Purpose

Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.

Patients and Methods

We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.

Results

Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.

Conclusion

High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.

Background

Whether milk and dairy intake after a prostate cancer diagnosis is associated with a poorer prognosis is unknown. We investigated post-diagnostic milk and dairy intake in relation to risk of lethal prostate cancer (metastases and prostate cancer death) among participants in the Health Professionals Follow-Up Study.

Methods

The cohort consisted of 3,918 men diagnosed with apparently localized prostate cancer between 1986 and 2006, and followed to 2008. Data on milk and dairy intake were available from repeated questionnaires. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) of the association between post-diagnostic milk and dairy intake and prostate cancer outcomes.

Results

We ascertained 229 prostate cancer deaths and an additional 69 metastases during follow-up. In multivariate analysis, total milk and dairy intakes after diagnosis were not associated with a greater risk of lethal prostate cancer. Men with the highest versus lowest intake of whole milk were at an increased risk of progression (HR 2.15; 95% CI: 1.28-3.60; P trend<0.01). Men in the highest versus lowest quintile of low-fat dairy intake were at a decreased risk of progression (HR 0.62; 95% CI: 0.40-0.95; P trend=0.07).

Conclusions

With the exception of whole milk, our results suggest that milk and dairy intake after a prostate cancer diagnosis is not associated with an increased risk of lethal prostate cancer.

Impact

This is the first larger prospective study investigating the relation between post-diagnostic milk and dairy intake and risk of lethal prostate cancer.

Background

Common genetic variants in the Toll-like receptor 4 (TLR4), which is involved in inflammation and immune response pathways, may be important for prostate cancer.

Methods

In a large nested case-control study of prostate cancer in the Physicians’ Health Study (1982–2004), 10 single nucleotide polymorphisms (SNPs) were selected and genotyped to capture common variation within the TLR4 gene as well as 5 kilobases up and downstream. Unconditional logistic regression was used to assess associations of these SNPs with total prostate cancer incidence, and with prostate cancers defined as advanced stage/lethal (T3/T4, M1/N1(T1-T4), lethal) or high Gleason grade (7 (4+3) or greater). Cox-proportional hazards regression was used to assess progression to metastases and death among prostate cancer cases.

Results

The study included 1267 controls and 1286 incident prostate cancer cases, including 248 advanced stage/lethal and 306 high grade cases. During a median follow-up of 10.6 years, 183 men died of prostate cancer or developed distant metastases. No statistically significant associations between the TLR4 SNPs were found for total prostate cancer incidence, including SNPs for which an association was reported in other published studies. Additionally, there were no significant associations with TLR4 SNPS and the incidence of advanced stage/lethal, or high grade cancers; nor was there evidence among prostate cancer cases for associations of TLR4 SNPs with progression to prostate cancer specific mortality or bony metastases.

Conclusions

Results from this prospective nested case-control study suggest that genetic variation across TLR4 alone is not strongly associated with prostate cancer risk or mortality.

OBJECTIVE

Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain.

RESEARCH DESIGN AND METHODS

We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss.

RESULTS

We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0–6) going in the opposite direction to that in the weight maintenance/regain phase (months 7–24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B.

CONCLUSIONS

hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns.

Background

α-Methylacyl-CoA racemase (AMACR) is an enzyme that serves as a diagnostic biomarker of prostate cancer in clinical practice. Recent studies suggest that low AMACR expression is associated with biochemical recurrence and the development of fatal disease.

Methods

We conducted a prospective cohort study among 920 men aged 47–84 years, who were diagnosed with prostate cancer in the Physicians’ Health Study and the Health Professionals Follow-up Study cohorts, and whose resected tissue specimens were available for immunohistochemical analysis. We used Cox proportional hazards regression to evaluate the association of AMACR expression with lethal prostate cancer over a 20-year follow-up period.

Results

In total, 68 men died from prostate cancer, and an additional 18 developed bony metastases during follow-up. We found that lower AMACR intensity was associated with higher prostate-specific antigen levels (p=0.003) and more advanced clinical stage (p=0.06) at diagnosis, and a non-significant trend for higher risk of lethal outcomes. The hazard ratio comparing the lowest to the highest quartile of AMACR expression intensity was 1.53 ((95% CI: 0.86, 2.73), p-for-trend across quartiles=0.07); this trend was further attenuated after adjustment for age, Gleason score, stage and cohort with a hazard ratio of 1.24 (95% CI 0.69, 2.22), p-for-trend=0.23.

Conclusions

Low AMACR expression in primary tumor specimens was not independently associated with the development of metastatic and lethal prostate cancer after treatment over a 20-year follow-up period, after adjustment for important clinical covariates at diagnosis.

Context

Studies of smoking in relation to prostate cancer mortality or recurrence in prostate cancer patients are limited, with few prostate cancer-specific outcomes.

Objective

To assess the relation of cigarette smoking and smoking cessation with overall, prostate cancer-specific, and CVD mortality and biochemical recurrence among men with prostate cancer.

Design, Setting, and Participants

Prospective observational study of 5 366 men diagnosed with prostate cancer between 1986–2006 in the Health Professionals Follow-Up Study.

Main Outcome Measures

Hazard ratios (HRs) for overall, prostate cancer-specific, and CVD mortality, and biochemical recurrence, defined by PSA rise.

Results

We documented 1,630 deaths, 524 (32%) due to prostate cancer and 416 (26%) due to CVD, and 878 biochemical recurrences. The absolute crude rates for prostate cancer-specific death for never smokers vs. current smokers were 9.6 vs. 15.3 per 1,000 person-years; for all-cause mortality the corresponding rates were 27.3 and 53.0 per 1,000 person-years. In multivariable analysis, compared with never smokers, current smokers had an increased risk of prostate cancer mortality (HR, 1.61; 95% confidence interval [CI], 1.11–2.32 and among men with clinical stage T1–T3: HR, 1.80; 95% CI, 1.04–3.12), biochemical recurrence (HR, 1.61; 95% CI, 1.16–2.22), total mortality (HR, 2.28; 95% CI, 1.87–2.80), and CVD mortality (HR, 2.13; 95% CI, 1.39–3.26). After adjusting for clinical stage and grade which are likely intermediates of the relation of smoking with prostate cancer recurrence and survival, the estimates for current smoking were as follows: prostate cancer mortality (HR, 1.38; 95% CI, 0.94–2.03 and HR, 1.41; 95% CI, 0.80–2.49); biochemical recurrence (HR, 1.47; 95% CI, 1.06–2.04). A greater number of pack-years was associated with a significantly increased risk of prostate cancer mortality but not biochemical recurrence: for current smokers of 40+ pack-years compared to never smokers: prostate cancer mortality (HR, 1.82; 95% CI, 1.03–3.20; biochemical recurrence (HR, 1.48; 95% CI, 0.88–2.48). Compared to current smokers, those who had quit smoking for 10 or more years, or who had quit for less than 10 years but smoked less than 20 pack-years, had prostate cancer mortality risks similar to never smokers: former smoker, quit 10+ years (HR, 0.60; 95% CI, 0.42–0.87); quit <10 years and <20 pack-years (HR, 0.64; 95% CI, 0.28–1.45); never smoker (HR, 0.61; 95% CI, 0.42–0.88).

Conclusions

Smoking at the time of prostate cancer diagnosis is associated with increased overall and CVD mortality and prostate cancer-specific mortality and recurrence. 10-year quitters have prostate cancer-specific mortality risks similar to never smokers.

Background

Laboratory studies suggest vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting.

Methods

To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D) (IDS Inc. enzymeimuunoassay) were associated with risk of pancreatic cancer, we performed a pooled analysis of nested case-control studies with 451 cases and 1167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in HPFS, 18.3 years in NHS, 25.3 years in PHS, 12.2 years in WHI, and 14.4 years in WHS. Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D.

Results

Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L, P=0.005). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. Participants in quintiles two through five had multivariable-adjusted odds ratios (OR [95% confidence intervals]) of 0.79 (0.56–1.10), 0.75 (0.53–1.06), 0.68 (0.48–0.97), and 0.67 (0.46–0.97); P-trend=0.03), respectively, compared to the bottom quintile. Compared to those with insufficient levels (25[OH]D<50 nmol/L), ORs were 0.75 (0.58–0.98) for subjects with relative insufficiency (25[OH]D 50–<75 nmol/L) and 0.71 (0.52–0.97) for those with sufficient levels (25[OH]D≥75 nmol/L). No increased risk was noted in subjects with 25(OH)D≥100 nmol/L, as suggested in a prior study. In subgroup analyses, ORs for the top versus bottom quartile of 25(OH)D were 0.72 (0.48–1.08) for women, 0.73 (0.40–1.31) for men, and 0.73 (0.51–1.03) for Whites.

Conclusions

Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer.

Impact

Low circulating 25(OH)D may predispose individuals to the development of pancreatic cancer.

Red and processed meat may increase risk of advanced prostate cancer. Data on post-diagnostic diet and prostate cancer are sparse, but post-diagnostic intake of poultry with skin and eggs may increase risk of disease progression. Therefore, we prospectively examined total, unprocessed, and processed red meat, poultry, and eggs in relation to risk of lethal prostate cancer (e.g. men without cancer at baseline who developed distant organ metastases or died from prostate cancer during follow-up) among 27, 607 men followed from 1994–2008. We also performed a case-only survival analysis to examine post-diagnostic consumption of these foods and risk of lethal prostate cancer among the 3,127 men initially diagnosed with non-metastatic prostate cancer during follow-up. In the incidence analysis, we observed 199 events during 306,715 person-years. Men who consumed 2.5 or more eggs per week had an 81% increased risk of lethal prostate cancer compared to men who consumed less than 0.5 eggs per week (HR: 1.81; 95% confidence interval (CI): 1.13, 2.89; p-trend: 0.01). In the case-only survival analysis, we observed 123 events during 19,354 person-years. There were suggestive, but not statistically significant, positive associations between post-diagnostic poultry (HR ≥3.5 vs. <1.5 servings per week: 1.69; 95%CI: 0.96, 2.99; p-trend: 0.07) and post-diagnostic processed red meat (HR ≥3 vs. <0.5 servings per week: 1.45; 95%CI: 0.73, 2.87; p-trend: 0.08) and risk of progression of localized prostate cancer to lethal disease. In conclusion, consumption of eggs may increase risk of developing a lethal-form of prostate cancer among healthy men.

Purpose

We examined patient-reported outcomes among prostate cancer patients managed by watchful waiting (WW) in a nationwide cohort.

Materials and Methods

We collected treatment information and patient-reported outcomes from 1230 prostate cancer patients diagnosed with T1-T2 prostate cancer in the Physicians’ Health Study; 125 were initially managed by WW. Cox proportional-hazards regression was used to identify predictors of treatment initiation among WW patients. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to assess disease-targeted quality of life by initial treatment or WW.

Results

At 7.3 years’ mean follow-up, 41% of WW patients remained free of treatment while 34% underwent radiotherapy or brachytherapy, 16% underwent primary hormonal therapy, and 10% underwent prostatectomy. Younger age, higher clinical stage, higher Gleason score, and higher PSA at diagnosis predicted progression to treatment. Watchful waiting compared to immediate treatment was associated with less urinary incontinence (3.5% vs 10%) and impotence (68% vs 78%) but more common obstructive urinary symptoms (22% vs 13%) in univariate analyses (p< 0.05 for each), with incontinence and impotence differences remaining significant after adjustment for age, comorbidity, and time after cancer diagnosis. Quality of life outcomes among men who underwent delayed treatment after initially waiting were not worse than among men who underwent immediate treatment.

Conclusions

Our findings suggest quality of life benefits subsequent to WW among select patients with early-stage prostate cancer compared to men treated immediately following diagnosis. Younger age and greater cancer severity at diagnosis predicted progression to treatment.

Experimental studies suggest a role for aspirin in the chemoprevention of prostate cancer and epidemiological evidence supports a modest inverse association between regular aspirin use and prostate cancer risk, especially for advanced disease. In a prospective cohort study of 51,529 health professionals aged 40–75 years at baseline, we evaluated long-term aspirin use and the incidence of total, high-grade (Gleason 8–10, n=488), regionally advanced (T3b-T4 or N1, n=228) and lethal prostate cancer (M1, bony metastases or prostate cancer death, n=580) from 1988–2006. We used Cox proportional hazards regression to evaluate risk associated with frequency (days/week), quantity (tablets/week), recency and duration of aspirin use after multivariable adjustment for confounders and other predictors of prostate cancer risk. A total of 4,858 men were diagnosed with prostate cancer during the 18-year study period. Men taking ≥ 2 adult-strength aspirin tablets a week had a 10% lower risk of prostate cancer (p-for-trend=0.02). For regionally advanced cancer, we observed no significant associations with aspirin use. For high-grade and lethal disease, men taking ≥ 6 adult-strength tablets/week experienced similar reductions in risk (HR=0.72 (95% CI: 0.54, 0.96) and HR=0.71 (95% CI: 0.50, 1.00)). Analytical approaches to address bias from more frequent PSA screening among aspirin users did not yield different conclusions. We observed reductions in the risk of high-grade and lethal prostate cancer associated with higher doses of aspirin, but not with greater frequency or duration, in a large, prospective cohort of health professionals. Our data support earlier observations of modest inverse associations with advanced prostate cancer.

It remains unknown whether increased risk with low levels of vitamin D is present for colon and/or rectal cancer. To investigate the association between circulating vitamin D levels and colon and rectal cancer, we examined the associations between plasma levels of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) and colon and rectal cancer in the Physicians’ Health Study and then conducted a meta-analysis of eight prospective studies of circulating levels of 25-hydroxyvitamin D (25(OH)D) and colon and rectal cancers, including the Physicians’ Health Study. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using a random-effects model. A total of 1822 colon and 868 rectal cancers were included in the meta-analysis. We observed a significant inverse association for colorectal cancer (OR = 0.66; 95% CI = 0.54–0.81), comparing top versus bottom quantiles of circulating 25(OH)D levels. The inverse association was stronger for rectal cancer (OR = 0.50 for top versus bottom quantiles; 95% CI = 0.28–0.88) than colon cancer (OR = 0.77; 95% CI = 0.56–1.07; P for difference between colon and rectal cancer = 0.20). These data suggest an inverse association between circulating 25(OH)D levels and colorectal cancer, with a stronger association for rectal cancer.

Background

Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.

Methods

We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.

Results

The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, Ptrend = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, Ptrend = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (≥6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.

Conclusions

We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.

Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically-used drugs might have utility for treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large, prospective cohort study. In stage 1, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate given its potency in inhibiting proliferation in vitro (mean IC50=163 nM) and common use. In stage 2, we evaluated the association between the leading candidate drug from stage 1 and prostate cancer risk in 47,884 men followed 1986–2006. Regular digoxin users (versus nonusers: RR=0.76, 95% CI 0.61–0.95), especially users for ≥10 years (RR=0.54, 95% CI 0.37–0.79, P-trend<0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro and its use was associated with a 25% lower prostate cancer risk.

Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case–control study nested within the Physicians’ Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis.

Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression, an outcome less susceptible to reverse causation, among 1,455 men diagnosed with clinically localized prostate cancer. Cox proportional hazards regression was used to examine vigorous activity, non-vigorous activity, walking duration, and walking pace after diagnosis and risk of prostate cancer progression. We observed 117 events (45 biochemical recurrences, 66 secondary treatments, 3 bone metastases, 3 prostate cancer deaths) during 2,750 person-years. Walking accounted for nearly half of all activity. Men who walked briskly for ≥3 hours/week had a 57% lower rate of progression compared to men who walked at an easy pace for <3 hours/week (hazard ratio (HR): 0.43; 95% confidence interval (CI): 0.21, 0.91; p-value: 0.03). Walking pace was associated with decreased risk of progression independent of duration (HR brisk vs. easy pace: 0.52; 95% CI: 0.29, 0.91; p-trend: 0.01). Few men engaged in vigorous activity, but there was a suggestive inverse association (HR ≥3 hours per week vs. none: 0.63; 95% CI: 0.32, 1.23; p-trend: 0.17). Walking duration and total non-vigorous activity were not associated with risk of progression independent of pace or vigorous activity respectively. Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinically localized prostate cancer.

Background

Fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and phosphorus all have been proposed as plasma biomarkers for the development of coronary heart disease (CHD) in individuals with normal renal function.

Methods

In a nested case-control study of men in the Health Professionals Follow-up Study free of diagnosed cardiovascular disease at blood draw, we prospectively examined associations between plasma FGF23, PTH, and phosphorus and risk of coronary heart disease (CHD). During 10 years of follow-up, 422 men developed nonfatal myocardial infarction or fatal CHD. Controls were selected in a 2:1 ratio and matched for age, date of blood collection, and smoking status.

Results

Mean estimated glomerular filtration rate was 86 mL/min per 1.73 m2 in cases and controls. At baseline, there were no statistically significant differences between cases and controls in plasma levels of FGF23, PTH, or phosphorus. After adjusting for matching factors, family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, plasma 25-hydroxyvitamin D and other factors, the odds ratios for incident CHD for participants in the highest compared to lowest quartiles were 1.03 (95% CI 0.70-1.52; P for trend 0.84) for FGF23, 1.20 (95% CI 0.82-1.76; P trend 0.99) for PTH, and 0.72 (95% CI 0.51-1.02; P trend 0.13) for phosphorus.

Conclusions

Plasma FGF23, PTH, and phosphorus are not associated with the development of incident CHD in men without chronic kidney disease.

Purpose

To determine whether higher physical activity after prostate cancer (PCa) diagnosis decreases risk of overall and PCa-specific death.

Patients and Methods

We evaluated physical activity in relation to overall and PCa mortality among 2,705 men in the Health Professionals Follow-Up Study diagnosed with nonmetastatic PCa observed from 1990 to 2008. Proportional hazards models were used to evaluate physical activity and time to overall and PCa-specific death.

Results

Among men who lived at least 4 years after their postdiagnosis physical activity assessment, we documented 548 deaths, 20% of which were a result of PCa. In multivariable analysis, men who were physically active had lower risk of all-cause mortality (Ptrend < .001) and PCa mortality (Ptrend = .04). Both nonvigorous activity and vigorous activity were associated with significantly lower overall mortality. Those who walked ≥ 90 minutes per week at a normal to very brisk pace had a 46% lower risk of all-cause mortality (hazard ratio [HR] 0.54; 95% CI, 0.41 to 0.71) compared with shorter durations at an easy walking pace. Men with ≥ 3 hours per week of vigorous activity had a 49% lower risk of all-cause mortality (HR, 0.51; 95% CI, 0.36 to 0.72). For PCa-specific mortality, brisk walking at longer durations was suggestively inverse but not statistically significant. Men with ≥ 3 hours per week of vigorous activity had a 61% lower risk of PCa death (HR, 0.39, 95% CI, 0.18 to 0.84; P = .03) compared with men with less than 1 hour per week of vigorous activity. Men exercising vigorously before and after diagnosis had the lowest risk.

Conclusion

In men with PCa, physical activity was associated with lower overall mortality and PCa mortality. A modest amount of vigorous activity such as biking, tennis, jogging, or swimming for ≥ 3 hours a week may substantially improve PCa-specific survival.

The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum <7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum <7, n=635) and high-grade (Gleason sum ≥7, n=515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12–1.78, p-trend=0.001) for IGF-1 and 1.58 (95% CI 1.24–2.01, p-trend=0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR=1.61 top versus bottom quartile, 95% CI 1.16–2.25, p-trend=0.01), than with high-grade (OR=1.29, 95% CI 0.89–1.88, p-trend-0.12) prostate cancer (p-heterogeneity=0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.

Context

Sudden cardiac death (SCD) accounts for over half of all cardiac deaths, and the majority occur as the first manifestation of heart disease, especially among women. Primary preventive strategies are needed to reduce SCD incidence.

Objective

To estimate the degree to which adherence to a healthy lifestyle may lower risk of SCD among women.

Design, setting and participants

We conducted a prospective cohort study among 81,722 US women from the Nurses' Health Study, from June 1984 to June 2010. Lifestyle factors were assessed via questionnaires every 2-4 years. A low-risk lifestyle was defined as not smoking, BMI <25 kg/m2, exercise ≥30 minutes/day, and top 40% of the Alternate Mediterranean Diet Score, which emphasizes high intake of vegetables, fruits, nuts, legumes, whole grains, fish and moderate intake of alcohol.

Main Outcome Measure

SCD defined as death occurring within 1 hour of symptom onset without evidence of circulatory collapse.

Results

We documented 321 cases of SCD over 26 years. All 4 low-risk lifestyle factors were significantly and independently associated with lower risk of SCD. The absolute risks of SCD were 22, 17, 18, 13 and 16 cases/100,000 person-years among women with 0, 1, 2, 3 and 4 low-risk factors, respectively. Compared to women with 0 low-risk factors, the multivariate relative risk of SCD was 0.54 (95%CI: 0.34, 0.86), 0.41 (95%CI: 0.25, 0.65), 0.33 (95%CI: 0.20, 0.54) and 0.08 (95%CI: 0.03, 0.23) for women with 1, 2, 3, and 4 low-risk factors, respectively. The proportion of SCD attributable to smoking, inactivity, overweight, and poor diet was 81% (95%CI: 52%, 93%). Among women without clinically diagnosed CHD, the PAR% was 79% (95%CI: 40%, 93%).

Conclusions

Adherence to a low-risk lifestyle is associated with a low risk of SCD and may be an effective strategy for the prevention of SCD in the general population.

Objective

To study the effects of oxidative stress on prostate cancer development as the exact biological mechanisms behind the relationship remain uncertain. We previously reported a statistically significant interaction between circulating selenium levels, variants in the superoxide dismutase 2 gene (SOD2; rs4880), and risk of developing prostate cancer and presenting with aggressive prostate cancer.

Patients and methods

We genotyped men with localized/regional prostate cancer for 26 loci across eight genes that are central to cellular antioxidant defence: glutathione peroxidase (GPX1, GPX4), peroxisome proliferator-activated receptor γ coactivator (PPARGC1A, PPARGC1B), SOD1, SOD2, and SOD3, and ‘X-ray repair complementing defective repair in Chinese hamster cell 1’ (XRCC1). Among 489 men, we examined the relationships between genotypes, circulating selenium levels, and risk of presenting with aggressive prostate cancer at diagnosis, as defined by stage, grade and prostate-specific antigen (PSA) level (213 aggressive cases).

Results

Two variants in SOD2 were significantly associated with the risk of aggressive prostate cancer (rs17884057, odds ratio 0.83, 95% confidence interval 0.70–0.99; and rs4816407, 1.27, 1.02–1.57); men with A alleles at rs2842958 in SOD2 had lower plasma selenium levels (median 116 vs 121.8 μg/L, P = 0.03); and the association between plasma selenium levels and risk of aggressive prostate cancer was modified by SOD1 (rs10432782) and SOD2 (rs2758330).

Conclusion

While this study was cross-sectional and these associations might be due to chance, further research is warranted on the potential important role of antioxidant defence in prostate cancer.

The authors prospectively examined the relation of fruit and vegetable intake to breast cancer risk among 51,928 women aged 21–69 years at enrollment in 1995 in the Black Women's Health Study. Dietary intake was assessed by using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate incidence rate ratios and 95% confidence intervals, adjusted for breast cancer risk factors. During 12 years of follow-up, there were 1,268 incident cases of breast cancer. Total fruit, total vegetable, and total fruit and vegetable intakes were not significantly associated with overall risk of breast cancer. However, total vegetable consumption was associated with a decreased risk of estrogen receptor-negative/progesterone receptor-negative breast cancer (incidence rate ratio = 0.57, 95% confidence interval: 0.38, 0.85, for ≥2 servings/day relative to <4/week; Ptrend = 0.02). In addition, there was some evidence of inverse associations with breast cancer risk overall for cruciferous vegetable intake (Ptrend = 0.06) and for carrot intake (Ptrend = 0.02). Study findings suggest that frequent consumption of vegetables is inversely associated with risk of estrogen receptor-negative/progesterone receptor-negative breast cancer, and that specific vegetables may be associated with a decreased risk of breast cancer overall.

Background

The comparative importance of physical inactivity and obesity as predictors of coronary heart disease (CHD) risk remains unsettled.

Methods and Results

We followed 88 393 women, 34 to 59 years of age, in the Nurses’ Health Study from 1980 to 2000. These participants did not have cardiovascular disease and cancer at baseline. We documented 2358 incident major CHD events (including nonfatal myocardial infarction and fatal CHD) during 20 years of follow-up, including 889 cases of fatal CHD and 1469 cases of nonfatal myocardial infarction. In a multivariate model adjusting for cardiovascular risk factors, overweight and obesity were significantly associated with increased risk of CHD, whereas increasing levels of physical activity were associated with a graded reduction in CHD risk (P<0.001). In joint analyses of body mass index (BMI) and physical activity in women who had a healthy weight (BMI, 18.5 to 24.9 kg/m2) and were physically active (exercise ≥3.5 h/wk) as the reference group, the relative risks of CHD were 3.44 (95% confidence interval [CI], 2.81 to 4.21) for women who were obese (BMI ≥30 kg/m2) and sedentary (exercise <1 h/wk), 2.48 (95% CI, 1.84 to 3.34) for women who were active but obese, and 1.48 (95% CI, 1.24 to 1.77) for women who had a healthy weight but were sedentary. In combined analyses of waist-hip ratio and physical activity, both waist-hip ratio and physical activity were significant predictors of CHD, and the highest risk was among women in the lowest category of physical activity and the highest tertile of waist-hip ratio (relative risk=3.03; 95% CI, 1.96 to 4.18). Even a modest weight gain (4 to 10 kg) during adulthood was associated with 27% (95% CI, 12% to 45%) increased risk of CHD compared with women with a stable weight after adjusting for physical activity and other cardiovascular risk factors.

Conclusions

Obesity and physical inactivity independently contribute to the development of CHD in women. These data underscore the importance of both maintaining a healthy weight and regular physical activity in preventing CHD.

Prospective studies of tea and coffee intake and breast cancer risk have yielded inconsistent results. None of these studies has reported separately on African-American women. We prospectively examined the relation of tea and coffee consumption to risk of breast cancer among 52,062 women aged 21 to 69 at enrollment in 1995 in the Black Women’s Health Study. Dietary intake was assessed in 1995 and 2001 using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI), adjusted for breast cancer risk factors. During 12 years of follow-up through 2007, there were 1,268 incident cases of breast cancer. Intakes of tea, coffee, and caffeine were not associated with risk of breast cancer overall. The IRRs for consumption of ≥ 4 cups/day compared with none were 1.13 (95% CI 0.78–1.63) for tea and 1.03 (95% CI 0.77–1.39) for coffee, and the IRR for the top quintile relative to the bottom quintile of caffeine intake was 1.04 (95% CI 0.87–1.24). Consumption of tea, coffee, and caffeine was not associated with breast cancer risk according to menopausal status or hormone receptor status. Our findings suggest that intakes of tea, coffee, and caffeine are not associated with risk of breast cancer among African-American women.

Background

A pressing clinical issue in prostate cancer (PCa) is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal PCa could inform clinical decision making.

Methods

We conducted a genome-wide association study comparing lethal PCa cases to cases surviving at least ten years beyond their initial diagnosis. Genotyping was performed with the Affymetrix 5.0 chip (~500,000 single nucleotide polymorphisms (SNPs) and 1483 copy number variants (CNVs)) on DNA from participants in the Physicians’ Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was performed using PLINK software.

Results

No SNP reached genome-wide significance (p≤1×10−7), however three independent SNPs had p<1×10−5. One top-ranked SNP replicated (p=0.05) in an independent follow-up study. While no CNV had genome-wide significance, 14 CNVs showed nominal association with PCa mortality (p<0.05).

Conclusions

No variants were significantly associated at a genome-wide level with PCa mortality. Common genetic determinants of lethal PCa are likely to have odds ratios <2.0.

Impact

Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect genetic causes of PCa mortality.

Background

Moderate alcohol intake is associated with lower risk of coronary heart disease, but the association with SCD is less clear. In men, heavy alcohol consumption may increase risk of SCD, while light-to-moderate alcohol intake may lower risk. There are no parallel data among women.

Objective

We assessed the association between alcohol intake and risk of sudden cardiac death (SCD) among women, and investigated how this risk compared to other forms of CHD.

Methods

We conducted a prospective cohort study among 85,067 women from the Nurses’ Health Study free of chronic disease at baseline. Alcohol intake was assessed every 4 years through questionnaires. Primary end points included SCD, fatal CHD, and nonfatal myocardial infarction.

Results

We found a U-shaped association between alcohol intake and risk of SCD, with the lowest risk among women who drank 5.0–14.9 g/day of alcohol (p for quadratic trend= 0.02). Compared to abstainers, the multivariate relative risk (95% confidence interval) for SCD was 0.79 (0.55-1.14) for former drinkers, 0.77 (0.57, 1.06) for 0.1– 4.9 g/day, 0.64 (0.43– 0.95) for 5.0 –14.9 g/day, 0.68 (0.38–1.23) for 15.0 –29.9 g/day, and 1.15 (0.70-1.87) for ≥30.0 g/day. In contrast, the relationship of alcohol intake and nonfatal and fatal CHD was more linear (P for linear trend<0.001).

Conclusions

In this cohort of women, the relationship between light-to-moderate alcohol intake and SCD is U-shaped with a nadir at 5.0–14.9 g/day. Low levels of alcohol intake do not raise risk of SCD and may lower risk in women.