ABC | Volume 111, Nº2, August 2018

Review Article Leite et al Aspirin and hormonal therapy in breast cancer Arq Bras Cardiol. 2018; 111(2):205-212 artery disease (CAD). Evidence suggests a modest protective effect of tamoxifen against death from CAD. There is a controversy over the effects of SERMs on atherosclerosis and its complications (Table 2). The publication of the RUTH (Raloxifene Use for The Heart) study 21 confirmed a neutral effect of raloxifene. Evidence available in the world literature suggests neutral effects or discrete benefits of SERM use in overall cardiovascular risk. 25 In the NSABP study, 26 13,388 women at increased risk of breast cancer were assigned to receive tamoxifen 20 mg/day or placebo. Cardiovascular follow-up was available for 13,194 women, of which 1,048 had clinically manifest CAD. The rates of cardiovascular events were not significantly different between women receiving tamoxifen and those receiving placebo, regardless of the preexisting disease. A case-control study of women diagnosed with breast cancer found that the use of tamoxifenwas not associatedwith a reduced risk of myocardial infarction for the observed 137 cases of myocardial infarction. 27 Another case-control study demonstrated that womenwith breast cancer who received tamoxifen had a reduced risk of angina pectoris or myocardial infarction (OR = 0.4, 95%CI: 0.2‑0.7) compared to patients who did not receive it. 28 Nordenskjold et al. 29 reported a significant reduction in mortality due to CAD in women who received 5 years vs. 2 years of tamoxifen, with a higher dose of 40 mg/day. The study carried out by the Early Breast Cancer Trialists' Collaborative Group 30 reported a reduction in mortality from CAD in more than 15,000 women randomized to receive approximately 5 years of tamoxifen vs. placebo, although there was no statistical significance (120 vs. 132 deaths, p = 0.06). Selective estrogen receptor modulators and aspirin Cancer can lead to a state of hypercoagulability, platelet abnormalities and thromboembolic events. Platelets can contribute to the metastasis process by promoting angiogenesis and by releasing the Vascular Endothelial Growth Factor (VEGF). 31,32 the platelets and coagulation cascade components involve tumor cells, which prevents lysis by natural killer cells, allowing the spread of metastases. Tamoxifen rapidly increases free calcium in human platelets. 33,34 Jhonson et al. 35 demonstrated that tamoxifen and its metabolite 4-hydroxytamoxifen altered the platelet function, with a reduction in the angiogenic and metastatic potential. Angiogenic proteins are released during the platelet activation process, and platelet deposition is observed at the tumor site. 36 The alpha and beta forms of ER were found in the platelet membrane. 37,38 Some studies have suggested that estradiol, as well as the tamoxifen metabolites, can increase platelet aggregation, suggesting that ER function may influence the release of intraplatelet proteins, such as VEGF and endostatin, when platelets are stimulated in the tumor environment. 39 Holmes et al. 40 carried out a study that evaluated the concentrations of VEGF and endostatin before and after tamoxifen or aromatase inhibitors in 30 women with breast cancer. Tamoxifen therapy resulted in increased VEGF concentrations in platelets, but no change in plasma VEGF levels. The use of aspirin attenuated the increase in the VEGF levels associated with tamoxifen and reduced serum levels of VEGF. The data from this study suggest that antiplatelet therapy may interfere with angiogenic protein levels in women treated with endocrine therapy. Women with breast cancer who used tamoxifen and 45 days of aspirin had reduced intraplatelet VEGF levels, as well as increased serum and intraplatelet levels of the antiangiogenic factor thrombospondin-1. 41 These changes were reversedwith the aspirin discontinuation. In this study, a dose of 325 mg/day was used. Aspirin decreased the pro‑angiogenic effects of tamoxifen, suggesting that antiplatelet therapymay improve tamoxifenefficacy. Table 2 – Events associated with the use of selective estrogen receptor modulators (SERMs) Study, year Type of study Patients (n) Assessed/ compared SERMs Breast cancer VTE CVA CAD STAR, Vogel et al. 11 2006 Clinical trial 19,747 postmenopausal women Tamoxifen and raloxifene Risk reduction of 50% ( in situ - tamoxifen and raloxifene and invasive - tamoxifen) Increase, raloxifene < tamoxifen of 30% Reduction (tamoxifen and raloxifene) Increase (tamoxifen and raloxifene) MORE, Cauley et al. 13 2001 Clinical trial 7,705 postmenopausal women Raloxifene and placebo Risk reduction of 72% after 4 years Increase Neutral Neutral CORE / Martino et al. 14 / 2004 Clinical trial 5,213 postmenopausal women Raloxifene and placebo Risk reduction of 59% Increase NSABP / Fisher et al. 9 / 1998 Clinical trial 13,388 at risk for breast cancer Tamoxifen and placebo Risk reduction of 49% Increase Increase Neutral IBIS-1 / Cuzick et al. 8 / 2002 Clinical trial 7,152 at risk of breast cancer Tamoxifen and placebo Risk reduction of 32% Increase Neutral Neutral RUTH / Barret- Connor et al. 21 / 2006 Clinical trial 10,101 postmenopausal women Raloxifene and placebo Invasive cancer risk reduction of 55% Increase of 44% Increase of 49% Neutral VTE: venous thromboembolism; CAD: coronary artery disease. 208