Statin improves survival in patients with EGFR-TKI lung cancer: A nationwide population-based study

Abstract

Long-term use of statins has been reported to reduce the risk of death in patients with lung cancer. This study investigated the effect of statin use among patients with lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy. A nationwide, population-based case-control study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 1997 to December 31, 2012, a total of 1,707 statin and 6,828 non-statin matched lung cancer cohorts with EGFR-TKIs treatment were studied. Statin use was associated with a reduced risk of death (HR: 0.58, 95% CI: 0.54–0.62, p < 0.001). In addition, statin use was associated with a significantly longer median progression-free survival (8.3 months, 95% CI: 7.6–8.9 vs. 6.1 months, 95% CI: 6.0–6.4, p < 0.001) and median overall survival (35.5 months, 95% CI: 33.8–38.1 vs. 23.9 months, 95% CI: 23.4–24.7, p < 0.001). In conclusion, statins might potentially enhance the therapeutic effect and increase survival in patients with lung cancer receiving EGFR-TKI therapy.

Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis

“…23,26,48 Total cellular cholesterol was shown to be upregulated in gefitinib resistant cells. 18,20,27,28 Several studies have shown that elevated levels of mitochondrial cholesterol in cancer cells may be able to protect cancer cells against mitochondrial apoptosis by reducing the ability of Bax to insert into the mitochondrial membrane thus impairing MOMP and the release of cytochrome c. [29][30][31] To our knowledge, no previous studies have linked this phenomenon to EGFR TKI exposure and resistance. The cells were not under exposure to gefitinib when cholesterol was isolated, but rather they were comparing levels between the different cell lines.…”

“…EGFR TKIs have been shown to mediate their apoptotic effects via inhibition of Akt/Erk signaling, which downregulates anti-apoptotic Bcl-2 family proteins that are responsible for binding and inhibiting Bax and Bak, which once free, can cause MOMP and activate apoptotic cell death. 18,20,27,28 Several studies have shown that elevated levels of mitochondrial cholesterol in cancer cells may be able to protect cancer cells against mitochondrial apoptosis by reducing the ability of Bax to insert into the mitochondrial membrane thus impairing MOMP and the release of cytochrome c. [29][30][31] To our knowledge, no previous studies have linked this phenomenon to EGFR TKI exposure and resistance.…”

“…1,3 Numerous cellular signaling pathways have been implicated in EGFR TKI resistance. 18 It has been found that a combination treatment of EGFR TKIs and simvastatin is able to overcome T790M mediated EGFR TKI resistance through downregulation of AKT/β-catenin survival signaling. A population-based case-control study, including 1707 statin and 6828 non-statin matched lung cancer cohorts with EGFR TKI treatment, found that statin use was associated with a reduced risk of death, a significantly longer median progression-free survival, and significantly longer median overall survival.…”

“…A population-based case-control study, including 1707 statin and 6828 non-statin matched lung cancer cohorts with EGFR TKI treatment, found that statin use was associated with a reduced risk of death, a significantly longer median progression-free survival, and significantly longer median overall survival. 18 It has been found that a combination treatment of EGFR TKIs and simvastatin is able to overcome T790M mediated EGFR TKI resistance through downregulation of AKT/β-catenin survival signaling. 16 Simvastatin treatment was shown to be able to restore expression of proapoptotic protein, BIM and induce apoptotic cell death in H1975 cells which harbor the T790M EGFR mutation.…”

Antidepressant Prescription and Risk of Lung Cancer: A Nationwide Case-Control Study

“…Potential confounding medical conditions, including type 2 diabetes mellitus (T2DM), hypertension, hypercholesterolemia, pneumonia, pulmonary tuberculosis (TB), asthma, chronic obstructive pulmonary disease (COPD), coal worker pneumoconiosis, asbestosis, toxic effect of arsenic, human immunodeficiency virus (HIV), and smoking were adjusted for in the analysis. Furthermore, prescription of medications known to moderate the risk for lung cancer (e. g., aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], and statins) was controlled for in the analysis [29][30][31][32][33]. Potential confounding variables including socioeconomic status (SES) was adjusted for by using income and urbanization of living area as proxies in the model.…”