Combination of Simvastatin and FAC Improves Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

Abstract

Purpose The efficacy of neoadjuvant chemotherapy for locally advanced breast cancer (LABC) is limited due to drug resistance and cardiotoxic effects. Preclinical studies have shown that statin induces apoptosis and decreases breast cancer cell growth. This study aims to evaluate the role of statin in combination with fluorouracil, adriamycin, and cyclophosphamide (FAC) therapy in LABC patients.Materials and Methods We undertook a randomized, double-blinded, placebo-controlled trial in two centers of Indonesia. Patients were randomly assigned to FAC plus simvastatin (40 mg/day orally) or FAC plus placebo (40 mg/day) for 21 days. The FAC regimen was repeated every 3 weeks. We evaluated the clinical response, pathological response, and toxicities.Results The objective response rate (ORR) for FAC plus simvastatin was 90% (95% confidence interval [CI], 0.99 to 1.67) by per-protocol analysis. No complete responses (CR) were recorded, but there were 48 partial responses. No significant difference was observed between the two groups with the ORR (p=0.103). The pathological CR rate was 6.25% (2 in simvastatin group and 1 in placebo group). Adverse events in both arms were generally mild, mainly consisted of myotoxicity. Human epidermal growth factor receptor 2 (HER2) expression was a factor related to the success of therapeutic response (odds ratio, 4.2; 95% CI, 1.121 to 15.731; p=0.033).Conclusion This study suggests that simvastatin combined with FAC shows improvements in ORR and pathological response in patients with LABC. Although no statistically significant difference was documented, there was a trend for better activity and tolerability. The addition of 40 mg simvastatin may improve the efficacy of FAC in LABC patients with HER2 overexpression.

Statins: a repurposed drug to fight cancer

“…Statins have also been shown exert antitumor effects by enhancing the response of combination therapy. Recently, Yulian et al found that simvastatin combined with FAC (Fluorouracil, adriamycin and cyclophosphamide) improved the response to neoadjuvant chemotherapy in patients with advanced local breast cancer [49]. Cantini et al found that high-intensity statins enhanced the clinical activity of programmed death receptor-1 (PD-1) inhibitors in patients with malignant pleural mesothelioma and advanced non-small cell lung cancer [69].…”

Simvastatin in the Treatment of Colorectal Cancer: A Review

“…Simvastatin can slow down the proliferation of cancer stem cells. Possibly, it is related to the fact that simvastatin inhibits the activity of DNMT, which in turn affects the two promitogenic signaling pathways PI3K/AKT and MEK/ERK in colorectal cancer [ 24 ]. However, some scholars believe that simvastatin, as an inhibitor of DNMT, can demethylate the promoter region of the bone morphogenetic protein (BMP), tissue inhibitor of metalloproteinase (TIMP3), and HIC-1 gene and can reactivate BMP to inhibit tumor stem cells and resensitize colorectal cancer cells to 5-Fu treatment [ 25 ].…”

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer

“…A trend for better activity and tolerability is observed in 66 patients with locally advanced breast cancer; however, fluorouracil, adriamycin, and cyclophosphamide (FAC) plus simvastatin did not statistically improve ORR and OS compared with FAC alone. Human epidermal growth factor receptor-related 2 (HER2) expression is the factor related to therapeutic response in that study [120]. However, the study populations were not stratified with molecular markers.…”