Statin use and breast cancer survival: A Swedish nationwide study

Background A sizeable body of evidence suggests that statins can cease breast cancer progression and prevent breast cancer recurrence. The latest studies have, however, not been supportive of such clinically beneficial effects. These discrepancies may be explained by insufficient power. This considerably sized study investigates the association between both pre- and post-diagnostic statin use and breast cancer outcome. Methods A Swedish nation-wide retrospective cohort study of 20,559 Swedish women diagnosed with breast cancer (July 1st, 2005 through 2008). Dispensed statin medication was identified through the Swedish Prescription Registry. Breast cancer related death information was obtained from the national cause-of-death registry until December 31st, 2012. Cox regression models yielded hazard ratios (HR) and 95% confidence intervals (CI) regarding associations between statin use and breast cancer-specific and overall mortality. Results During follow-up, a total of 4,678 patients died, of which 2,669 were considered breast cancer related deaths. Compared to non- or irregular use, regular pre-diagnostic statin use was associated with lower risk of breast cancer related deaths (HR=0.77; 95% CI 0.63–0.95, P=0.014). Similarly, post-diagnostic statin use compared to non-use was associated with lower risk of breast cancer related deaths (HR=0.83; 95% CI 0.75–0.93, P=0.001). Conclusion This study evidently supports the notion that statin use is protective regarding breast cancer related mortality in agreement with previous Scandinavian studies, although less so with studies in other populations. These disparities should be further investigated to pave the way for future clinical trials investigating the role of statins in breast cancer.


Introduction
Breast cancer tends to occur in older women with a median age at diagnosis of 60 years in developed countries. Consequently, many breast cancer patients may be treated for both preand post-diagnostic comorbidities. Frequently prescribed drugs are statins, which are cholesterol-lowering HMG-CoA reductase inhibitors used for prevention of cardiovascular diseases. In Sweden, around 20% of the adult female population is currently prescribed a statin according to The National Board of Health and Welfare of Sweden (www.socialstyrelsen.se). Statins block the rate-limiting step in the mevalonate pathway by inhibiting HMG-CoA reductase, predominantly in hepatocytes 1 . The reduction in intracellular cholesterol levels in the liver induces up-regulation of the low-densitylipoprotein receptor resulting in lower levels of circulating cholesterol. Beyond cholesterol metabolism, the mevalonate pathway is essential for tumor promoting effects of the oncogene p53 2 . Additionally, isoprenoid production plays a fundamental role in cell growth regulation 3 . Recent observational studies have reported an inverse association between pre-diagnostic statin use and risk of breast cancer-related death 4,5 . These findings have, however, been replicated to a lesser degree in studies performed outside of Scandinavia 6, 7 A recent systematic review summarized relative risks of statin use with breast cancer recurrence 8 .
Given the epidemiological findings from other Scandinavian populations, we hypothesized that statins may also have anticancer effects and therefore reduce cancer related mortality in a Swedish population. In this nationwide study, we investigated breast cancer related and allcause mortality among breast cancer patients according to statin use prior to and/or following their breast cancer diagnosis.

Study population
All breast cancer cases were identified through the Swedish Cancer Registry, which has a high level of completeness and is considered to be of good quality as approximately 99% of the cases have been morphologically verified. Incident breast cancer cases were identified in the registry using the code ICD7=170* (according to the International Classification of Diseases). Men were excluded from this study given the low incidence of male breast cancer.
Breast cancer patients <40 years of age at diagnosis were excluded from the analyses since this age group is unlikely to receive statins, and if so, were considered as being in a certain high-risk group (such as familial hypercholesterolemia Information on TNM-stage was retrieved from the Swedish Cancer Registry summarizing breast cancer into stages 0-IV according to the international staging system. To account for missing information regarding stage, a separate missing factor level was introduced. Censoring would occur in case of death due to any cause other than breast cancer prior to this date. Ethical permission was obtained from The Regional Ethical Review Board in Lund, Sweden (Dnr 2013/787).

Statin use
Statin use was obtained from the Swedish Prescription Registry. Patients were classified as exposed to statins if they had at least one statin prescription logged in their pharmaceutical record with an Anatomic Therapeutic Chemical code (ATC code) beginning with "C10AA".
Consequently, women prescribed a statin at least once were classified as statin-users, whereas others were assumed to be unexposed to statins and therefore classified as non-users.
Three types of statin-users were defined: 1) regular, pre-diagnostic statin users, 2) irregular, pre-diagnostic statin users, and 3) post-diagnostic statin users. The regular pre-diagnostic users were defined as women with a statin prescription within six months before their breast cancer diagnosis along with another prescription during the two years prior to the diagnosis.
The irregular statin users were defined as statin users not fulfilling the regular-user criteria

Statistical analyses
The main purpose was to compare mortality, both breast cancer related and overall deaths, between statin and non-statin users. Additionally, the impact of statin dose was assessed.

To make different statin doses comparable across the various statins, the World Health
Organization-recommended daily dose definition was applied 9 , and a defined daily dose covariates was used in the analysis of post diagnostic use. The latter approach made it possible for a subject to provide data both as a non-and as statin user. All multivariable standard Cox regression analyses (time dependent excluded) were adjusted for age at diagnosis, breast cancer stage (0-IV), and diabetes diagnosed prior to breast cancer diagnosis.
Pre-diagnostic statin usage and mortality were analyzed using two different approaches: 1.) Evaluating the impact of regular usage compared to non-usage and/or 2.) Evaluating the effects of usage rate. In this method, survival time was measured in years since diagnosis. In the second type of analysis, a Cox proportional hazards model with time varying covariates (Cox regression with late entry) was used to allow for medication changes along the way and to assess the impact of cumulative doses. In this case, the time scale was age. In the analysis of the effects of cumulative number of statin prescriptions, a Cox regression with time and varying covariates was employed after log transformation of the number of prescriptions plus one. A sensitivity analysis addressed exposure lag-time to control for potential protopathic bias 11 . One year was decided as lag-time based on our calculations lagging exposure, or rather set exposure less than a certain amount equal to zero, not with respect to time, but with respect to cumulative dose. The results suggest that the effect rises to a plateau at one year (Supplemental Figure 1). We also calculated the effect of a varying lag-time (Supplemental Figure 2). However, the follow-up in our study cannot exceed eight years, so that defines the range. As may be expected the hazard ratio decreased as the lag increased. Using no lag will likely yield a conservative estimate according to this analysis. This agrees with the intuition, since time periods where the drug may not yet have had an effect still counts in the calculation, when no lag is applied.
All statistical analyses were performed using R version 3.2.1 (R Core Team, 2015). Twotailed P-values were used.

Results
This nationwide study included 20,559 Swedish women diagnosed with breast cancer after 40  Table 2). In this entire study cohort, 2,518 patients were prescribed a statin before their breast cancer diagnosis. For analyses of regular use and prognosis, the cohort of women with more than two years of follow-up were used (N=8,809), and among these 1,092 were regular statin users (Table 1). Simvastatin was the most frequently prescribed statin accounting for 82% (among the 17,804 patients considered for pre-diagnostic statin use) of all recorded statin prescriptions followed by pravastatin, atorvastatin, rosuvastatin, and fluvastatin. The numbers for post-diagnostic use similarly showed that simvastatin was the most frequently prescribed statin (93%) followed by pravastatin, rosuvastatin, lovastatin, and atorvastatin.
When comparing use of pre-and post-diagnostic statins, the majority of pre-diagnostic statin users would expectedly also be post-diagnostic statin users (N=2,503/2,739, 91.3%). In addition, a substantial numbers of the non-pre-diagnostic statin users would become users of statins in the post-diagnostic setting (N=2,082/17,801, 11.7%).

Statin use and breast cancer related mortality
Regular pre-diagnostic statin use  Table 3.

Post-diagnostic statin use
Statin use following breast cancer diagnosis was associated with lower risks of breast cancer related deaths compared to non-users (HR=0.83; 95%CI 0.75-0.93, P=0.001), as shown in Table 4. A sensitivity analysis considering one-year lag time showed a similar association (HR=0.94; 95%CI 0.92-0.96, P<0.001).

Pre-diagnostic statin use
All-cause mortality according to pre-diagnostic statin use provided results similar to breast cancer related mortality with a lower risk of death among regular statin users compared to non-regular users (HR=0.76; 95%CI 0.66-0.88, P<0.001) as shown in Table 3.  Table 3.

Post-diagnostic statin use
All-cause mortality among the post-diagnostic statin user was similar to breast cancer related mortality with a lower risk of overall death among statin users compared to non-regular statin users (HR=0.89; 95% CI 0.82-0.96, P=0.003) as shown in Table 4. Similarly, daily statin use was associated with improved overall survival (HR=0.96; 95% CI 0.95-0.97, P<0.001).
These associations held true for both lipophilic and hydrophilic statin use as shown in Table   4. A sensitivity analysis considering one-year lag time strengthened the association (HR=0.95; 95%CI 0.93-0.96, P<0.001).

Discussion
This large-scaled nationwide Swedish study demonstrates that the use of cholesterol-lowering statins is associated with lower risk of breast cancer related and overall deaths among women diagnosed with breast cancer, irrespective of whether statins were used pre-or post-diagnosis.
These results confirm previously presented studies based on Scandinavian cohorts 4,5,9 although the results have been less evident in studies from England 12 , Ireland 7 , and Scotland 6 . In line with our results, a recent comprehensive meta-analysis addressing statin use and breast cancer survival demonstrated significant survival benefits among statin users, both in terms of overall survival and disease-specific survival, which was true for both pre-and postdiagnosis statin use 13 . Another systematic review on statin use and cancer mortality, including breast cancer mortality, showed consistent findings 14 . In summary, consistent observational evidence support a reduced risk of breast cancer recurrence/mortality among statin users 4,5,[15][16][17][18] , which have paved the way for multiple ongoing clinical trials, which are investigating the role of statins in breast cancer (such as #NCT02483871, #NCT02958852, #NCT01988571). Nevertheless, treatment predictive biomarkers enabling a more targeted approach and selection of patients likely to respond to statin treatment is required 19  In conclusion, statin users, particularly simvastatin users, had a lower risk of breast cancer related deaths compared to non-users in this nationwide cohort of Swedish women with breast cancer diagnosed after the age of 40. Considering previous evidence from functional-, clinical-and epidemiological studies, this study adds evidence to the notion that statins possess beneficial effects against breast cancer progression along with its cardiovascular benefits. Above all, there is a need for confirmative results based on clinical trials before statin treatment can be recommended for patients newly diagnosed with breast cancer.

Financial Support
This work was supported by grants attracted by H. Olsson from The European Council in addition to grants received from the Swedish Research Council and the Swedish Cancer Foundation by S. Borgquist.