Background: Previous studies have shown that statin use may reduce prostate cancer risk. In the current study, we evaluated the association between serum cholesterol–lowering medication use and prostate cancer risk at the population level. Materials and Methods: All newly diagnosed prostate cancer cases in Finland during 1995 to 2002 and matched controls (24,723 case control pairs) were identified from the Finnish Cancer Registry and the Population Register Center, respectively. Detailed information on cholesterol-lowering drug purchases during the study period was obtained from the prescription database of the Social Insurance Institution of Finland. Results: After adjustment for potential confounders, having ever-use of any statin was associated with marginally elevated overall prostate cancer risk [odds ratio (OR), 1.07; 95% confidence interval (95% CI), 1.00-1.16]. However, none of the statins was associated with the overall prostate cancer risk when analyzed separately. On the other hand, the risk of advanced prostate cancer was decreased among users of atorvastatin, lovastatin, and simvastatin (OR 0.61, 95% CI 0.37-0.98; OR 0.61, 95% CI 0.43-0.85; and OR 0.78, 95% CI 0.61-1.01, respectively). The risk was not affected among users of other cholesterol drug groups. Conclusions: Our large population-based study showed no evidence for reduced overall prostate cancer risk among users of cholesterol-lowering drugs, whereas the risk of advanced cancer was decreased among statin users. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2226–32)

Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995–2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08–9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38–0.55 and HR 0.54, 95% CI 0.44–0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins’ effect on survival in breast cancer patients.

Decreased risk of prostate cancer in diabetic men has been reported. The authors evaluated the association between antidiabetic medication use and prostate cancer at the population level. All incident prostate cancer cases in Finland during 1995–2002 were identified from the Finnish Cancer Registry. Matched controls were provided by the Population Register Center (24,723 case-control pairs). Information on medication use was obtained from a comprehensive prescription database. Multivariable-adjusted odds ratios were computed by using conditional logistic regression. The authors found that prostate cancer risk was decreased for antidiabetic medication users (odds ratio = 0.87, 95% confidence interval: 0.82, 0.92). The decrease was observed for most drug groups. The odds ratio decreased in a dose-dependent fashion by quantity of use. Duration of antidiabetic treatment was inversely associated with overall prostate cancer risk and risk of advanced cancer. Similar risk reduction for users of different antidiabetic drugs suggests that diabetes, instead of the medication itself, is behind the association. This finding is unlikely to be secondary because of differential uptake of the prostate-specific antigen test or different prostate-specific antigen levels between medication users and nonusers; prevalence of testing in Finland is low. Dose and time dependency of the relation probably indicates that duration of diabetes is negatively associated with risk.

Cholesterol-lowering treatment has been suggested to delay progression of prostate cancer by decreasing serum LDL. We studied in vitro the effect of extracellular LDL-cholesterol on the number of prostate epithelial cells and on the expression of key regulators of cholesterol metabolism. Two normal prostatic epithelial cell lines (P96E, P97E), two in vitro immortalized epithelial cell lines (PWR-1E, RWPE-1) and two cancer cell lines (LNCaP and VCaP) were grown in cholesterol-deficient conditions. Cells were treated with 1–50 µg/ml LDL-cholesterol and/or 100 nM simvastatin for seven days. Cell number relative to control was measured with crystal violet staining. Changes in mRNA and protein expression of key effectors in cholesterol metabolism (HMGCR, LDLR, SREBP2 and ABCA1) were measured with RT-PCR and immunoblotting, respectively. LDL increased the relative cell number of prostate cancer cell lines, but reduced the number of normal epithelial cells at high concentrations. Treatment with cholesterol-lowering simvastatin induced up to 90% reduction in relative cell number of normal cell lines but a 15–20% reduction in relative number of cancer cells, an effect accompanied by sharp upregulation of HMGCR and LDLR. These effects were prevented by LDL. Compared to the normal cells, prostate cancer cells showed high expression of cholesterol-producing HMGCR but failed to express the major cholesterol exporter ABCA1. LDL increased relative cell number of cancer cell lines, and these cells were less vulnerable than normal cells to cholesterol-lowering simvastatin treatment. Our study supports the importance of LDL for prostate cancer cells, and suggests that cholesterol metabolism in prostate cancer has been reprogrammed to increased production in order to support rapid cell growth.

Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non‐users of statins or other cholesterol‐lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996–2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate‐specific antigen (PSA) level was compared between current users and non‐users of cholesterol‐lowering drugs. Compared with medication non‐users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63–0.89]. The inverse association was dose‐dependent with cumulative amount of statin use, and strongest for low‐grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol‐lowering drugs (HR 0.62, 95% CI 0.28–1.38), but without dose‐dependence. Age‐adjusted median serum PSA tended to be lower among users of cholesterol‐lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non‐users was eliminated by systematical prostate cancer screening. Cholesterol‐lowering with statins seems beneficial for prostate cancer prevention.