An important question is whether or not statins have the potential to reduce tumor proliferation and/or volume neoadjuvantly. To help answer this question, Garwood et al32 randomized patients with a diagnosis of ductal carcinoma in situ or stage I breast cancer to a perioperative trial of high-dose (80 mg/day) or low-dose (20 mg/day) fluvastatin 3–6 weeks prior to surgery. The authors then examined the effect of this treatment on tumor proliferation (Ki-67 and MRI tumor volume), apoptosis (cleaved caspase-3), and inflammation (C-reactive protein). Fluvastatin significantly reduced the proliferation of high-grade tumors by 7.2%, and more high-grade than low-grade tumors had an increase in apoptosis (60 vs 13%). Results were significant regardless of whether the patients received the high-dose or the low-dose regimen. Fluvastatin also decreased median tumor size by 12.7%, although this finding was not significant. Additional studies are warranted to determine whether or not statins can prove an effective neoadjuvant therapy for high-grade breast cancers.

It would be ideal to have a biomarker that could predict neoadjuvant tumor response to statin therapy and help select patients who would benefit the most from it. Bjarnadottir et al analyzed statin-induced effects on tumor proliferation in association with HMG-CoA reductase (HMGCAR) expression in patients with invasive breast cancer.33 Patients were given high-dose atorvastatin (80 mg/day) for 2 weeks prior to surgery. The authors found a significant decrease (7.6%) in Ki-67 expression specifically for tumors expressing HMGCAR in the pretreatment sample. Furthermore, posttreatment Ki-67 expression was inversely correlated to posttreatment HMGCAR levels, implying that HMGCAR can be used as a predictive biomarker for statin tumor response.33

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The studies mentioned earlier strongly suggest that statins alone facilitate apoptosis in breast cancer cells. Their effectiveness in combination with other therapies, however, is yet to be explored. Koyuturk et al34 report that one of the mechanisms by which statins induce apoptosis is activation of the JNK-signaling pathway. Since inhibition of JNK activation is a major mechanism behind tumor resistance to cisplatin and vinblastine,35,36 perhaps the addition of statins to either of these drugs could help overcome any chemoresistance. Although these chemotherapies are more commonly used in the treatment of Hodgkin’s lymphoma, non-small-cell lung cancer, bladder cancer, melanoma, head and neck cancer, and cervical cancer, it would be worth examining whether or not statins can potentiate tumor response to more conventional breast cancer chemotherapies, eg, docetaxel, doxorubicin, and cyclophosphamide (TAC).


Although most of the studies discussed thus far included only patients with stage 0–III breast cancer diagnoses, work by Denoyelle et al37 and Alonso et al38 suggests a potential role for cerivastatin and lovastatin in the prevention of metastases in triple-negative breast cancer (TNBC) and sarcomatoid mammary carcinoma, respectively. The former found that in the aggressive TNBC cell line MDA-MB-231, cerivastatin inhibited the production of cholesterol precursors farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are responsible for translocation of Ras and Rho, respectively, to the cell membrane. Under normal circumstances, this final step allows the initiation of cell proliferation and migration. The introduction of cerivastatin in vitro, however, inhibited both cell proliferation and invasion through Matrigel (Becton Dickinson, Franklin Lakes, NJ, USA) and induced a loss of cell attachment in a dose-dependent manner. Alonso et al38 found in a murine animal model of F3II sarcomatoid mammary carcinoma that lovastatin treatment prolonged tumor latency, reduced tumor formation, and decreased metastatic dissemination. Given these results, studies examining the effect of statins on clinical outcomes for metastatic breast cancer patients specifically may be warranted.


A potential role for statins as a radiosensitizer for aggressive breast cancers has been suggested in both the basic science and the clinical realms. We have shown that simvastatin radiosensitizes various aggressive breast cancer subtypes in vitro – namely, IBC cell lines MDA-IBC3, Sum149, and Sum190, as well as the aggressive non-IBC TNBC cell line Sum159 – as evidenced by monolayer and mammosphere-based clonogenic assays. Furthermore, our findings were supported on clinical grounds, as statins were associated with a significant decrease in locoregional recurrence (LRR) rates for stage III IBC patients who underwent adjuvant radiotherapy. The actuarial 2- and 5-year local control rates for patients in the no-statin group were 76 and 69%, respectively, and for patients in the statin group were 92 and 85%, respectively.39

Resistance to radiation therapy resulting in LRR predicts a decreased OS.40 TN IBC and TNBC have especially high 5-year actuarial rates of local failure after radiotherapy: 11–35 and 45%, respectively.41,42 This aggressive IBC phenotype is proposed to be caused by an enriched population of stem-like cells within these tumors.43–45 Since statins have been shown to decrease normal tissue damage following radiotherapy,46–48 they may serve a dual purpose for patients with aggressive breast cancers by, 1) radiosensitizing the tumor, and 2) permitting more aggressive protocols in the hope of further reducing LRR.


Statins represent a new potential therapy to improve local control and provide a benefit for patients with breast cancer. Future studies evaluating the role of statins neoadjuvantly, in combination with chemotherapies, and as a radiosensitizer are required. It is unclear if any particular statin performs exceptionally, although the prevalence of simvastatin in these studies favors better outcomes in patients with breast cancer.


The authors report no conflicts of interest in this work.

Renae D. Van Wyhe,1,2 Omar M. Rahal,1 Wendy A. Woodward1

1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 2Baylor College of Medicine, Houston, TX, USA 


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Source:Breast Cancer: Targets and Therapy
Originally published December 1, 2017.