Background: Almost one-third of breast cancers (BC) will not be influenced by hormonal interventions because of the absence of ER expression. Thus, there is an urgent need to confirm in the clinical setting the potential efficacy of new compounds in contrasting hormone non-responsive BC, which are often marked by higher biological aggressiveness, early onset and worse prognosis. Over expression of COX-2 and HMG-CoA pathway seems to be involved in breast carcinogenesis and several studies have shown the ability of NSAIDs and statins to reduce the incidence of BC.

Material and Methods: We conducted a randomized phase II, double blind, placebo controlled trial with simvastatin (20 mg/day) and nimesulide (100 mg/day) for 1 year in 150 high risk women for ER negative BC in a 1:1:1 fashion. Participants were treated for one year and followed-up for an additional year. The primary endpoint was the change in prevalence of atypical cells obtained by ductal lavage or ultrasound guided fine needle aspirate and cellular proliferation (measured by Ki-67), while the secondary objective was to analyze the efficacy of these drugs in modifying the levels of circulating inflammatory and cardiovascular risk biomarkers. Circulating concentrations of high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, antithrombin III and fibrinogen were measured on morning fasting blood samples drawn at baseline and after 12 and 24 months.

Results: Analysis of the primary endpoint is ongoing and here we present results on circulating biomarkers. After 12 months of treatment, simvastatin was associated to a statistically significant mean decrease of hsCRP compared to the placebo arm (0,90 mg/L vs 3,57 mg/L; p=0.008), while an attenuated effect of nimesulide was observed (1.61 mg/L vs 3.57 mg/L; p=0.077). As expected, simvastatin significantly decreased LDL and total cholesterol levels with respect to placebo (89.1 vs 130 mg/dL and 176.8 vs 218 mg/dL respectively; both p<0.0001). Interestingly, after 1 year of treatment interruption, at 24 months from baseline, hsCRP serum levels were significantly lower with both simvastatin (p = 0.012) and nimesulide (p = 0.017) as compared to placebo. We did not observe a significant change in mean concentrations of triglycerides, antithrombin III and fibrinogen during treatment and follow-up.

Conclusions: Our findings demonstrate a favourable anti-inflammatory effect of both agents on circulating levels of hsCRP, although simvastatin achieved a greater decrease. These results will be correlated with the main endpoint to further assess the potential role of simvastatin and nimesulide in breast carcinogenesis and the potential use of hsCRP as a surrogate endpoint biomarker.

Citation Format: Valentina Aristarco, Davide Radice, Harriet Joahnsson, Debora Macis, Serena Mora, Massimiliano Cazzaniga, Laura Cortesi, Isabella Marchi, Maria Teresa Sandri, Bernardo Bonanni. Effect of Simvastatin and Nimesulide on inflammation and cardiovascular risk biomarkers in a phase II breast cancer prevention trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2013-161