Metformin in neoadjuvant systemic therapy of breast cancer patients with metabolic syndrome

Abstract

Received 2018-02-09 Accepted 2018-06-23 INTRODUCTION Breast cancer (BC) is one of the most spread cancers among women worldwide. In 2012 breast cancer incidence was 43.3 per 100 000 in female population, with 1 676 633 new registered cases along with 521 907 deaths from this disease in the world. This accounts for 25.2% of cases and 14.7% of deaths among all cancers in women (1). According to the National Cancer Registry of Ukraine, in 2012 there were 17407 new breast cancer cases and 7727 deaths. This accounts for 19.6% of cases and 20.2% of deaths among all cancers in women in Ukraine. In Ukraine, breast cancer incidence increased from 38.6 cases per 100 000 in female population in 2006 to 41.4 cases in 2011. However, the death rate from breast cancer seems to have a tendency to decrease from 7826 cases in 2006 to 7727 in 2011, or 20.3% (2006) and 20.2% (2011) of the death cases among all cancers in the female population (2, 3). In 2005, in connection with the overall mortality rate the International Diabetes Federation (IDF) defined metabolic syndrome (MS) as one of the main problems of modern medicine. Prevalence of MS has reached pandemic proportions. In developed countries MS was found in 25-35% of the population and in all age groups. This value increased with age and reached 42-43.5% in the age group above 60 years old (4). A number of epidemiological, experimental and clinical studies proved that the metabolic abnormalities, associated with MS, increase the risk of breast cancer and worsen its prognosis. For example, in MS patients decreased sensitivity of the tumor to systemic anticancer therapy, increased rate of postoperative complications as well as reduced overall and disease-free survival compared to patients without MS was reported (5-8). In addition, some drugs that are used in systemic anticancer therapy of breast cancer increase insulin resistance the main pathogenetic link of MS. Specifically, dexamethasone, which is commonly used in breast cancer chemotherapy, causes hyperglycemia. In menopausal women with obesity tamoxifen reduced insulin sensitivity by almost seven fold and increased incidence of type 2 diabetes mellitus compared to women who did not intake tamoxifen (9,10). Experimental studies have found that anti-tumor effect of metformin is associated with activation of AMP-dependent protein kinase (AMPK), which plays a key role in the cell energy balance. Activation of AMPK leads to inhibition of anabolic processes depression of neoglucogenesis in hepatocytes and lipolysis in adipocytes, protein synthesis reduction by inhibiting mTOR (mammalian target of rapamycin), and launching of catabolic processes in the cell (increased glycolysis and fatty acid oxidation), arrest of the cell cycle in G0/G1-phase and the stimulation of the p53-dependent cell autophagy (11, 12). Furthermore, metformin can directly (without AMPK activation) block protein mTOR, which stimulates the biosynthesis of proteins and promotes cell growth and proliferation, thereby demonstrating antiproliferative activity (11). The aim of this prospective randomized trial was to investigate the influence of metformin on the effectiveness of neoadjuvant systemic anticancer therapy of breast cancer patients with metabolic syndrome.