ABSTRACT
Endocrine-disrupting compounds (EDC) play an important role in the increased incidence of breast cancer (BC). There are some 160 xenoestrogens that may be involved in the development of BC. Much less is known about the influence of xenoestrogens on the effectiveness of the treatment of BC. The aim of this study was to analyze the interaction of metalloestrogens (aluminum and chromium (III)) and drugs used in the treatment of hormone-dependent BC-aromatase inhibitors (AI)-letrozole and exemestane. A cell viability assay, a flow cytometer analysis of apoptosis and cell cycle phases, and protein activity of BAX and Bcl-2 were performed on two human breast cancer cell lines-MCF-7 and MCF-7/DOX. In MCF-7 cells, the lower concentration of exemestane and higher of letrozole, in combination with metalloestrogens, results in a decrease in the effectiveness of drugs. Additionally, in the MCF-7/DOX cell line, we observed that the combination of metalloestrogens and AI leads to a decrease in the drug's effectiveness due to an increase in the viability of breast cancer cells (both concentrations of letrozole and higher concentration of exemestane). In both cell lines, the reduction in the effectiveness of AI, in combination with metalloestrogens, is not related to the influence on the cell cycle. Our results confirm that exposure to metalloestrogens may negatively affect the effectiveness of hormone therapy with AI. Further studies are needed to fully explain the mechanism of these interactions.
ABSTRACT
Aromatase inhibitors (AIs) have been considered first-line therapy for patients with hormone-dependent breast cancer due to their high efficacy and good tolerability. However, AIs are not free of adverse events, and studies show that therapy with AIs is associated with an increased risk of cardiovascular events and the development of insulin resistance and diabetes. We searched the Cochrane Central Register of Controlled Trials, PubMed and EMBASE up to 27 October 2020 for the prevalence of cardiovascular and/or metabolic adverse effects during treatment with AIs in postmenopausal women with breast cancer. A meta-analysis was performed using a random effects model. Odds ratios and 95% confidence intervals were calculated and illustrated using forest plot charts. We performed separate analyses depending on trial design. Twenty two studies met the inclusion criteria. AIs were associated with a higher risk of cardiovascular events, especially when we compared study arms in which AIs were used (alone or in sequence with TAM) with the arms in which TAM was used alone (OR = 1.16; 95%CI 1.04-1.30) or when comparing patients taking AIs alone to patients taking TAM alone or in sequence with AIs (OR = 1.24; 95%CI 1.11-1.38). A pooled analysis of five trials comparing adjuvant AIs to TAM showed the odds for arterial hypertension being 1.31 times higher for patients taking AIs; however, this did not reach statistical significance (OR = 1.31; 95%CI 0.47-3.65). We have not shown an increased risk of dyslipidemia or weight gain with the use of AIs. Our results suggest that postmenopausal women with breast cancer treated with AIs have an increased risk of cardiovascular events in comparison with TAM, potentially due more to a cardioprotective effect of the latter than the cardiotoxicity of AIs. We were unable to prove a similar association for hypertension, dyslipidemia, hyperglycemia or weight gain. Further high-quality RCTs and post-marketing safety observational studies are needed to definitively evaluate the impact of AIs on metabolic disorders in breast cancer patients.
ABSTRACT
INTRODUCTION: Breast cancer is the most common cancer occurring in women and causing the highest number of deaths among them. The role of xenoestrogens has been the subject of many studies in the pathogenesis of breast cancer. Less is known about the impact of xenoestrogens on the effectiveness of hormone therapy used to treat breast cancer, and thus possible drug-xenostrogen interactions. OBJECTIVE: The aim of this review is to summarize the current state of knowledge and present perspectives for further research on the impact of xenoestrogens on the effectiveness of drugs used in the treatment of hormone-dependent breast cancer. CURRENT STATE OF KNOWLEDGE: Phytoestrogens, in particular flavonoid genistein, are the best studied group of xenoestrogens in terms of interaction with drugs used in the treatment of breast cancer, due to their frequent use, including their use in alleviating the adverse effects of hormone therapy. Analyzing the current state of knowledge, it seems that phytoestrogens intake should be avoided during conventional anti-cancer treatment. Of the other xenoestrogens, bisphenol A (BPA) is one of the best-tested compounds for interactions with drugs used to treat breast cancer. It has been shown that bisphenol A could reduced therapeutic effect of active tamoxifen metabolite and cytostatics used in breast cancer treatment. CONCLUSIONS: Confirmation in clinical trials of the results obtained in vitro and in vivo tests, would enable the creation of specific recommendations for patients undergoing breast cancer treatment, especially hormone therapy. An area requiring further research is the analysis of the effects of xenoestrogens other than phytoestrogens, e.g. metalloestrogens, on the effects of drugs used in the treatment of breast cancer.
