Relation of statin use with non-melanoma skin cancer: Prospective results from the Women’s Health Initiative

The relationship between the use of statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) and multiple cancer types has been the focus of many studies. A recent prospective study by Wang et al. ¹ investigated the relationship between statin use and non-melanoma skin cancer (NMSC) in the large, prospective Women’s Health Initiative (WHI). NMSC includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Although usually not life-threatening, NMSC is the most common cancer in the United States (over 5.4 million cases yearly) and leads to a high economic burden. ² With the high incidence of NMSC and the 2013 American College of Cardiology/American Heart Association guidelines ³ which have increased the indications for statin use in the United States, better understanding of the relationship between statin use and NMSC is particularly important. The WHI study found that among a cohort of 118,357 women, use of any statin at baseline was associated with increased NMSC (odds ratio (OR), 1.21, 1.07–1.35). The study also found that the effect was most pronounced for lipophilic statins (OR 1.39, 1.18–1.64), including lovastatin and simvastatin.

Statins carry a photosensitivity warning, and prior clinical studies have suggested that statins may be associated with increased NMSC incidence. In the Scandinavian Simvastatin Survival Study (4S) and the Heart Protection Study (HPS) randomized controlled trials (RCTs), NMSC was found to have a higher incidence in the treatment groups.^4,5 A large meta-analysis of RCTs, cohort studies, and case–control studies on statins and all-cancer incidence also found increased NMSC risk among statin users. ⁶ Additionally, two large European studies found increased NMSC or BCC incidence associated with the use of all or particular statin types.^7,8 However, some conflicting evidence exists in literature, as other studies including meta-analyses of randomized controlled trials (RCTs) have reported no significant relationship between statin use and NMSC risk,^7,9,10 and studies have also suggested decreased NMSC risk associated with statin use.^11,12 These conflicting findings are somewhat difficult to put into context, as prospective studies and RCTs investigating this relationship have been limited.

In contrast to the findings on skin cancer and statin use, the literature on statin use and other non-cutaneous cancers has mostly reported decreased incidence^13–16 or no effect.^6,10 Additionally, several studies on cancer mortality and statin use have found protective effects, including a retrospective study of 295,925 cancer patients in Denmark ¹⁷ and a retrospective study in Finland among 31,114 patients which examined statin use and breast cancer mortality specifically. In contrast, a meta-analysis of RCTs in the Cholesterol Treatment Trialists’ (CTT) Collaboration ¹⁸ database reported no association between statin use and either cancer mortality or incidence. Nonetheless, overall the literature on statin use and non-cutaneous cancers is more suggestive of a positive relationship than statin use and NMSC, though reasons for such a difference are unclear.

Given these conflicting findings in literature, a future research priority suggested by the Wang et al. research is clarifying the biological mechanisms that may mediate statin use and increased NMSC risk and in particular if the cutaneous effects on statins differ from their non-cutaneous effects. As the use of statins continues to expand under the 2013 American College of Cardiology/American Heart Association guidelines and cancer is currently the second leading cause of death in the United States, it is crucial to understand whether or not statins actually affect cancer incidence and progression and if this effect differs depending on the type of cancer. Several biological mechanisms linking statin use and cancer have been proposed, though none are definitive.

Both protective and non-protective biological mechanisms have been suggested in relation to statin use and cancer incidence and progression. In terms of protective mechanisms, lower cholesterol levels may block cell proliferation that is essential to cancer progression. ¹⁹ Statins have also been hypothesized to halt the cell cycle, ²⁰ interfere with angiogenesis, ²¹ and affect cell adhesion and inflammation; ²² all of these mechanisms may lead to lower cancer risk. Statins are also believed to inhibit the prenylation of G-proteins which may also decrease cancer risk and progression. ²³

For NMSC specifically, statins may cause apoptosis of keratinocytes through decreasing levels of cholesterol and affecting the RAF-mitogen-activated protein kinase 1 (MEK) pathway. ²⁴ Lower cholesterol levels are also hypothesized to inhibit the Hedgehog signaling pathway which is believed to be important for progression of BCC. ²⁵ However, in terms of non-protective mechanisms, statins have been implicated in increasing pro-inflammatory cytokines and as well as regulatory T cells; these effects may lead to increased NMSC risk. ²⁶ Overall, although many biological mechanisms have been proposed, it is unclear which of these mechanisms actually affect cancer risk, and some of these proposed mechanisms may counteract the effects of other mechanisms.

The intriguing and somewhat conflicting findings on statin use and cancer in the literature point to the need for two major areas of additional research: (1) randomized controlled trials to investigate if any causal effect exists between statin use and cancer risk and (2) better understanding of the biological mechanisms that may mediate this relationship. RCTs investigating this relationship have been lacking (particularly with cancer incidence as a primary endpoint), and understanding if any causal relationship exists between statin use and cancer incidence is an important future area of investigation for not only NMSCs but also other cancer types. In particular, as the findings on NMSC and statin use appear to be more negative than non-cutaneous cancers and statin use, it is important to keep in mind that cancer is a heterogeneous group of diseases and that effects of statins on different types of cancers may differ. Elucidation of the basic science pathways affecting statins and specific cancer types is crucial to personalized treatment and education for statin users.