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Utility of Statin Use for Inflammatory Breast Cancer Treatment

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Review of “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” from Stem Cells TM by Stuart P. Atkinson.

Inflammatory breast cancer (IBC) is an aggressive, metastasis-associated, therapy resistant, variant of breast cancer [1]. These characteristics correlate to an enrichment in cancer stem/progenitor cells which are resistant to radiation [2, 3], and may even be induced by chemotherapy [4]. Use of statins, a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, has been linked to a reduction in cancer-related mortality [5], and a reduction in the “stemness” of colorectal cancer cells [6] and breast cancer cells [7]. Now, the group of Wendy Woodward at the University of Texas MD Anderson Cancer Center, Houston, Texas, USA have studied the effect of the statin simvastatin on breast cancer cell lines in vitro and its influence in vivo in patients receiving post mastectomy radiation therapy [8].

Initial sensitization assessments using both inflammatory breast cancer (IBC) and non-inflammatory breast cancer cell (IBC) lines in monolayer- (2D) and mammosphere- (3D) growth conditions demonstrated that combined simvastatin and radiation treatment displayed differing effects on IBC and non-IBC cell lines cultured as monolayer or mammospheres. All IBC cell lines in 3D culture responded to combined therapy, with statin radiosensitizing mammosphere-initiating cells (MICs), while the non-IBC triple-negative receptor cell line (SUM159) was also affected similarly in 3D culture. Similar analyses also found that statin use radioprotected MICs of two non-IBC cell lines (MCF-7 and SKBR3).

After these radiosensitivity studies, the researchers retrospectively assessed a clinical study. The researchers analyzed 519 patients with stage III IBC who received post-mastectomy radiotherapy, with 10.2% using statins. Among the entire cohort, 23.1% experienced local or regional recurrence (LRR), however in the statin-usage group, only 11.3% patients experienced an LRR, compared with 24.5% of patients in the no statin-usage group (See Figure for the Kaplan-Meier estimate of LRR). Furthermore actuarial 3-year local recurrence-free survival (LRFS) was higher among statin users. Excitingly, multivariate analysis demonstrated an association of reduced LRR/higher LRFS with statin use, and additionally, non-triple negative breast cancer, absence of lymphatic invasion, and neoadjuvant pathological tumor response to preoperative chemotherapy.

This suggests that statin use alongside radiation therapy can reduce LRR in breast cancer, and has the potential for immediate use as it has been approved worldwide, has a safe toxicity profile, and is commercially available in generic forms. The authors do note the limits of the retrospective study; inherent biases are common in all such studies, but looking forward, randomized prospective trials should demonstrate the potential utility of statin use. However, they also note that they match preclinical findings and are therefore of interest and consideration.
References

  1. Dawood S, Merajver SD, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol 2011;22:515-523.
  2. Chen MS, Woodward WA, Behbod F, et al. Wnt/beta-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line. J Cell Sci 2007;120:468-477.
  3. Woodward WA, Chen MS, Behbod F, et al. WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci U S A 2007;104:618-623.
  4. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 2009;106:13820-13825.
  5. Nielsen SF, Nordestgaard BG, and Bojesen SE Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792-1802.
  6. Kodach LL, Jacobs RJ, Voorneveld PW, et al. Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell 'stemness' via the bone morphogenetic protein pathway. Gut 2011;60:1544-1553.
  7. Ginestier C, Monville F, Wicinski J, et al. Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target. Stem Cells 2012;30:1327-1337.
  8. 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.