STATINS IN THE NEOADJUVANT SETTING
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
ROLE FOR STATINS IN INCLUDING CHEMOSENSITIVITY
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).
ROLE FOR STATINS IN PREVENTING AND MANAGING BREAST CANCER METASTASES
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.
ROLE FOR STATINS IN COMBINATION WITH RADIOTHERAPY
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
1. American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer Society; 2017.
2. Bese NS, Sut PA, Ober A. The effect of treatment interruptions in the postoperative irradiation of breast cancer. Oncology. 2005;69(3):214–223.
3. Ohri N, Rapkin BD, Guha C, Kalnicki S, Garg M. Radiation therapy noncompliance and clinical outcomes in an urban academic cancer center. Int J Radiat Oncol Biol Phys. 2016;95(2):563–570.
4. Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011;126(2):529–537.
5. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer. 2008;99(11):1763–1768.
6. Gu Q, Paulose-Ram R, Burt V, Kit B. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003–2012. NCHS Data Brief. 2014;(177):1–8.
7. Lazar LD, Pletcher MJ, Coxson PG, Bibbins-Domingo K, Goldman L. Cost-effectiveness of statin therapy for primary prevention in a low-cost statin era. Circulation. 2011;124(2):146–153.
8. Mach F. Toward a role for statins in immunomodulation. Mol Interv. 2002;2(8):478–480.
9. Mulhaupt F, Matter CM, Kwak BR, et al. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc Res. 2003;59(3):755–766.
10. Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A. Non-lipid-related effects of statins. Ann Med. 2000;32(3):164–176.
11. Hess DC, Fagan SC. Pharmacology and clinical experience with simvastatin. Expert Opin Pharmacother. 2001;2(1):153–163.
12. Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008;109(3):573–579.
13. Ahern TP, Pedersen L, Tarp M, et al. Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst. 2011;103(19):1461–1468.
14. Manthravadi S, Shrestha A, Madhusudhana S. Impact of statin use on cancer recurrence and mortality in breast cancer: a systematic review and meta-analysis. Int J Cancer. 2016;139(6):1281–1288.
15. Chae YK, Valsecchi ME, Kim J, et al. Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest. 2011;29(9):585–593.
16. Boudreau DM, Yu O, Chubak J, et al. Comparative safety of cardiovascular medication use and breast cancer outcomes among women with early stage breast cancer. Breast Cancer Res Treat. 2014;144(2):405–416.
17. Sakellakis M, Akinosoglou K, Kostaki A, Spyropoulou D, Koutras A. Statins and risk of breast cancer recurrence. Breast Cancer. 2016;8:199–205.
18. Brewer TM, Masuda H, Liu DD, et al. Statin use in primary inflammatory breast cancer: a cohort study. Br J Cancer. 2013;109(2):318–324.
19. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS One. 2014;9(10):e110231.
20. Cardwell CR, Hicks BM, Hughes C, Murray LJ. Statin use after diagnosis of breast cancer and survival: a population-based cohort study. Epidemiology. 2015;26(1):68–78.
21. Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J. Statin use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Cancer Treat Rev. 2015;41(6):554–567.
22. Mc Menamin ÚC, Murray LJ, Hughes CM, Cardwell CR. Statin use and breast cancer survival: a nationwide cohort study in Scotland. BMC Cancer. 2016;16(1):600.
23. Bonovas S, Filioussi K, Tsavaris N, Sitaras NM. Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies. J Clin Oncol. 2005;23(34):8606–8612.
24. Undela K, Srikanth V, Bansal D. Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Res Treat. 2012;135(1):261–269.
25. Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295(1):74–80.
26. Browning DRL, Martin RM. Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer. 2007;120(4):833–843.
27. Kuoppala J, Lamminpää A, Pukkala E. Statins and cancer: a systematic review and meta-analysis. Eur J Cancer. 2008;44(15):2122–2132.
28. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–1278.
29. Desai P, Lehman A, Chlebowski RT, et al. Statins and breast cancer stage and mortality in the Women’s Health Initiative. Cancer Causes Control. 2015;26(4):529–539.
30. McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI. Long-term statin use and risk of ductal and lobular breast cancer among women 55 to 74 years of age. Cancer Epidemiol Biomarkers Prev. 2013;22(9):1529–1537.
31. Arun BK, Gong Y, Liu D, et al. Phase I biomarker modulation study of atorvastatin in women at increased risk for breast cancer. Breast Cancer Res Treat. 2016;158(1):67–77.
32. Garwood ER, Kumar AS, Baehner FL, et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res Treat. 2010;119(1):137–144.
33. Bjarnadottir O, Romero Q, Bendahl PO, et al. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013;138(2):499–508.
34. Koyuturk M, Ersoz M, Altiok N. Simvastatin induces apoptosis in human breast cancer cells: p53 and estrogen receptor independent pathway requiring signalling through JNK. Cancer Lett. 2007;250(2):220–228.
35. Brozovic A, Fritz G, Christmann M, et al. Long-term activation of SAPK/JNK, p38 kinase and fas-L expression by cisplatin is attenuated in human carcinoma cells that acquired drug resistance. Int J Cancer. 2004;112(6):974–985.
36. Brantley-Finley C, Lyle CS, Du L, et al. The JNK, ERK and p53 pathways play distinct roles in apoptosis mediated by the antitumor agents vinblastine, doxorubicin, and etoposide. Biochem Pharmacol. 2003;66(3):459–469.
37. Denoyelle C, Vasse M, Körner M, et al. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis. 2001;22(8):1139–1148.
38. Alonso D, Farina H, Skilton G, Gabri M, De Lorenzo M, Gomez D. Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the mevalonate pathway of cholesterol synthesis. Breast Cancer Res Treat. 1998;50(1):83–93.
39. Lacerda L, Reddy JP, Liu D, et al. Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl Med. 2014;3(7):849–856.
40. Abe O, Abe R, Enomoto K, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087–2106.
41. Panoff J, Hurley J, Takita C, et al. Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation. Breast Cancer Res Treat. 2011;128(3):899–906.
42. Meyers MO, Klauber-Demore N, Ollila DW, et al. Impact of breast cancer molecular subtypes on locoregional recurrence in patients treated with neoadjuvant chemotherapy for locally advanced breast cancer. Ann Surg Oncol. 2011;18(10):2851–2857.
43. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res. 2010;16(1):45–55.
44. Rosenthal DT, Zhang J, Bao L, et al. RhoC impacts the metastatic potential and abundance of breast cancer stem cells. PLoS One. 2012;7(7):e40979.
45. Xiao Y, Ye Y, Yearsley K, Jones S, Barsky SH. The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype. Am J Pathol. 2008;173(2):561–574.
46. Ostrau C, Hülsenbeck J, Herzog M, et al. Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo. Radiother Oncol. 2009;92(3):492–499.
47. Wang J, Boerma M, Fu Q, Kulkarni A, Fink LM, Hauer-Jensen M. Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism. Int J Radiat Oncol Biol Phys. 2007;68(5):1483–1490.
48. Haydont V, Bourgier C, Pocard M, et al. Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats. Clin Cancer Res. 2007;13(18):5331–5340.
Source:Breast Cancer: Targets and Therapy
Originally published December 1, 2017.