Statins Use and Risk of Breast Cancer Recurrence and Death: A Systematic Review and Meta-Analysis of Observational Studies.

PURPOSE
Statins are widely prescribed drugs for lowering cholesterol. Some studies have suggested that statins can prevent breast cancer recurrence and reduce mortality rate. However they are not conclusive. Present systematic review and meta-analysis of published cohort studies was conducted to determine the effects of statins intake and risk of breast cancer recurrence and mortality rate.


METHODS
Online databases (PubMed, Embase, Scopus, EBSCO and Cochrane Collaboration) were searched through October 2014. Pooled relative risks and 95 % confidence intervals were calculated with random-effects.


RESULTS
A total of 8 cohort studies (4 for recurrence 2 for mortality and 2 for both) involving 124669 participants with breast cancer were eligible. Our results suggest a significant reduction in recurrence (OR= 0.79. I2= 38%) and death (OR = 0.84, I2 = 8.58 %) among statin users.


CONCLUSION
Our meta-analysis suggests that breast cancer patients will benefit from statin intake, however from these cohorts we are unable to differentiate between various statins in terms of effectiveness and duration of use. We highly propose conducting randomized clinical trials.


INTRODUCTION
Breast cancer is one of the most invasive cancers and a leading cause of mortality in women (1). Despite the discovery of new adjuvant treatments, breast cancer recurrence is not an uncommon problem in these patients. Therefore, finding new strategies to overcome cancer recurrence seem reasonable (2). Statins are well-known lipid-lowering drugs which can prevent cardiovascular diseases (3). They are well-tolerated and serious side effects are rare (4). Statins also show some promising effects on inhibiting mammary tumor growth and exhibit possible anti-carcinogenic properties (5). Previous studies in triple negative breast cancer cell lines have shown that statins prevent DNA binding of nuclear factor kappa beta at the phosphate and tensin homolog promoter (6). Statins also block the mevalonate pathway and deplete cholesterol precursors such as farnesyl pyrophosphate (FPP) and geranyl pyrophosphate (GPP), which decrease the ability of cells to perform post-translational protein prenylation, resulting in blocking the function of proteins in breast cancer cell lines (7,8). Despite the preclinical results, no prospective randomized control trials (RCTs) have evaluated the effects of statins on reduction of breast cancer risk. However, several studies have investigated the association between statin use and risk of breast cancer. Two meta-analyses have been conducted to evaluate the combined results of heterogeneous populations. The authors in both studies found no association between statin use and the risk of breast cancer, however there were some limitations in these studies especially among high risk populations (9). Subsequently, we propose that exposure to statin 1 year before tumor detection may influence the cancer phenotype and decrease the grade and stage _________________________________________ of tumors in comparison with the total number of tumors (10). Statins also target histone deacetylase (11). Drugs which inhibit histone deacetylation have been approved for lymphoma and some other cancer treatment except for breast cancer (12). Based on these evidences some other studies have hypothesized that patients with already diagnosed breast cancer may benefit from statin administration. However, these studies have yielded mixed results, some indicate significant reduction in secondary breast cancer recurrence and mortality (2,13,14) while others have found non-meaningful effects (14, [15][16][17]. We aimed to conduct a systematic review and meta-analysis of these studies to summarize the evidence between statin use and risk of secondary breast cancer and mortality. We also tried to evaluate whether these associations varied by study design, type of statin use and breast cancer site, which may help resolve inconsistencies among the results from the different studies.

Material and methods
The present study was conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines for reviews of observational studies (18). The following information was abstracted from each study: study design, country of participants, definition and numbers of cases and control subjects, frequency of recurrence cases, and number of cancer-specific motility. All studies taken into account presented preferably estimated HRs corrected for potential confounders.

STATISTICAL ANALYSIS
Heterogeneity was assessed using the Cochran Q and I 2 statistics. For the Q statistic, a P value<0.10 was considered statistically significant for heterogeneity; for the I 2 statistic, heterogeneity was interpreted as moderate (I 2 : 50%-75%), or high (I 2 >75%) (19). The overall analysis including all eligible studies was performed to assess the association between statin use and breast cancer recurrence and mortality rate. Pooled HR estimates and corresponding 95% CIs were calculated using the inverse variance method. In the absence of a statistically significant heterogeneity (I 2 : 0%-25%), fixed model was used. To test the robustness of association and characterize possible sources of statistical heterogeneity, sensitivity analysis was carried out by excluding studies one-by-one and by analyzing the homogeneity and effect size for the remaining studies. Publication bias was assessed using Begg and Mazumdar adjusted rank correlation test and the Egger regression asymmetry test (20,21). All Pvalues were two-tailed. For all tests, a probability level of <0.05 was considered statistically significant. All calculations and graphs were carried out using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ). Figure.1 shows the process of study selection for the meta-analysis. Twenty one relevant references were initially identified during our search. After screening titles and abstracts, 8 were selected for full-text review. Table 1 summarizes the characteristics of qualified studies in this meta-analysis. The 8 studies, involving 124669 participants with breast cancer, were published up until October 2014. Among the study participants, 25927 were statin users. There were 38071 cases of breast cancer recurrences or death, determined.

Breast Cancer Recurrence rate and the use of statins
On meta-analysis of all studies assessing the risk of recurrence, the use of statins was associated with a statistically significant 21% reduction in recurrence rate (unadjusted OR= 0.792; 95% CI: 0.735-0.853) ( Figure.2). There was no considerable heterogeneity observed across studies (Cochran's Q-test, P < 0.061; I 2 = 38%). To assess whether any one study had a dominant effect on the meta-analytic HR, each study was excluded and its effect on the main summary estimate and Cochran's Q-test P value for heterogeneity was evaluated. No study significantly affected the summary estimate. There was no evidence of significant publication bias, both quantitatively (Egger's regression test, P = 0.084) and on visual inspection of the funnel plot ( Figure 3).

Breast cancer-specific mortality and the use of statins
On meta-analysis of all studies assessing breast cancer-specific mortality, the use of statins was associated with a statistically significant 16% reduction in cancer-specific mortality rate (unadjusted OR= 0.849; 95% CI: 0.827-0.870) ( Figure.4). There was no considerable heterogeneity observed across studies (Cochran's Q-test, P =0.360; I 2 =8.58%). To assess whether any one study had a dominant effect on the meta-analytic HR, each study was excluded and its effect on the main summary estimate and Cochran's Q-test P value for heterogeneity was evaluated. No study significantly affected the summary estimate. There was no evidence of significant publication bias, both quantitatively (Egger's regression test, P = 0.464) and on visual inspection of the funnel plot ( Figure 5).

DISCUSSION
Despite some authors' belief that the use of statins may not have any significant protective effects on breast cancer recurrence (17), findings from our systematic review and meta--analysis propose that statin intake will significantly decrease the risk of recurrence (OR= 0.79) and rate of mortality (OR=0.84). To the best of our knowledge this is the first meta-analysis on statin use and breast cancer recurrence and mortality. We analyzed 6 and 4 cohort studies (2 for both mortality and death) for detection of statins effect on recurrence and mortality rate, respectively.
High doses of fluvastatin as neo-adjuvants significantly decreases breast cancer proliferation (22), (23). As another possible mechanism, it is proposed that simvastatin stimulates production of a variant of the p53 transcription factor and reduces bone metastases (24). Statins inhibit breast cancer cell growth in vitro which may demonstrate the biological plausibility to statins' preventive effect on breast cancer progression (25). A pre-surgical clinical trial reported antiproliferative effect of atorvastatin on invasive breast cancer at 80 mg/day dose for two weeks (26). This effect was shown only in tumors expressing HMGCR (3-Hydroxy-3-Methylglutaryl-CoA Reductase), proposing that statins target this enzyme in breast cancer tissue. They also decreased estrone sulfate level which is another possible mechanism for the anti-cancer action (27).
Mutant p53 up-regulates the mevalonate pathway which induces an invasive phenotype. Adding simvastatin to the culture medium reverses this phenotype to normal morphology, however the malignant phenotype persist when both simvastatin and geranylgeranylpyrophosphate (GGPP) are present in the medium (28).
The initial report of association between postdiagnosis statin use and risk of breast cancer came from a large US cohort. The mean duration of statin use was 1.96, and HR of 0.67, 0.8 and 0.38 were obtained from less than 100 days, between 100 days and two years, and more than 2 years of treatment respectively. In this study the patients mainly used lipophilic statin (16).
A second report was obtained from a cohort study of Danish breast cancer patients. In this study patients were followed up for 6.8 years after diagnosis. Overall HR was 0.83, but 0.7 for simvastatin alone. The authors concluded that while simvastatin had significant effects, hydrophilic statins had no effects(13).
In a cohort of 703 breast cancer patients, it had been showed that use of statins for more than 6 months significantly reduced the risk of cancer recurrence. The study associated usage of statins with a lower recurrence rate (adjusted HR = 0·48) (2).
Mortality rate was assessed among patients 40 years and older who had used statin, in a cohort of Danish population. Authors evaluated risk with daily doses of statins and found HR of 0.83, 0.87 and 0.87 for 0.01-0.75, 0.75-1.5 and higher than 1.5 daily, respectively (15).
In 2013, one study evaluated the effect of statins on recurrence and mortality in primary inflammatory breast cancer, a rare form of breast cancer. This study also supports the protective role of lipophilic statins on inflammatory breast cancer (29).
Another large study on a prospective cohort of 3,024 non-metastatic breast cancer was conducted recently, which showed non-significant reduction in cancer recurrence with HR of 0.83 for stage I and III and 0.84 for menopausal women, however the authors also found an overall increase in the risk of cancer mortality rate. The authors in this study did not support the role of statins in the reduction of breast cancer recurrence and mortality rate (17).
In a U.S. prospective cohort study of 4,216 women with breast cancer, use of lipophilic statins decreased the rate of breast cancer recurrence (HR = 0·76), however hydrophilic statins had no effect (HR = 1·01) (14).
The most recent cohort from Finland (31236 participants) showed decreased risk of mortality in patients taking statin post and pre diagnostic (HR=0.46 and HR= 0.54). Authors believed that decrease due to post-diagnostic statin use was likely affected by healthy adherer bias and was not clearly dose-dependent (30).
Although these results propose that statins, especially simvastatin, can reduce cancer recurrence, it should be mentioned that perhaps other patient characteristics and not lipid-lowering medication is responsible for the underlying mechanism for the observed results. Also increased levels of cholesterol might reduce the risk of metastases (31). In a recent meta-analysis, the authors have shown the beneficial effects of statin in prevention of cancer death especially in colon cancer patients. The previous study did not calculate the effect of statin use on breast cancer recurrence risk (32). Well-designed studies considering statins consumption, as well as cholesterol levels, are required in order to clarify the specific role of statins in the chemoprevention of breast cancer recurrence.
In conclusion, our analysis of the available data suggests that statin use results in 21% reduction in breast cancer recurrence and 16% reduction in mortality rate. This provides a justification for launching further randomized clinical trials.