Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, account for most cholesterol-lowering drug use in the United States. A recent large case-control study reported that use of statins for more than 5 years was associated with a 47% reduction in risk of colorectal cancer. No other large studies have examined this association. We examined the association between use of cholesterol-lowering drugs and colorectal cancer incidence among 132,136 men and women in the Cancer Prevention Study II Nutrition Cohort. We identified 815 incident cases of colorectal cancer among study participants during follow-up from the date of completion of a study questionnaire in 1997 through August 31, 2001. Current use of cholesterol-lowering drugs was not associated with colorectal cancer incidence (multivariable adjusted rate ratio [RR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.26). Current use of cholesterol-lowering drugs for 5 years or more was also not associated with colorectal cancer incidence (multivariable adjusted RR = 1.09, 95% CI = 0.83 to 1.43). Our results do not support the hypothesis that statin use strongly reduces risk of colorectal cancer. However, we cannot rule out a small reduction in risk or an effect associated with only specific types or doses of statins.     

Statin use and risk of prostate cancer in the California Men's Health Study cohort.

Statins have known anticarcinogenic effects, however, evidence for long-term statin use as effective chemoprevention for prostate cancer is inconsistent. We examined the association between statin use and risk of prostate cancer among 69,047 eligible participants in the California Men's Health Study, a prospective cohort of Northern and Southern California Kaiser Permanente (KP) members, ages 45 to 69 years, initiated in 2002. Prostate cancer cases were identified by linkage to the KP California Cancer Registries. Statin exposure, estimated from automated KP outpatient pharmacy records (available since 1991 in Southern California and since 1994 in Northern California), was treated as time-varying and defined as the cumulative days dispensed of any statin from the first dispensing until a prostate cancer diagnosis, radical prostatectomy, termination of membership, or end of study (December 31, 2004). Cox proportional hazards models with age as the time scale were used to estimate rate ratios, while controlling for confounding variables. During follow-up, 888 prostate cancer cases, including 131 advanced cases, were identified. There was no association between ever statin use or <5 years use and prostate cancer. Conversely, >or=5 years use was associated with a 28% lower risk for prostate cancer compared with nonuse (adjusted rate ratio, 0.72; 95% confidence interval, 0.53-0.99). This association did not differ markedly for advanced disease. However, the association did seem to be restricted to those who regularly take nonsteroidal anti-inflammatory drugs. Our findings suggest that long-term statin use might be associated with a reduced risk of prostate cancer but perhaps only among regular nonsteroidal anti-inflammatory drug users.     

Statin use and prostate cancer risk in a large population-based setting

BACKGROUND: Statins are a commonly used cholesterol-lowering drug, which also have the potential to affect cancer risk and progression. Results from previous studies offer mixed conclusions. METHODS: To evaluate the relation between statin use and prostate cancer risk, we conducted a retrospective cohort study during 1 January 1990 to 31 August 2005 among men 45-79 years receiving care within Group Health, an integrated healthcare delivery system. Information on statin use and covariates were obtained from health plan databases. We identified incident prostate cancer cases through the Surveillance, Epidemiology, and End Results cancer registry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for prostate cancer among statin users compared to non-users. RESULTS: Among 83,372 men studied, median follow-up time was 5.7 years and 2,532 prostate cancer cases were identified. About 14.4% used statins over the study period and median duration of use was 3.3 years. Compared to non-users, hydrophobic statin users had a reduced risk of prostate cancer (HR = 0.79; 95% CI, 0.66-0.94), and results are suggestive of a reduced risk among ever users of statins (HR = 0.88; 95% CI, 0.76-1.02) and hydrophilic statin users (HR = 0.67; 95% CI, 0.33-1.34). There was no trend in risk by duration of statin use, and no association between statin use and cancer aggressiveness, stage, or grade. CONCLUSION: Overall, this study does not support an associated between statin use and prostate cancer but a reduced risk cannot be ruled out.     

Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort

HMG-coA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use. However, little is known about the association between long-term statin use and incidence of most types of cancers. We examined the association between long-term use of cholesterol-lowering drugs, predominantly statins, and the incidence of ten common cancers, as well as overall cancer incidence, among 133,255 participants (60,059 men and 73,196 women) in the Cancer Prevention Study II Nutrition Cohort during the period from 1997 to 2007. Multivariate Cox proportional hazards regression was used to estimate relative risks (RR). Current use status and duration of use were updated during follow-up using information from biennial follow-up questionnaires. Current use of cholesterol-lowering drugs for five or more years was not associated with overall cancer incidence (RR = 0.97, 95% CI = 0.92-1.03), or incidence of prostate, breast, colorectal, lung, bladder, renal cell, or pancreatic cancer but was associated with lower risk of melanoma (RR = 0.79, 95% CI = 0.66-0.96), endometrial cancer (RR = 0.65, 95% CI = 0.45-0.94), and non-Hodgkin lymphoma (NHL; RR = 0.74, 95% CI = 0.62-0.89). These results suggest that long-term use of statins is unlikely to substantially increase or decrease overall cancer risk. However, associations between long-term statin use and risk of endometrial cancer, melanoma, and NHL deserve further investigation.     

Statin use and risk of lymphoid neoplasms: results from the European Case-Control Study EPILYMPH.

BACKGROUND: Statins, drugs used to treat dyslipidemia, may have anticancer properties. We have evaluated lymphoma risk associated with regular statin use in an international case-control study. METHODS: This case-control study included 2,362 cases of incident B- and T-cell lymphoma from Czech Republic, France, Germany, Ireland, Italy, and Spain and 2,206 hospital or population controls. Information on drug use, diagnosis at admission (for hospital controls), and putative risk factors for lymphoma was collected with personal interviews. Hospital controls admitted for diseases possibly entailing use of statins were excluded from the analysis. RESULTS: The odds ratio for regular statin use was 0.61 (95% confidence interval, 0.45-0.84); all major lymphoma subtypes showed similarly decreased risks. Decreased risks were observed in all centers. Duration of statin use was not associated with a greater reduction in the risk of lymphoma. Use of other lipid lowering drugs, such as fibrates, did not significantly modify the risk of lymphoma (odds ratio, 0.75; 95% confidence interval, 0.44-1.27). CONCLUSION: Statin use was associated with an important reduction in lymphoma risk, adding to the growing evidence of anticancer properties of this group of drugs. These results are reassuring for the increasing number of patients taking statins on a regular basis.     

Vitamin E supplements and risk of prostate cancer in U.S. men.

Supplementation with alpha-tocopherol (a form of vitamin E) was associated with decreased risk of prostate cancer in a randomized trial among Finnish smokers. We examined the association between vitamin E supplement use and prostate cancer incidence in the Cancer Prevention Study II Nutrition Cohort. Participants in the study completed a detailed questionnaire at enrollment in 1992-1993. Historical information was also available from a questionnaire completed in 1982 at enrollment in a previous cohort. Through August 31, 1999, we documented 4,281 cases of incident prostate cancer among 72,704 men. Multivariate-adjusted rate ratios (RRs) were calculated using Cox Proportional Hazards models. Regular vitamin E supplement use (>/=4 times per week) was not associated with overall risk of prostate cancer or with risk of advanced prostate cancer at diagnosis. No trend was seen with increasing dose of vitamin E. Men who reported regular vitamin E use in both 1982 and in 1992-1993 were not at lower risk of prostate cancer. Among current smokers, there was a suggestion of slightly reduced risk with regular vitamin E supplement use [RR = 0.87, 95% confidence interval (CI) = 0.67-1.11]. Our results do not support an important role for vitamin E supplements in prostate cancer prevention.     

Risk of prostate cancer in a randomized clinical trial of calcium supplementation.

BACKGROUND: In some studies, high calcium intake has been associated with an increased risk of prostate cancer, but no randomized studies have investigated this issue. METHODS: We randomly assigned 672 men to receive either 3 g of calcium carbonate (1,200 mg of calcium), or placebo, daily for 4 years in a colorectal adenoma chemoprevention trial. Participants were followed for up to 12 years and asked periodically to report new cancer diagnoses. Subject reports were verified by medical record review. Serum samples, collected at randomization and after 4 years, were analyzed for 1,25-(OH)2 vitamin D, 25-(OH) vitamin D, and prostate-specific antigen (PSA). We used life table and Cox proportional hazard models to compute rate ratios for prostate cancer incidence and generalized linear models to assess the relative risk of increases in PSA levels. RESULTS: After a mean follow-up of 10.3 years, there were 33 prostate cancer cases in the calcium-treated group and 37 in the placebo-treated group [unadjusted rate ratio, 0.83; 95% confidence interval (95% CI), 0.52-1.32]. Most cases were not advanced; the mean Gleason's score was 6.2. During the first 6 years (until 2 years post-treatment), there were significantly fewer cases in the calcium group (unadjusted rate ratio, 0.52; 95% CI, 0.28-0.98). The calcium risk ratio for conversion to PSA >4.0 ng/mL was 0.63 (95% CI, 0.33-1.21). Baseline dietary calcium intake, plasma 1,25-(OH)2 vitamin D and 25-(OH) vitamin D levels were not materially associated with risk. CONCLUSION: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect.     

Statin use and the risk of prostate cancer: A metaanalysis of 6 randomized clinical trials and 13 observational studies

Statins have been suggested to prevent prostate cancer. Our aim was to examine statin use in relation to both total prostate cancer and the more clinically important advanced prostate cancer, through a detailed metaanalysis of the epidemiologic studies published on the subject in peer-reviewed literature. A comprehensive search for articles published up to November 2007 was performed, reviews of each study were conducted and data were abstracted. Prior to metaanalysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup and sensitivity analyses were also performed. Nineteen studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] contributed to the analysis. There was no evidence of an association between statin use and total prostate cancer among either RCTs (RR = 1.06, 95% CI: 0.93-1.20) or the observational studies (RR = 0.89, 95% CI: 0.65-1.24). However, high heterogeneity was detected among the observational studies. Moreover, long-term statin use did not significantly affect the risk of total prostate cancer (RR = 0.93, 95% CI: 0.77-1.13). In contrast, synthesis of the available reports that had specifically examined statin use in relation to advanced prostate cancer indicated a protective association (RR = 0.77, 95% CI: 0.64-0.93). Our results do not support the hypothesis that statins reduce the risk of total prostate cancer. However, further research is required to investigate whether the particular association of statin use with lower risk of advanced prostate cancer is indeed causal.     

BRCA1 mutations and prostate cancer in Poland.

Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.     

BRCA mutations and risk of prostate cancer in Ashkenazi Jews.

PURPOSE: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study. EXPERIMENTAL DESIGN: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age. RESULTS: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64-7.06; P = 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P = 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased. CONCLUSIONS: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.     

Aspirin and other nonsteroidal anti-inflammatory drugs and breast cancer incidence in a large U.S. cohort.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has consistently been associated with reduced risk of breast cancer in case-control studies. However, results from prospective studies have been less consistent. We examined the association between NSAID use and breast cancer incidence, adjusting for multiple breast cancer risk factors among 77,413 women in the Cancer Prevention Study II Nutrition Cohort. During follow-up from 1992 to 2001, we observed 3,008 cases of incident breast cancer. Information on NSAID use was obtained from a questionnaire completed at enrollment in 1992 or 1993 and was updated using follow-up questionnaires in 1997 and 1999. NSAID use was modeled using time-dependent variables to update exposure status. Neither current total NSAID use (aspirin and other NSAIDs combined) nor current aspirin use were associated with breast cancer incidence even at relatively high levels of use [rate ratio (RR), 1.07; 95% confidence interval (95% CI), 0.96-1.21 for > or =60 NSAID pills per month compared with no reported use of NSAIDs; RR, 1.01; 95% CI, 0.84-1.20 for > or =60 aspirin per month compared with no reported use of aspirin]. Even long-duration regular use (> or =30 pills per month for > or =5 years) was not associated with breast cancer incidence (RR, 1.05; 95% CI, 0.88-1.26 for total NSAIDs; RR, 0.88; 95% CI, 0.69-1.12 for aspirin). Although we cannot exclude a small reduction in breast cancer risk associated with NSAID use, the results of this study provide evidence against a large reduction in risk.     

The relationship between a polymorphism in CYP17 with plasma hormone levels and prostate cancer.

The A2 allele of the CYP17 gene has been thought to be associated with increased functional activity of this steroidogenic enzyme. Consequently, the A2 allele has been examined as a biomarker of individual susceptibility to hormone-related diseases among men and women. We prospectively assessed the association between the A2 allele of CYP17 and prostate cancer risk among 590 cases and 782 controls in a case-control study nested within the Physicians' Health Study cohort. We also evaluated associations between CYP17 genotype and plasma steroid hormones among controls and the potential interaction between CYP17 and SRD5A2 V89L polymorphisms in relationship with prostate cancer risk and circulating steroid hormone levels. We observed a borderline significant association between the A2 allele and prostate cancer risk (odds ratio, 1.23; 95% confidence interval, 0.99-1.54), however, we did not observe evidence of a gene-dosage effect (versus A1/A1 genotype: A1/A2 genotype; odds ratio, 1.26; 95% confidence interval, 0.99-1.59; A2/A2 genotype: odds ratio, 1.17; 95% confidence interval, 0.85-1.61). The A2 allele was not overrepresented among cases with advanced prostate cancer. Among controls, carriers of the A2 allele had steroid hormone levels similar to noncarriers. We also found no evidence of a gene-gene interaction between CYP17 and SRD5A2 V89L polymorphisms on prostate cancer risk or endogenous steroid hormone levels. These results suggest that CYP17 genotype may possibly confer a small increased susceptibility to prostate cancer but is not a strong predictor of endogenous steroid hormone levels in men.     

Inverse association between nonsteroidal anti-inflammatory drugs and prostate cancer.

BACKGROUND: Prostate cancer is considered a major health problem in western countries. Promising results from observational studies on cancer at other sites fuelled the publication of several studies assessing the association between nonsteroidal anti-inflammatory drug (NSAID) use and prostate cancer. However, these studies show conflicting results. METHODS: We conducted a cohort study with a nested case-control analysis to further study the association between NSAIDs and prostate cancer. We used data from the General Practice Research Database in United Kingdom. RESULTS: Aspirin use was associated with a reduced risk of prostate cancer [odds ratio (OR) = 0.70, 95% confidence interval (95% CI) = 0.61-0.79]. We also found that paracetamol use with a treatment duration longer than 1 year was associated with a decreased risk (OR = 0.65, 95% CI = 0.54-0.78). Non-aspirin-NSAID (NA-NSAID) and paracetamol short-term use was associated with a small increased risk whereas long-term users of NA-NSAIDs presented an OR of 0.89 (95% CI = 0.73-1.08). DISCUSSION: Our findings support a protective effect of aspirin and paracetamol against prostate cancer. The transient elevated risk observed among newly started users of NA-NSAIDs and paracetamol is most likely explained by prothopathic bias. We found some suggestion of a reduced risk with long-term use of NA-NSAID.     

COX2 genetic variation, NSAIDs, and advanced prostate cancer risk

Collective evidence suggests that cyclooxygenase 2 (COX2) plays a role in prostate cancer risk. Cyclooxygenase 2 is the major enzyme that converts arachidonic acid to prostaglandins, which are potent mediators of inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic activity of COX2 and long-term use of NSAIDs appears to modestly lower the risk of prostate cancer. We investigated whether common genetic variation in COX2 influences the risk of advanced prostate cancer. Nine single-nucleotide polymorphisms (SNPs) in COX2 were genotyped among 1012 men in our case-control study of advanced prostate cancer. Gene-environment interactions between COX2 polymorphisms and NSAID use were also evaluated. Information on NSAID use was obtained by questionnaire. Three SNPs demonstrated nominally statistically significant associations with prostate cancer risk, with the most compelling polymorphism (rs2745557) associated with a lower risk of disease (odds ratio (OR) GC vs GG=0.64; 95% confidence interval (CI): 0.49-0.84; P=0.002). We estimated through permutation analysis that a similarly strong result would occur by chance 2.7% of the time. Nonsteroidal anti-inflammatory drug use was associated with a lower risk of disease in comparison to no use (OR=0.67; 95% CI: 0.52-0.87). No significant statistical interaction between NSAID use and rs2745557 was observed (P=0.12). Our findings suggest that variation in COX2 is associated with prostate cancer risk.     

Soy product and isoflavone consumption in relation to prostate cancer in Japanese men.

The incidence of prostate cancer is much lower in Asian than Western populations. Environmental factors, such as dietary habits, may play a major role in the causation of prostate cancer. Although isoflavones have been suggested to show a preventive effect against prostate cancer in animal experiments, the results of epidemiologic studies are inconsistent. Here, we conducted a population-based prospective study in 43,509 Japanese men ages 45 to 74 years who generally have a high intake of isoflavones and low incidence of prostate cancer. Participants responded to a validated questionnaire, which included 147 food items. During follow-up from 1995 through 2004, 307 men were newly diagnosed with prostate cancer, of which 74 cases were advanced, 220 cases were organ localized, and 13 cases were of an undetermined stage. Intakes of genistein, daidzein, miso soup, and soy food were not associated with total prostate cancer. However, these four items decreased the risk of localized prostate cancer. In contrast, positive associations were seen between isoflavones and advanced prostate cancer. These results were strengthened when analysis was confined to men ages >60 years, in whom isoflavones and soy food were associated with a dose-dependent decrease in the risk of localized cancer, with relative risks for men in the highest quartile of genistein, daidzein, and soy food consumption compared with the lowest of 0.52 [95% confidence interval (95% CI), 0.30-0.90], 0.50 (95% CI, 0.28-0.88), and 0.52 (95% CI, 0.29-0.90), respectively. In conclusion, we found that isoflavone intake was associated with a decreased risk of localized prostate cancer.