The current evidence on statin use and prostate cancer prevention: are we there yet?

Abstract

An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell-based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed.

Figure 1. Statin use, high cholesterol and prostate cancer deaths in the USA

Age-adjusted US prostate cancer-specific mortality peaked in 1993 at 39 deaths per 100,000 men and has since been declining. The percentage of US men ≥20 years of age with high total serum cholesterol (≥240 mg/dl per National Cholesterol Education Program guidelines) has also declined, from 19% in 1987 to 12% in 2012(REFS 21,116). This reduction coincided with increasing prevalence of statin use (~26% of US adults ≥40 years of age in 2011–2012)^,. Currently, seven statin drugs are being marketed in the USA. Lovastatin was the first agent to be approved by the FDA in 1987. The newest agent, pitavastatin, was approved in 2009. *Data of statin use before 2011–2012 relates to US adults aged ≥45 years, data for 2011–2012 relates to US adults aged ≥40 years.

Figure 2. Mechanisms of prostate cancer growth affected by the mevalonate pathway

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that results in the synthesis of cholesterol and isoprenoids. Cholesterol is the sole precursor for sex steroid biosynthesis and has been shown to increase tumour androgen signalling and stimulate tumour growth in mouse models of prostate cancer. In addition, cholesterol is a key component of lipid rafts, which facilitate intracellular signalling processes by serving as organizing centres for the assembly of signalling molecules, such as the epidermal growth factor (EGF) and IL-6. EGF and IL-6 activate the PI3K AKT and JAK–STAT pathways, respectively, enhancing the transcription of genes involved in cholesterol homeostasis. The mevalonate pathway can also support prostate tumour growth via non-cholesterol-mediated mechanisms. For example, resulting isoprenoids, such as farnesyl pyrophosphate and geranyl pyrophosphate, facilitate recruitment of G-proteins Ras and Rho to the plasma membrane. High mevalonate levels suppress levels of the cyclin-dependent kinase inhibitor 1 (p21), thereby promoting cell cycle progression via activation of cyclin-dependent kinase 2 (CDK2) activity. SREBPs, sterol-regulatory-element-binding proteins.

Figure 3. Effects of statin use during the clinical course of prostate cancer

The clinical course of prostate cancer can be followed using measurements of serum PSA levels, serving as a marker of tumour burden. Rising PSA levels indicate prostate cancer growth and clinical diagnosis. Primary therapy (for example, surgery or radiation) causes a rapid drop in PSA level, showing tumour removal or eradication. Prostate cancer recurrence is detected by rising PSA level after primary treatment. Subsequent androgen deprivation therapy initially results in a reduction in tumour burden and PSA level but most patients eventually develop castration-resistant prostate cancer. Currently, castration-resistant disease cannot be cured and these patients will eventually die of their disease. Statins have been shown to have a protective role at various stages of the clinical course of prostate cancer.