Fluvastatin has biologic effects on stage 0 and 1 breast cancer.

Abstract

#4122 Introduction: Statins are safe, reduce cardiovascular risk, and impact pathways critical to cancer progression. We and others have shown lipophilic statins cause apoptosis and growth suppression in vitro and in vivo, and though epidemiologic data are mixed, statin effect appears most evident in estrogen receptor (ER) negative or grade 3 disease. To look for a direct biologic effect of lipophilic statins, we conducted a perioperative pilot window trial in women with breast cancer (BC).
 Methods: 40 subjects with stage 0,1 BC were randomized to high dose (80mg/day) or low dose (20mg/day) fluvastatin for 3-6 weeks prior to surgery. Paired tissue (core biopsy and surgical specimen), peripheral blood and MRI were obtained. Primary endpoint was Ki-67 (proliferation) change. Secondary endpoints included cleaved caspase-3 (CC3, apoptosis), longest diameter (LD) by MRI, and C-reactive protein (CRP) change. Subgroup analyses was planned by grade (3 vs. 1,2), statin dose; and ER status. Immunohistochemistry (IHC) on paraffin tissue used standard streptavidin biotin methods. A single breast pathologist reviewed all slides; a single radiologist read all MRIs, both blinded to timepoint.
 Results: Median serum cholesterol decreased by 16% (-23% and -12% for high and low dose, respectively p=0.012), indicating drug effect and compliance. 29 patients had sufficient tumor for paired IHC, 14 and 15 were grade 3 and 1,2, and 10 and 19 were ER - and +, respectively. In grade 3 (73% of which were ER-) vs. 1,2 tumors, there was a significant decrease in Ki-67, -7.2% (interquartile range (IQR) -13.4%, 0% ) vs. -0.3% (IQR -3%, .8%), respectively, p=0.04. CC3 (apoptosis) increased, 60% vs. 13% for grade 3 vs. 1,2 tumors, respectively, p=0.015. ER- and ER+ cases had a similar reduction in Ki67 with a median drop of 2% (IQR -13.4%, 1%) and 1.2% (IQR -6.6%,0.8%), respectively, p=0.56. While CC3 was increased in ER- vs. + (55% vs. 29%), the difference was not statistically significant. There was no dose dependent effect on Ki-67or CC3.There was no evidence of Ki67 or CC3 change when all grades were analyzed together (median drop 1.2%) and no change in CRP. Of 14 subjects with paired MRIs, 4 grade 3 cases showed a significant decrease in LD, marked ductal dilatation and increased necrosis.with statin exposure.
 Conclusions: A lipophilic statin, fluvastatin, reduced cholesterol and had measurable biologic changes (reduced proliferation, size and increased apoptosis) in stage 0,1 BC after only 3-6 weeks of exposure, specifically in the grade 3 subset. Results support the study of statins for chemoprevention for women at risk for or with stage 0 grade 3 BC, where new agents are needed. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4122.

Cytotoxic evaluation of fluvastatin and rosuvastatin and effect of fluvastatin in the hela cell cycle

“…properties such as antiviral (Bader et al, 2008;Bader and Korba, 2010;Jameson et al, 2010;Milazzo et al, 2010) and antitumor activities (Takahashi et al, 2006;Takahashi and Nishibori, 2007;Garwood et al, 2010), however the antitumor molecular mechanisms by which the statin block cancer cell growth are poorly understood (Ghosh-Choudhury et al, 2010), and there are emerging interests to explore the anticancer potentials of HMGCoA reductase inhibitors in the clinical setting, particularly in tumor sites sensitive to these agents in vitro (Chan et al, 2003), some mechanism proposes for anticancer activities are apoptotic inducer, antiangiogenic and antimetastatic. These properties are associates with the inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway (Slawinska and KandeferSzerszen, 2008 …”

Cytotoxic evaluation of fluvastatin and rosuvastatin and effect of fluvastatin in the hela cell cycle

“…Takahashi and Nishibori, 2007;Garwood et al, 2010), however the antitumor molecular mechanisms by which the statin block cancer cell growth are poorly understood (Ghosh-Choudhury et al, 2010), and there are emerging interests to explore the anticancer potentials of HMGCoA reductase inhibitors in the clinical setting, particularly in tumor sites sensitive to these agents in vitro (Chan et al, 2003), some mechanism proposes for anticancer activities are apoptotic inducer, antiangiogenic and antimetastatic. These properties are associates with the inhibition of the synthesis of isoprenoid intermediates of the mevalonate pathway (Sławińska and KandeferSzerszeń, 2008).…”