Statins in Lung Cancer
There is mounting evidence that COPD and lung cancer are related by much more than smoking or aero-pollutant exposure alone. Epidemiological studies dating back 30 years have suggested that the propensity to lung cancer is substantially increased in those with COPD, even after correction for smoking exposure. In both non-CT-based and CT-based studies of lung cancer, it has been shown that between 50 and 90% of lung cancer cases have features of COPD, primarily spirometry-defined COPD and/or CT-based emphysema. Using data from more recent CT screening studies has revealed that the lung cancer detection rates are four- to fivefold greater in smokers with existing COPD (or emphysema) compared with smokers with normal lungs. Genetic epidemiological studies show that genes implicated from large genome-wide association studies overlap between COPD and lung cancer, implicating receptors expressed on the bronchial epithelium and mediating smoking-related inflammatory responses. These current findings suggest that some of the pathological pathways involved in COPD (particularly inflammatory pathways mediated by NF-κB1 and STAT3 molecular signaling of inflammation (Figure 1), are relevant to both diseases implicating inflammation in their pathogenesis and providing a potential target for chemopreventive treatment. Numerous prospective studies have reported associations between elevated CRP (systemic inflammation) and mortality from cancers of the lung, breast, prostate and colon. Of these, the results are most consistent for lung cancer, in particular squamous cell and small cell cancers (i.e., exclusively smoking-related lung cancers). Based on these observations, we and others propose that it is, in part, through these pathways that genetic variation predisposes smokers to a heightened inflammatory response and susceptibility to both COPD and lung cancer (Figure 1).
Using nation-wide cancer mortality data, Nielsen et al. recently reported that statin users have a 20–30% reduction in mortality from several cancers. We note that the majority of these cancers are those associated with either smoking (lung, pharynx, esophagus, urinary) or obesity (colon, prostate, breast; see Figures 1 & 7). While Nielsen et al. suggested this finding might be secondary to cholesterol lowering, we suggest it might be secondary to the attenuation of systemic inflammation. As stated above, large prospective studies report that elevated serum CRP is associated with increased mortality from lung, breast, colon and prostate cancers, but in particular lung cancer where systemic inflammation is implicated and clearly predates the cancer. Interestingly, smoking- and obesity-related cancers are often associated with systemic inflammation and NF-κB-mediated elevation of inflammatory cytokines (e.g., IL-6, TNF-α). In regards to lung cancer, which accounts for more deaths per annum than breast, colon and prostate cancers combined, several large studies have also reported 30% or more reduction in lung cancer mortality with statin use. Moreover, in a small prospective study of smokers with COPD (also associated with systemic inflammation) statin use was associated with a 20–30% reduction in both pulmonary and extrapulmonary cancers. While statin use is consistently associated with an overall 20–30% reduction in cancer mortality for the common cancers (Figure 7), the absolute reduction in mortality attributed to lung cancer is substantial. Relative to other cancers, where cancer-specific mortality (and frequency) is much less, the absolute number of lives saved for lung cancer attributed to statin therapy is significant accounting for ≈43% of all lives saved. While the mechanism underlying this statin effect on lung cancer is unknown, a recently published study in mice showed chronic systemic inflammation induces oxidant-related DNA damage in the lung epithelium (i.e., direct evidence of a 'reverse effect') (Figure 1). Given these observations implicating systemic inflammation in lung cancer, and the likelihood that smoking-related and obesity-related cancers will remain prevalent in the coming decades, we suggest targeted statin-based chemoprevention requires urgent investigation.
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Figure 7.
Statin use and reduced risk of death from cancer (matched and adjusted analysis). In a large systematic review of statin use and cancer mortality, several cancers were found to have lower mortality in statin users compared with non-users after adjustment for confounding variables. We noted that it was cancers primarily related to smoking and obesity, where cancer risk is associated with elevations of C-reactive protein and significant reductions in mortality were found with statin therapy. Such an observation supports the hypothesis that statin-induced reduction of systemic inflammation (and/or tumor-related inflammation) might reduce mortality in specific cancers where systemic inflammation is important (e.g., lung cancer).
HR: Hazard ratio.
Data taken from [61].