STATINS AND BREAST CANCER RECURRENCE AND PROGNOSIS
Clinical data suggest that statins reduce breast cancer recurrence rates when administered postdiagnostically. In one prospective study of 1,945 early-stage breast cancer survivors, initiation of statin use <3 years after diagnosis was independently associated with decreased 5-year breast cancer recurrence rates in a duration-dependent manner. It is important to note that 98% of the statins prescribed were lipophilic statins, ie, lovastatin (84.4%), simvastatin (10.9%), and atorvastatin (2.5%).12 Similarly, in a nationwide, population-based prospective study, Ahern et al found that in women diagnosed with stages I–III breast cancers, patients who took simvastatin in particular after diagnosis experienced 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up. Low outcome frequency precluded the authors from modeling recurrence associations for the exclusive use of the other lipophilic statins. After accounting for potential confounders, hydrophilic statin use was not associated with recurrence outcomes.13 Findings from Manthravadi et al’s14 meta-analysis were in agreement with those from the study by Ahern et al, namely, that a recurrence-free survival benefit was observed for lipophilic statin use only.
Even short-term statin therapy administered after diagnosis may be beneficial. In a retrospective study of 703 stage II/III breast cancer patients, Chae et al found that statin use for as little as 6 months after the initial diagnosis was independently associated with a reduced likelihood of recurrence out to 4.5 years, especially when combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Interestingly, the majority of patients in this study took atorvastatin (60.2%), followed by simvastatin (17.2%), lovastatin (10.2%), and pravastatin (7.8%), perhaps suggesting that no one statin is superior regarding breast cancer recurrence outcomes.15 This idea is supported by Boudreau et al, who, in a prospective cohort study of 4,216 women diagnosed with stage I/II breast cancer, reported similar adjusted outcomes for a second breast cancer event (SBCE) between lipophilic and hydrophilic statin users. For all statin users, the authors found a nonsignificant reduced risk of an SBCE.16 Finally, regarding recurrence, in a retrospective study with the most extensive follow-up, Sakellakis et al17 found that statin users had a longer mean relapse-free survival by ~6 years, and younger statin users (<56 years old) were observed to benefit the most by ~10 years as compared with other users (refer Table 1 for an overview of the association between statin use and risk of recurrence after multivariate analysis).
(To view a larger version of Table 1, click here.)
The effect of statins on progression-free survival (PFS), overall survival (OS), and disease-specific survival for inflammatory breast cancer (IBC), an especially aggressive subtype, was retrospectively examined. Interestingly, and contrary to most reports for other breast cancers, a longer PFS was independently observed for patients taking hydrophilic or weakly lipophilic statins after initial evaluation, ie, atorvastatin (29%), pravastatin (9%), and rosuvastatin (1%), while lipophilic statins were not associated with any outcome parameters.18 Note that atorvastatin in the latter study was classified as a weakly lipophilic statin and was thus analyzed with hydrophilic statins. Thus, specific types of statins may be more beneficial in patients with aggressive breast cancers.
STATINS AND BREAST CANCER MORTALITY
Various other studies suggest a survival benefit for breast cancer patients who take statins. Murtola et al followed a large cohort of Finnish patients for a median of 3.25 years and found that both pre- and postdiagnostic statin use in both localized and metastatic cases were associated with a decreased risk of death from breast cancer. Furthermore, this finding was dose dependent and time dependent for users taking statins prior to diagnosis. These parameters could not be adequately evaluated for postdiagnostic use due to a likely healthy adherer bias. Interestingly, when results were stratified according to statin type, hydrophilic statins had a benefit only when taken postdiagnostically and timing did not matter for lipophilic statins.19 In a population-based cohort study, Cardwell et al20evaluated postdiagnostic statin use in particular and found a significant reduction in both breast cancer and all-cause mortality for simvastatin only. No associations were found for any other type of statin. Zhong et al’s21 meta-analysis found that statins improved all-cause mortality for breast cancer patients when taken prior to diagnosis. Similarly, in Manthravadi et al’s14 recent meta-analysis of eight and six studies, statin users had an improved OS and cancer-specific survival, respectively. Conversely, a prospective Scottish cohort study found no association between statin use and all-cause or breast cancer-specific mortality. However, a weak, nonsignificant reduction in breast cancer-specific mortality was observed in patients who took simvastatin specifically at relatively any time in relation to diagnosis22 (refer Table 2 for an overview of the association between statin use and risk of breast cancer-specific death after multivariate analysis).
(To view a larger version of Table 2, click here.)
In conclusion, since a breast cancer event cannot realistically be predicted for any one patient, we should consider primarily the effect of postdiagnostic statin use on breast cancer clinical outcomes. Nonrandomized studies suggest a clear recurrence benefit for breast cancer patients taking lipophilic statins after diagnosis, although hydrophilic or weakly lipophilic statins appear to be most effective for IBC patients in particular. Evidence is less clear regarding statins and breast cancer mortality, although a role for simvastatin specifically is apparent.