Curr Atheroscler Rep (2014) 16:383 DOI 10.1007/s11883-013-0383-z
STATIN DRUGS (MB CLEARFIELD, SECTION EDITOR)
The Spectrum of Statin Therapy in Cancer Patients: Is There a Need for Further Investigation? Michael J. Gonyeau
Published online: 5 December 2013 # Springer Science+Business Media New York 2013
Abstract Although our understanding of the relationship between cancer and statin use continues to improve, it remains a complex association requiring further research focusing on both biologic and clinical end points in a wide range of patient populations. To date, most of the published results are from observational studies detailing the risk of incident cancers or from randomized controlled trials with cardiovascular primary end points and cancer only as a secondary end point. Although there is certainly great value in the information obtained from observational studies, they cannot prove a causal link between statins and cancer, and it would then seem appropriate to design and implement clinical trials. Such studies should consider three main end products of the mevalonate pathway (cholesterol, geranyl pyrophosphate, and farnesyl pyrophosphate) from a mechanistic perspective, as well as the potential for cancer cell mediation with statin use, in addition to pertinent clinical end points including cancer incidence and mortality. Keywords Cancer . 3-Hydroxy-3-methylglutaryl coenzyme a reductase inhibitors . Statins . Neoplasm . Pleiotropic effects . Clinical trials . Prostate cancer . Breast cancer . Lung cancer . Colorectal cancer
Introduction Debate regarding cholesterol, statins, and cancer is ongoing. Data demonstrating an increased risk of cancer in patients This article is part of the Topical Collection on Statin Drugs M. J. Gonyeau (*) Clinical Professor and Director of Undergraduate Programs, Northeastern University School of Pharmacy, Clinical Pharmacist, Brigham and Women’s Hospital, 360 Huntington Ave, Boston, MA 02115, USA e-mail: [email protected]
with low cholesterol levels date back to the 1970s. Pleiotropic effects of statins have been associated with both positive and negative outcomes in relation to cancer occurrence. There are several mechanisms by which statins may cause such results. Increases in cancer incidence may be attributed to statininduced mitotic abnormalities, extreme reduction in cholesterol levels, which is known to be an independent carcinogenic factor, and/or immunosuppression. Decreases in cancer incidence may be attributed to statin-induced suppression of tumor growth, induction of apoptosis, and/or inhibition of angiogenesis. Figure 1 outlines the mechanistic theories for potential positive and negative effects of statins in cancer [1]. Data suggest that low serum cholesterol concentrations may be associated with increased cancer risk, and the question of what threshold confers increased patient risk continues to be researched and debated. A more recent potential explanation for this correlation relates to the estimated 15-20 % of cancers found to have a viral and/or bacterial origin [2]. It has been demonstrated that lipoproteins bind to and deactivate microorganisms and their toxic products [3]. The size of LDL particles may also play a role in cancer risk, as larger LDL particles may be cancer-protective by participating in immune system activities and transporting toxic substances. An association between statins and increased frequency of hepatocellular tumors, pulmonary adenomas, thyroid cancers, squamous papillomas, follicular cell adenomas, and lymphomas has been demonstrated in rodents [4]. Statins may stimulate the signaling of transforming growth factor through reduction in cholesterol concentrations, increasing the factor that may aid in progression of renal fibrosis, which could lead to renal carcinoma [5]. Lovastatin has been associated with increased mitotic abnormalities, which interfere with development and function of centromeres, increasing the risk of mutations and malignancies [6]. Statins may also inhibit the inducible type IV promoter of the class II transactivator and cause binding to leukocyte function antigen, resulting in
383, Page 2 of 7
Curr Atheroscler Rep (2014) 16:383
Fig. 1 Potential statin-associated cancer mechanisms
immunosuppression [7]. Most such negative results have been associated primarily with the lipophilic statins: atorvastatin, simvastatin, lovastatin, and fluvastatin. Hydrophilic statins, such as rosuvastatin and pravastatin, have been theorized to have no effect on tumor development because of their impaired ability to cross biologic membranes [8]. Statins may inhibit tumor cell growth through the isoprenoid intermediates farnesyl pyrophosphate (FPP) and geranyl pyrophosphate (GPP) (Fig. 1) [9]. Dolichol is involved in cell growth regulation and has a stimulatory effect on DNA synthesis [10]. The isoprenoid intermediates are essential for modification of the intracellular G proteins Rho, Rac, and
Ras. These G proteins bind to FPP and/or GPP through isoprenylation, after which T cell proliferation, differentiation, and apoptosis occur [9]. By inhibiting this process, statins can potentially decrease DNA synthesis by inhibiting production of dolichol and ultimately inhibiting cell growth. This is of special importance in cancer cells, as there is an increase in G protein activity in some tumor types such as non-small-cell lung, colorectal, pancreatic, bladder, kidney, thyroid, and hepatocellular carcinomas, melanoma, and hematologic malignancies [11]. Tumor cells also often mutate, and a common target for such mutation is the protein p53, which may contribute to tumor growth and development. Mutations of p53
Curr Atheroscler Rep (2014) 16:383
have been associated with the mevalonate pathway, thereby implying that agents that affect this pathway, such as statins, may be a mechanism by which therapeutic effects may be seen in tumor cells with p53 mutations. Another mechanism by which statins can inhibit tumor cell growth is through downregulation of cell-cycle-promoting mediators, such as cyclindependent kinases, and upregulation of cell-cycle inhibitors, p21 and/or p27 [12]. These actions increase the levels of factors that inhibit the cell proliferative cycle. Statins may also inhibit angiogenesis. It is widely recognized that tumors require the development of vasculature to supply oxygen and nutrients as they grow. As such, tumors induce hypoxia, which stimulates mediators for angiogenesis [13]. Statins have shown multiple effects on blood vessel formation by inhibiting angiogenesis through decreasing the levels of proangiogenic factors, including vascular endothelial growth factor, inhibiting endothelial cell proliferation, and blocking adhesion to the extracellular matrix [14]. Some data also suggest that statins do not affect vascular endothelial growth factor expression in patients with colorectal cancer [15]. These processes lead to decreased tumor cell growth and motility. However, an increase in angiogenesis and vessel growth through stimulation of protein kinase B and activation of endothelial nitric oxide synthase (eNOS) has been demonstrated [16]. Inhibition of angiogenesis is dependent on the presence of caveolin, a protein that decreases the level of eNOS. Endothelial cells with low caveolin concentrations may be more sensitive to the angiogenic effects of statins [17]. The evidence for angiogenic effects differs, and the effects may be related to statin concentration and/or potency. Statins can inhibit angiogenesis at increased concentrations (0.05 μmol/L or greater), which appears to be lipidindependent and reversible with administration of mevalonate and GPP [18]. This suggests that inhibition of isoprenylation may be important in angiogenesis inhibition. Statins can also stimulate angiogenesis by promoting eNOS activation at low to mid-range concentrations (0.005–0.05 μmol/L). Cerivastatin, a potent agent, inhibited human umbilical venous endothelial cell proliferation at a concentration of 0.1 μmol/L. Simvastatin induced this effect at 2.5 μmol/L and fluvastatin induced it at 1 μmol/L [19]. Therefore, depending on which statin is used, as well as its dose and resultant concentration, it may be possible to inhibit or stimulate blood vessel growth. In conjunction with angiogenesis, statins may inhibit tumor metastases. For metastases to occur, tumor cells must extravasate, break down extracellular matrix, migrate, and invade other tissues. Statins affect this process by inhibiting cell adhesion, migration, and invasion by decreasing the levels of endothelial adhesion molecules, including Eselectin and matrix metalloproteinase 9 [20]. They may also decrease epithelial-growth-factor-induced tumor cell invasion [21]. With both decreased levels of adhesion molecules for tumor cells to use for attachment and less cell growth
Page 3 of 7, 383
mediators, statins may reduce proliferation and the metastatic potential of cancer cells. Statins may also induce tumor cell apoptosis. Although tumor cells appear to be more resistant to apoptotic signals, statins may induce apoptosis by inhibiting GPP, which is needed for eventual Rho-mediated cell proliferation [22]. Administration of GPP reversed the apoptotic effect created by statin use in two studies [15,23]. Statins also upregulate proapoptotic proteins such as Bax and Bim and downregulate antiapoptotic proteins such as Bcl2 [24]. In addition, statins activate caspases, which induce cell death, demonstrating multiple potential mechanisms for apoptosis. A review of the literature regarding statins and cancer in the past year reveals additional information from which clinicians may be able to draw some conclusions.
Recent Articles Discussing Mechanisms of Statins in Cancer Ravnskov et al. [25] discussed the relationship between low cholesterol levels and cancer risk. Although the historical interpretation of this relationship has been designated as a secondary association because mechanistically preclinical cancers might use cholesterol, leading to lower levels, thereby showing a causal relationship between low LDL levels and cancer in the absence of other factors, Ravnskov et al. suggest that this is unlikely, as the liver should be able to produce any extra cholesterol needed by tumors. Also of importance as stated is that if statins cause cancer, it is unlikely that the cancer would manifest itself within 5 years of statin treatment in humans. As most prospective statin trials have an average follow-up of 5 years, it may be that an increased incidence of cancer was not observed. Consistent with this theory is that most cancers that have been identified in association with statins have been those cancers most likely to be detected early, such as skin, lymphoid, breast, prostate, and bladder cancer. To address the continued concern regarding low cholesterol levels and increased cancer incidence, Benn et al. [26] conducted a Mendelian randomization study to evaluate subjects with genetic polymorphisms predisposing them to low LDL levels and cancer risk in a Danish population. Adjustments were made for confounders including body mass index, hypertension, diabetes mellitus, current smoking, ischemic heart disease, and statin use. An LDL level below the tenth percentile (below 87 mg/dL) was associated with an increased risk of cancer after adjustment for confounders [relative risk (RR) 1.43, 95 % confidence interval (CI) 1.15-1.79]. These results persisted for specific cancer types, including gastrointestinal cancer (RR 1.61, 95 % CI 1.09-2.36), whereas other cancer types were not statistically significant but showed trends, such as hematological (RR 1.42, 95 % CI 0.55-3.67), respiratory
383, Page 4 of 7
(RR 1.41, 95 % CI 0.88-2.25), female-specific (RR 1.41, 95 % CI 0.9–2.19) and male-specific (RR 1.34, 95 % CI 0.63-2.85) cancers. However, the observed cancer risk in subjects with genetic-polymorphism-induced LDL level reduction was not associated with an increase in cancer. The limitations of this trial include its use of gene polymorphisms that explain only half of the genetic variation in LDL concentrations, potential selection bias, and the lack of racial diversity in the study population.
Large Observational Trials The Cholesterol Treatment Trialists group reviewed 175,000 patients in 27 large-scale statin trials whose primary end points were cardiovascular-related in an attempt to provide a detailed assessment of whether there is any effect of statininduced lowering of LDL levels on the incidence and mortality associated with specific cancer types [27•]. Newly diagnosed first cancers were compared in statin users versus nonstatin users, with no difference being observed (RR 1.0, 95 % CI 0.95-1.05). Likewise, no excess in newly diagnosed cancers that resulted in mortality in statin users was found. No significant associations were found between statins and any of the 23 categories of individual cancer sites evaluated, nor was an association observed in the incidence of cancer over time (trend p =0.57). Although no excess cancer risk was observed, there was also no evidence that statins may decrease the risk of cancer incidence, morbidity, or mortality, although the authors of the study did state that such an effect may have been missed if the latency period for cancer development is substantially longer than the 5-year treatment period studied. Jacobs et al. [28•] conducted a prospective study of 133, 255 subjects to examine if there is any association between long-term use of cholesterol-lowering drugs and the incidence of ten common cancers. Subject data were obtained from participants in the Cancer Prevention Study II Nutrition Survey cohort [29]. Biennial questionnaires were completed by participants to obtain information regarding the use of cholesterol-lowering medications, newly diagnosed cancers, and demographic, medical history, and lifestyle habits. The response rates for completion of follow-up questionnaires were at least 88 %. Any self-reported cancer diagnosis was confirmed through medical records and/or state cancer registries. Adjustments were made in the analysis for potential confounders such as comorbidities, smoking, and obesity. Use of cholesterol-lowering drugs for 5 years or more was not associated with overall cancer incidence or with risk of bladder, breast, colorectal, lung, pancreatic, prostate, or renal cell cancer but was associated with a statistically significant lower risk of melanoma (RR 0.79, 95 % CI 0.66-0.96, p =0.02), endometrial cancer (RR 0.65, 95 % CI 0.45-0.94, p =0.02), and non-Hodgkin lymphoma (RR 0.74, 95 % CI
Curr Atheroscler Rep (2014) 16:383
0.62-0.89, p 0.05 for all) [33]. Further, this trial also did not find an association between statin use and the efficacy of cancer treatment. To obtain additional insight into the mechanism of a statin effect on prostate cancer, Peng et al. [34] conducted studies to determine the effects of atorvastatin on the proliferation and differentiation of prostate cancer cells. Their theory was premised on the inhibition of the mevalonate pathway, specifically geranyl geranyl synthesis, and they observed statininduced death of one type of prostate cancer cell (PC3), and inhibition of proliferation of another type (LNCaP). A sustained, time-dependent inhibition of LNCaP cancer cells was noted for the duration of exposure to atorvastatin (6 days), whereas PC3 prostate cancer cells were inhibited by day 2, with significant cell death by day 4. MicroRNA, such as miR182, was found to mediate the antiproliferative and proautophagic activity of atorvastatin in prostate cancer cells, and may be a target of future trials. In another study involving prostate cancer, a meta-analysis of 27 (15 cohort and 12 case–control) observational studies evaluating whether there is an association between statin use and the development of prostate cancer in more than 1.8 million patients published before February 2012 was conducted by Bansal et al. [35]. Although heterogeneity among studies existed, there did not appear to be publication bias. Data on statin prescriptions were collected through patient self-report, medical records, or from a prescription database. Statin use was associated with a 7 % reduction in total prostate cancer risk (RR 0.93, 95 % CI 0.87-0.99, p =0.03), and a 20 % reduction in advanced prostate cancer risk (RR 0.8, 95 % CI 0.7-0.9, p
STATIN DRUGS (MB CLEARFIELD, SECTION EDITOR)
The Spectrum of Statin Therapy in Cancer Patients: Is There a Need for Further Investigation? Michael J. Gonyeau
Published online: 5 December 2013 # Springer Science+Business Media New York 2013
Abstract Although our understanding of the relationship between cancer and statin use continues to improve, it remains a complex association requiring further research focusing on both biologic and clinical end points in a wide range of patient populations. To date, most of the published results are from observational studies detailing the risk of incident cancers or from randomized controlled trials with cardiovascular primary end points and cancer only as a secondary end point. Although there is certainly great value in the information obtained from observational studies, they cannot prove a causal link between statins and cancer, and it would then seem appropriate to design and implement clinical trials. Such studies should consider three main end products of the mevalonate pathway (cholesterol, geranyl pyrophosphate, and farnesyl pyrophosphate) from a mechanistic perspective, as well as the potential for cancer cell mediation with statin use, in addition to pertinent clinical end points including cancer incidence and mortality. Keywords Cancer . 3-Hydroxy-3-methylglutaryl coenzyme a reductase inhibitors . Statins . Neoplasm . Pleiotropic effects . Clinical trials . Prostate cancer . Breast cancer . Lung cancer . Colorectal cancer
Introduction Debate regarding cholesterol, statins, and cancer is ongoing. Data demonstrating an increased risk of cancer in patients This article is part of the Topical Collection on Statin Drugs M. J. Gonyeau (*) Clinical Professor and Director of Undergraduate Programs, Northeastern University School of Pharmacy, Clinical Pharmacist, Brigham and Women’s Hospital, 360 Huntington Ave, Boston, MA 02115, USA e-mail: [email protected]
with low cholesterol levels date back to the 1970s. Pleiotropic effects of statins have been associated with both positive and negative outcomes in relation to cancer occurrence. There are several mechanisms by which statins may cause such results. Increases in cancer incidence may be attributed to statininduced mitotic abnormalities, extreme reduction in cholesterol levels, which is known to be an independent carcinogenic factor, and/or immunosuppression. Decreases in cancer incidence may be attributed to statin-induced suppression of tumor growth, induction of apoptosis, and/or inhibition of angiogenesis. Figure 1 outlines the mechanistic theories for potential positive and negative effects of statins in cancer [1]. Data suggest that low serum cholesterol concentrations may be associated with increased cancer risk, and the question of what threshold confers increased patient risk continues to be researched and debated. A more recent potential explanation for this correlation relates to the estimated 15-20 % of cancers found to have a viral and/or bacterial origin [2]. It has been demonstrated that lipoproteins bind to and deactivate microorganisms and their toxic products [3]. The size of LDL particles may also play a role in cancer risk, as larger LDL particles may be cancer-protective by participating in immune system activities and transporting toxic substances. An association between statins and increased frequency of hepatocellular tumors, pulmonary adenomas, thyroid cancers, squamous papillomas, follicular cell adenomas, and lymphomas has been demonstrated in rodents [4]. Statins may stimulate the signaling of transforming growth factor through reduction in cholesterol concentrations, increasing the factor that may aid in progression of renal fibrosis, which could lead to renal carcinoma [5]. Lovastatin has been associated with increased mitotic abnormalities, which interfere with development and function of centromeres, increasing the risk of mutations and malignancies [6]. Statins may also inhibit the inducible type IV promoter of the class II transactivator and cause binding to leukocyte function antigen, resulting in
383, Page 2 of 7
Curr Atheroscler Rep (2014) 16:383
Fig. 1 Potential statin-associated cancer mechanisms
immunosuppression [7]. Most such negative results have been associated primarily with the lipophilic statins: atorvastatin, simvastatin, lovastatin, and fluvastatin. Hydrophilic statins, such as rosuvastatin and pravastatin, have been theorized to have no effect on tumor development because of their impaired ability to cross biologic membranes [8]. Statins may inhibit tumor cell growth through the isoprenoid intermediates farnesyl pyrophosphate (FPP) and geranyl pyrophosphate (GPP) (Fig. 1) [9]. Dolichol is involved in cell growth regulation and has a stimulatory effect on DNA synthesis [10]. The isoprenoid intermediates are essential for modification of the intracellular G proteins Rho, Rac, and
Ras. These G proteins bind to FPP and/or GPP through isoprenylation, after which T cell proliferation, differentiation, and apoptosis occur [9]. By inhibiting this process, statins can potentially decrease DNA synthesis by inhibiting production of dolichol and ultimately inhibiting cell growth. This is of special importance in cancer cells, as there is an increase in G protein activity in some tumor types such as non-small-cell lung, colorectal, pancreatic, bladder, kidney, thyroid, and hepatocellular carcinomas, melanoma, and hematologic malignancies [11]. Tumor cells also often mutate, and a common target for such mutation is the protein p53, which may contribute to tumor growth and development. Mutations of p53
Curr Atheroscler Rep (2014) 16:383
have been associated with the mevalonate pathway, thereby implying that agents that affect this pathway, such as statins, may be a mechanism by which therapeutic effects may be seen in tumor cells with p53 mutations. Another mechanism by which statins can inhibit tumor cell growth is through downregulation of cell-cycle-promoting mediators, such as cyclindependent kinases, and upregulation of cell-cycle inhibitors, p21 and/or p27 [12]. These actions increase the levels of factors that inhibit the cell proliferative cycle. Statins may also inhibit angiogenesis. It is widely recognized that tumors require the development of vasculature to supply oxygen and nutrients as they grow. As such, tumors induce hypoxia, which stimulates mediators for angiogenesis [13]. Statins have shown multiple effects on blood vessel formation by inhibiting angiogenesis through decreasing the levels of proangiogenic factors, including vascular endothelial growth factor, inhibiting endothelial cell proliferation, and blocking adhesion to the extracellular matrix [14]. Some data also suggest that statins do not affect vascular endothelial growth factor expression in patients with colorectal cancer [15]. These processes lead to decreased tumor cell growth and motility. However, an increase in angiogenesis and vessel growth through stimulation of protein kinase B and activation of endothelial nitric oxide synthase (eNOS) has been demonstrated [16]. Inhibition of angiogenesis is dependent on the presence of caveolin, a protein that decreases the level of eNOS. Endothelial cells with low caveolin concentrations may be more sensitive to the angiogenic effects of statins [17]. The evidence for angiogenic effects differs, and the effects may be related to statin concentration and/or potency. Statins can inhibit angiogenesis at increased concentrations (0.05 μmol/L or greater), which appears to be lipidindependent and reversible with administration of mevalonate and GPP [18]. This suggests that inhibition of isoprenylation may be important in angiogenesis inhibition. Statins can also stimulate angiogenesis by promoting eNOS activation at low to mid-range concentrations (0.005–0.05 μmol/L). Cerivastatin, a potent agent, inhibited human umbilical venous endothelial cell proliferation at a concentration of 0.1 μmol/L. Simvastatin induced this effect at 2.5 μmol/L and fluvastatin induced it at 1 μmol/L [19]. Therefore, depending on which statin is used, as well as its dose and resultant concentration, it may be possible to inhibit or stimulate blood vessel growth. In conjunction with angiogenesis, statins may inhibit tumor metastases. For metastases to occur, tumor cells must extravasate, break down extracellular matrix, migrate, and invade other tissues. Statins affect this process by inhibiting cell adhesion, migration, and invasion by decreasing the levels of endothelial adhesion molecules, including Eselectin and matrix metalloproteinase 9 [20]. They may also decrease epithelial-growth-factor-induced tumor cell invasion [21]. With both decreased levels of adhesion molecules for tumor cells to use for attachment and less cell growth
Page 3 of 7, 383
mediators, statins may reduce proliferation and the metastatic potential of cancer cells. Statins may also induce tumor cell apoptosis. Although tumor cells appear to be more resistant to apoptotic signals, statins may induce apoptosis by inhibiting GPP, which is needed for eventual Rho-mediated cell proliferation [22]. Administration of GPP reversed the apoptotic effect created by statin use in two studies [15,23]. Statins also upregulate proapoptotic proteins such as Bax and Bim and downregulate antiapoptotic proteins such as Bcl2 [24]. In addition, statins activate caspases, which induce cell death, demonstrating multiple potential mechanisms for apoptosis. A review of the literature regarding statins and cancer in the past year reveals additional information from which clinicians may be able to draw some conclusions.
Recent Articles Discussing Mechanisms of Statins in Cancer Ravnskov et al. [25] discussed the relationship between low cholesterol levels and cancer risk. Although the historical interpretation of this relationship has been designated as a secondary association because mechanistically preclinical cancers might use cholesterol, leading to lower levels, thereby showing a causal relationship between low LDL levels and cancer in the absence of other factors, Ravnskov et al. suggest that this is unlikely, as the liver should be able to produce any extra cholesterol needed by tumors. Also of importance as stated is that if statins cause cancer, it is unlikely that the cancer would manifest itself within 5 years of statin treatment in humans. As most prospective statin trials have an average follow-up of 5 years, it may be that an increased incidence of cancer was not observed. Consistent with this theory is that most cancers that have been identified in association with statins have been those cancers most likely to be detected early, such as skin, lymphoid, breast, prostate, and bladder cancer. To address the continued concern regarding low cholesterol levels and increased cancer incidence, Benn et al. [26] conducted a Mendelian randomization study to evaluate subjects with genetic polymorphisms predisposing them to low LDL levels and cancer risk in a Danish population. Adjustments were made for confounders including body mass index, hypertension, diabetes mellitus, current smoking, ischemic heart disease, and statin use. An LDL level below the tenth percentile (below 87 mg/dL) was associated with an increased risk of cancer after adjustment for confounders [relative risk (RR) 1.43, 95 % confidence interval (CI) 1.15-1.79]. These results persisted for specific cancer types, including gastrointestinal cancer (RR 1.61, 95 % CI 1.09-2.36), whereas other cancer types were not statistically significant but showed trends, such as hematological (RR 1.42, 95 % CI 0.55-3.67), respiratory
383, Page 4 of 7
(RR 1.41, 95 % CI 0.88-2.25), female-specific (RR 1.41, 95 % CI 0.9–2.19) and male-specific (RR 1.34, 95 % CI 0.63-2.85) cancers. However, the observed cancer risk in subjects with genetic-polymorphism-induced LDL level reduction was not associated with an increase in cancer. The limitations of this trial include its use of gene polymorphisms that explain only half of the genetic variation in LDL concentrations, potential selection bias, and the lack of racial diversity in the study population.
Large Observational Trials The Cholesterol Treatment Trialists group reviewed 175,000 patients in 27 large-scale statin trials whose primary end points were cardiovascular-related in an attempt to provide a detailed assessment of whether there is any effect of statininduced lowering of LDL levels on the incidence and mortality associated with specific cancer types [27•]. Newly diagnosed first cancers were compared in statin users versus nonstatin users, with no difference being observed (RR 1.0, 95 % CI 0.95-1.05). Likewise, no excess in newly diagnosed cancers that resulted in mortality in statin users was found. No significant associations were found between statins and any of the 23 categories of individual cancer sites evaluated, nor was an association observed in the incidence of cancer over time (trend p =0.57). Although no excess cancer risk was observed, there was also no evidence that statins may decrease the risk of cancer incidence, morbidity, or mortality, although the authors of the study did state that such an effect may have been missed if the latency period for cancer development is substantially longer than the 5-year treatment period studied. Jacobs et al. [28•] conducted a prospective study of 133, 255 subjects to examine if there is any association between long-term use of cholesterol-lowering drugs and the incidence of ten common cancers. Subject data were obtained from participants in the Cancer Prevention Study II Nutrition Survey cohort [29]. Biennial questionnaires were completed by participants to obtain information regarding the use of cholesterol-lowering medications, newly diagnosed cancers, and demographic, medical history, and lifestyle habits. The response rates for completion of follow-up questionnaires were at least 88 %. Any self-reported cancer diagnosis was confirmed through medical records and/or state cancer registries. Adjustments were made in the analysis for potential confounders such as comorbidities, smoking, and obesity. Use of cholesterol-lowering drugs for 5 years or more was not associated with overall cancer incidence or with risk of bladder, breast, colorectal, lung, pancreatic, prostate, or renal cell cancer but was associated with a statistically significant lower risk of melanoma (RR 0.79, 95 % CI 0.66-0.96, p =0.02), endometrial cancer (RR 0.65, 95 % CI 0.45-0.94, p =0.02), and non-Hodgkin lymphoma (RR 0.74, 95 % CI
Curr Atheroscler Rep (2014) 16:383
0.62-0.89, p 0.05 for all) [33]. Further, this trial also did not find an association between statin use and the efficacy of cancer treatment. To obtain additional insight into the mechanism of a statin effect on prostate cancer, Peng et al. [34] conducted studies to determine the effects of atorvastatin on the proliferation and differentiation of prostate cancer cells. Their theory was premised on the inhibition of the mevalonate pathway, specifically geranyl geranyl synthesis, and they observed statininduced death of one type of prostate cancer cell (PC3), and inhibition of proliferation of another type (LNCaP). A sustained, time-dependent inhibition of LNCaP cancer cells was noted for the duration of exposure to atorvastatin (6 days), whereas PC3 prostate cancer cells were inhibited by day 2, with significant cell death by day 4. MicroRNA, such as miR182, was found to mediate the antiproliferative and proautophagic activity of atorvastatin in prostate cancer cells, and may be a target of future trials. In another study involving prostate cancer, a meta-analysis of 27 (15 cohort and 12 case–control) observational studies evaluating whether there is an association between statin use and the development of prostate cancer in more than 1.8 million patients published before February 2012 was conducted by Bansal et al. [35]. Although heterogeneity among studies existed, there did not appear to be publication bias. Data on statin prescriptions were collected through patient self-report, medical records, or from a prescription database. Statin use was associated with a 7 % reduction in total prostate cancer risk (RR 0.93, 95 % CI 0.87-0.99, p =0.03), and a 20 % reduction in advanced prostate cancer risk (RR 0.8, 95 % CI 0.7-0.9, p
