cohorts of men aged ≥35 years diagnosed with (i) acromegaly (n = 2,495) and (ii) hypogonadal‐associated diseases (n = 18,763): Klinefelter's syndrome (n = 1,992), testicular hypofunction (n = 8,086) and hypopituitarism (n = 10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a range of minor surgeries and conditions (n observed cases = 130,000, n prostate cancer deaths = 30,000). For men diagnosed with acromegaly, HR for prostate cancer diagnosis was 1.33 (95% CI 1.09–1.63; p = 0.005; n observed cases = 96), HR for prostate cancer death was 1.44 (95% CI 0.92–2.26; p = 0.11; n deaths = 19). Diagnosis with Klinefelter's syndrome was associated with a lower prostate cancer risk (HR = 0.58, 95% CI 0.37–0.91; p = 0.02; n observed cases = 19) and hypopituitarism was associated with a reduction in prostate cancer death (HR = 0.53, 95% CI 0.35–0.79; p = 0.002; n deaths = 23). These results support the hypothesised roles of IGF‐I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer aetiology.