Abstract: Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are medications that have been used for decades to lower cholesterol and to prevent or treat cardiovascular diseases. Since their approval by the US Food and Drug Administration in the 1980s, other potential uses for statins have been speculated on and explored. Basic science and clinical research suggest that statins are also effective in the management of breast cancer. Specifically, in various breast cancer cell lines, statins increase apoptosis and radiosensitivity, inhibit proliferation and invasion, and decrease the metastatic dissemination of tumors. Clinical trials in breast cancer patients support these laboratory findings by demonstrating improved local control and a mortality benefit for statin users. A role for statins in the management of aggressive breast cancers with poor outcomes – namely, inflammatory breast cancer and triple-negative breast cancer – is particularly implicated. However, data exist showing that statins may actually promote invasive breast disease after long-term use and thus should be prescribed cautiously. Furthermore, a general consensus on the type of statin that should be administered, for how long, and when in relation to time of diagnosis is lacking. Given their low toxicity profile, affordability, and ease of use, consideration of statins as a therapy for breast cancer patients is imminent. In this review, we summarize current evidence regarding statins and clinical breast cancer outcomes, as well as discuss potential future studies that could shed light on this increasingly relevant topic.
Keywords: statins, HMG-CoA reductase inhibitors, breast cancer, inflammatory breast cancer, triple-negative breast cancer, locoregional recurrence
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INTRODUCTION
Excluding dermatologic cancers, breast cancer is the most frequently diagnosed cancer among US women. In 2017, invasive breast disease is expected to account for 30% of all newly diagnosed cancers in women and to cause 16% of deaths in those affected.1 The current treatment regimen for breast cancer is multidisciplinary. Depending on the stage and histology of the cancer, patients may receive a combination or all of the following modalities: surgery, radiotherapy, chemotherapy, hormonal therapy, targeted therapy, and immunotherapy. Although a comprehensive approach is often necessary in order to eradicate disease, breast cancer treatment protocols can sometimes prove too cumbersome, distressing, and even, at times, toxic for the patient to complete successfully. Treatment noncompliance or the premature discontinuation of therapy has been reported to negatively affect outcomes.2–5 Given these obstacles, as well as the high mortality rate of aggressive breast cancers, consideration of other effective therapies is thus of paramount importance.
Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are a class of lipid-lowering medications that block the conversion of HMG-CoA to mevalonic acid, which under normal circumstances ultimately yields cholesterol as a part of the mevalonate pathway. Historically, statins have been marketed and prescribed for the primary and secondary prevention of cardiovascular disease, and their current use is widespread. According to a report by the Centers for Disease Control and Prevention in 2014, 23.6 and 38.9% of women over 45 or 75 years, respectively, were taking statins.6 Due to their growing popularity over the past 2 decades, generic statin medications now cost <$12/month and represent an affordable lipid-lowering agent for individuals at risk of developing heart disease or heart disease-related complications.7 Beyond their cardiovascular effects, however, statins have been reported to have possible benefits regarding immunomodulation in autoimmune diseases and organ transplantation, induction of bone marrow stimulation, and inhibition of cancer progression.8–11 Their role in breast cancer recurrence and mortality is of particular interest. Preclinical and clinical data exist to support a beneficial role for their use in breast cancer management. However, other studies are less promising and argue against the prescription of statins for purposes not related to cardiovascular disease. Furthermore, results differ depending on the type of statin used, ie, lipophilic (simvastatin, lovastatin, and atorvastatin) vs hydrophilic (pravastatin, rosuvastatin, and fluvastatin). In the following article, we summarize current findings regarding the effect of statins on breast cancer clinical outcomes and provide insight on potential future studies needed for this important topic.
CLINCAL DATA REGARDING THE USE OF STATINS IN BREAST CANCER MANAGEMENT
Several studies suggest a role for statin therapy in breast cancer management; however, the type of statin used, when it is used with respect to time of diagnosis, duration of treatment, follow-up time, and patient cohort characteristics differ significantly in these reports. Thus, it is important to consider all the findings together.
