NATURE REVIEWS | CLINICAL ONCOLOGY ADVANCE ONLINE PUBLICATION | 1 Pharmacoepidemiology and Pharmacogenetics Unit, Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology and Clalit National Israeli Cancer Control Center (NICCC), 7 Michal Street, Haifa 34362, Israel (N. Gronich, G. Rennert). Correspondence to: G. Rennert rennert@ tx.technion.ac.il Beyond aspirin—cancer prevention with statins, metformin and bisphosphonates Naomi Gronich and Gad Rennert Abstract | Cancer risk reduction using pharmacological means is an attractive modern preventive approach that supplements the classical behavioural prevention recommendations. Medications that are commonly used by large populations to treat a variety of common, non–cancer–related, medical situations are an attractive candidate pool. This Review discusses three pharmacological agents with the most evidence for their potential as cancer chemopreventive agents: anti–hypercholesterolaemia medications (statins), an antidiabetic agent (metformin) and antiosteoporosis drugs (bisphosphonates). Data are accumulating to support a significant negative association of certain statins with cancer occurrence or survival in several major tumour sites (mostly gastrointestinal tumours and breast cancer), with an augmented combined effect with aspirin or other non–steroidal anti–inflammatory drugs. Metformin, but not other hypoglycaemic drugs, also seems to have some antitumour growth activity, but the amount of evidence in human studies, mainly in breast cancer, is still limited. Experimental and observational data have identified bisphosphonates as a pharmacological group that could have significant impact on incidence and mortality of more than one subsite of malignancy. At the current level of evidence these potential chemopreventive drugs should be considered in high–risk situations or using the personalized approach of maximizing individual benefits and minimizing the potential for adverse effects with the aid of pharmacogenetic indicators. Gronich, N. & Rennert, G. Nat. Rev. Clin. Oncol. advance online publication 1 October 2013; doi:10.1038/nrclinonc.2013.169 Introduction Reducing the risk of disease using pharmacological means, commonly referred to as chemoprevention, is an attractive preventive approach. For medications to qualify as efficacious in chronic disease prevention in average-risk populations, a number of requirements need to be met. 1 These requirements are usually differ- ent to those needed for a medication to be approved for the treatment of active disease. The leading principle of prevention is ‘do no harm’; therefore, medications that are considered for disease prevention in a very large and otherwise healthy population should carry, on top of evidence of efficacy, an especially low adverse-effects profile. For cancer chemoprevention—the subject of this Review—medications that are commonly used by large populations to treat a variety of common, non-cancer- related, medical situations are an attractive candidate pool. For these agents, the experience gained from a large number of users and large number of years of use for other purposes allows for an accurate evaluation of the expected magnitude of adverse effects. With this approach in mind, at least four large classes of medication have been studied for their anticancer effects. These include aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) that have been studied extensively, shown to be effective in cancer prevention 2,3 and will not be discussed in detail in this Review; anti-hypercholesterolaemia medications (statins); an antidiabetic agent (metformin); and anti- osteoporosis drugs (bisphosphonates), all of which will be discussed in this Review. Several other drugs are under investigation for their possible role in cancer chemoprevention, such as levothyroxine, 4 colchicine 5 and allopurinol, 6 but will also not be discussed here owing to the lack of a sufficient number of studies. The role of nutritional agents in cancer prevention, such as soy isoflavones, lycopene, pomegranate, omega-3-fatty acids, curcumin 7 and vitamin D 8 is also not discussed in this pharmacological prevention-based Review. This Review aims to discuss the pharmacological agents with the most evidence available to assess them for their potential as chemopreventive agents. It will outline the pharmacological mechanisms of action of these agents, the supporting clinical evidence for their efficacy and safety in large populations, and discuss if and how these agents should be used in the ongoing aim of preventing cancer. Statins Background Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors that reduce the syn- thesis of intracellular cholesterol by reversibly inhibiting the conversion of HMG-CoA to mevalonate, the rate- limiting step in cholesterol biosynthesis (Figure 1). 9 Statins reduce cardiovascular disease incidence and Competing interests The authors declare no competing interests. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved