Main

Skin cancer is one of the most common cancers, which is divided into two major groups, melanoma and non-melanoma skin cancers (NMSCs). Melanoma is the major cause of death from skin cancer (Society, 2013) and considered as one of the most therapy-resistant malignancies (Gogas et al, 2013). If left untreated, NMSCs also can become destructive, invading local tissues and causing disfigurement (Miller et al, 2010).

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have received increasing attention owing to their possible anticancer effects (Sarrabayrouse et al, 2007; Coimbra et al, 2010; Zhang et al, 2011).

According to a meta-analysis of 16 randomized control trials (RCTs) before 2009 (Bonovas et al, 2010), no association was found between statins and melanoma. Several observational studies also presented that statins have not identified anticancer effects (Marelli et al, 2011; Leung et al, 2013). However, other recent observational studies showed that statins may be associated with a lower risk of melanoma (Haukka et al, 2010; Jacobs et al, 2011). Thus, the effect of statins on the skin cancer risk remains to be determined.

Materials and Methods

Selection criteria

The studies considered in this meta-analysis were RCTs, case–control or cohort studies that evaluated exposure to statins and risk of skin cancer (including melanoma and NMSCs). The following inclusion criteria had to be fulfilled: (1) clearly defined and evaluated exposure to statins; (2) skin cancer incidence as the outcome of interest; (3) reported RR or odds ratio (OR) with 95% CI or provided data for their calculation. Studies reporting different measures of RR such as risk ratio, rate ratio, hazard ratio and OR were included because in practice they yield a similar RR estimate, given the absolute risk of skin cancer is low.

Identifying studies

Broad searches were conducted to identify all published literatures and meeting abstracts in Pubmed (-2013) and Web of Science (1985–2013) limited to those human subjects without limitation on language. Search terms included 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitor), statin, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pravastatin, pitavastatin, rivastatin, rosuvastatin, simvastatin, combined with melanoma or non-melanoma or cancer or neoplasm or malignancy. Flow diagram is shown in Supplementary Figure 1. The detail of data collection is shown in Supplementary Material 1.

Quality assessment

The criteria adapted from the Cochrane handbook for systematic reviews of interventions (Higgins et al, 2011) and the validated Newcastle–Ottawa scale (NOS) (Wells et al, 2000) were used to assess the methodological quality of RCTs, case–control and cohort studies, respectively.

Statistical analysis

Study-specific risk estimates were extracted from each article, and log risk estimates were weighted by the inverse of their variances to obtain a pooled risk estimate. Heterogeneity was assessed by using Cochrane Q statistic and estimating I2 (Higgins et al, 2003). A fixed-effect model (Mantel–Haenszel) was used to calculate the pooled ORs when the test for heterogeneity was not statistically significant (P>0.10), otherwise the random-effect model (DerSimonian and Laird) was employed (Song et al, 2001). Evidence of publication bias was determined using funnel plot and Egger’s statistical test (Egger et al, 1997). Subgroup analyses were carried out by quality of study methodology, study design and duration of statin use. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis results (Trikalinos et al, 2006). Cumulative meta-analysis was conducted to identify the change in trend of reporting risk over time. Statistical analyses were performed using STATA 12.0 (STATA Corporation, College Station, TX, USA).

Results

Characteristics of included studies

A total of 21 articles with 29 studies were identified, among which 24 studies focused on melanoma, whereas 14 studies reported NMSCs and 3 studies did not specify the classification of skin cancer (Table 1).

Table 1 Characteristics of included studies assessing the risk of skin cancer with statin use
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With respect to melanoma, 17 studies were post-hoc analyses or RCTs, 5 were case–control studies, and 2 were cohort studies. A total of 8433 cases of melanoma were cumulatively reported in 414 627 patients, and 114 708 individuals were classified as statin users. Concerning the NMSCs, 12 studies were post-hoc analyses or RCTs, 1 was case–control study and 1 was cohort study, of which 3354 cases and 99 906 controls were eligible.

Quality assessment results

The qualities of studies were moderate to high (Table 1).

Melanoma

The association between statins and melanoma risk was not statistically significant assuming a random-effect model (RR, 0.94; 95% CI, 0.85–1.04). However, moderate heterogeneity was observed (P=0.07<0.1; I2=33.8%). The funnel plot was symmetric and no publication bias was observed using Egger’s test (P=0.95).

Subgroup analysis (see Supplementary Table 1) represented that none of the stratifications (study design, location and study duration) could account for the heterogeneity observed in the overall analysis. Regarding long-term statin use in particular, the results did not materially change (RR, 0.93; 95% CI, 0.73–1.18). Cumulative meta-analysis showed no significant change in trend of reporting risk from positive to negative.

NMSCs

The statin use with increased NMSCs was not statistically significant no matter assuming a fixed-effect model (RR, 1.12; 95% CI, 1.05–1.20) or a random-effect model (RR, 1.03; 95% CI, 0.90–1.19). The Cochran’s Q-test had a P-value of 0.007, and I2 was 61.7%, indicating there was moderate heterogeneity within the group. The P values for the Egger’s test were 0.16, showing no evidence of publication bias.

Subgroup analysis showed that the results were not substantially changed by study design. In the sensitivity analysis, we identified the study by Stein et al (2006) and Haukka et al (2010) contributed most to the between-study variability.

RR estimates and 95% CIs are listed in Tables 2 and 3.

Table 2 Summary of adjusted RRs assessing the risk of melanoma with statin exposure
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Table 3 Summary of adjusted RRs assessing the risk of skin cancer (except melanoma) with statin exposure
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Discussion

There are debates regarding the association between statin use and skin cancer.

One view is that the immunomodulatory effects of statins may impair the host antitumor immune response by suppressing tumor-specific effector T-cell response, therefore leading to an increased cancer risk (Goldstein et al, 2009). Notably, immunosuppression represents an emerging risk factor for NMSCs. The immunomodulatory pleiotropic actions of statins resemble the immune phenotype, which predicts risk for post-transplantation NMSCs (Mausner-Fainberg et al, 2008; Carroll et al, 2010; Mascitelli and Goldstein, 2013). In addition, immunosuppressive actions of statin therapy may in part be related to increasing risk of a rare and aggressive neuroendocrine skin cancer, Merkel cell carcinoma (Kaae et al, 2010; Sahi et al, 2012).

On the contrary, in several in vitro and in vivo pre-clinical models of melanoma, statins have been presented to involve in anticancer activity (Sarrabayrouse et al, 2007; Coimbra et al, 2010; Ivanov and Hei, 2011). They may have anticancer effects through targeting on HMGCR and the mevalonate pathway, which have a role in the metabolic reprogramming of cancer (Clendening et al, 2010; Clendening and Penn, 2012).

This meta-analysis showed no evidence that statin use is associated with a substantially decreased or increased risk of skin cancer (neither melanoma nor NMSCs). The results were not significantly affected by study design, study location and long-term statin use, which reinforce our confidence in the validity of the conclusion. Our findings are in line with recent meta-analyses on the association between statin use and melanoma (Freeman et al, 2006; Bonovas et al, 2010). However, unlike in vitro and animal studies, meta-analyses do not demenstrate an effect of statins in humans, it is possible because of the inconsistent dosage and drug concentrations, some malignant cell lines are not inhibited by the same concentrations of statins achieved in humans (Freeman et al, 2006).

Moderate heterogeneity was identified in our meta-analysis, which should be considered with caution. There may be several factors contributing to the heterogeneity. The first reason is the multiple criteria for the diagnosis of skin cancer, which may introduce spectrum-of-disease bias. Second, detailed information for the type of statins was not provided, which made it hard to further investigate the potential difference between lipophilic and hydrophilic statins.

There could be several potential limitations in this meta-analysis. First, skin cancer (melanoma or NMSCs) was not the primary end point of the included RCTs; we were not able to obtain primary data regarding skin cancer diagnosis for all study participants. Second, even though the included studies had acceptable quality, detailed information of confounding factors was not provided (such as family history, skin color and sun exposure). To minimize the risk of misleading conclusions led by the lack of confounder control, we extracted adjusted RRs for different confounding factors whenever available. The third aspect deals with the varied definitions of drug exposure among eligible studies. Jacobs et al (2011) divided the participants into ‘former user’, ‘current use’ and ‘no reported use’ groups, whereas in other studies, participants were identified as statin users or non-statin users.

However, the present study has several strengths. First of all, 21 articles with 29 studies were included, reporting data of 11 787 skin cancer cases. No exclusion criteria of language, location or study quality were applied. With large numbers of incident cases, meta-analysis could provide high statistical power. Moreover, no evidence of substantial publication bias was observed. Furthermore, the findings were similar in subgroup analysis of RCTs, case–control and cohort studies, although the methodological differences of original studies may introduce potential biases. In addition, even though moderate heterogeneity was observed, summary estimates were substantially unchanged after excluding the studies introducing most to the heterogeneity.

Two aspects should be noted in future studies. The potential use of statins for skin cancer prevention, especially melanoma, and the utility of testing statins as therapy in combination with chemotherapy are needed. In addition, because of the widespread use of statins, extending follow-up periods to identify potential effects on skin cancer in the longer-term statin use might be useful.

In conclusion, the meta-analysis indicates that there is no association between statin use and skin cancer risk on the basis of the findings of RCTs, case–control and cohort studies.