Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC tHdX3VjRRZdbfgwV8nrgbMc S0066-782X2018001400205 10.5935/abc.20180138 Review Article Antiplatelet Therapy in Breast Cancer Patients Using Hormonal Therapy: Myths, Evidence and Potentialities – Systematic Review Leite Andréa de Melo 1 2 Macedo Ariane Vieira Scarlatelli 3 Jorge Antonio José Lagoeiro 1 Martins Wolney de Andrade 1 Universidade Federal Fluminense Programa de Pós-graduação em Ciências Cardiovasculares Niterói RJ Brazil Programa de Pós-graduação em Ciências Cardiovasculares da Universidade Federal Fluminense (UFF), Niterói, RJ - Brazil Rede D'Or São Luiz Rio de Janeiro RJ Brazil Rede D'Or São Luiz, Rio de Janeiro, RJ – Brazil Grupo Oncoclínicas do Brasil Belo Horizonte MG Brazil Grupo Oncoclínicas do Brasil, Belo Horizonte, MG – Brazil Mailing Address: Andréa de Melo Leite Rua Marques do Paraná, 303. Postal Code 24030-215, Niterói, RJ - Brazil E-mail: andreamelo@cardiol.br, andreamelocardiologia@gmail.com

Author contributions

Conception and design of the research and Acquisition of data: Leite AM, Martins WA; Analysis and interpretation of the data: Leite AM, Macedo AVS, Jorge AJL, Martins WA; Writing of the manuscript: Leite AM; Critical revision of the manuscript for intellectual content: Macedo AVS, Jorge AJL, Martins WA.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 08 2018 111 2 205 212 25 10 2017 06 06 2018 12 06 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Breast cancer is the most frequently diagnosed tumor in women worldwide, with a significant impact on morbidity and mortality. Chemotherapy and hormone therapy have significantly reduced mortality; however, the adverse effects are significant. Aspirin has been incorporated into clinical practice for over 100 years at a low cost, making it particularly attractive as a potential agent in breast cancer prevention and as an adjunct treatment to endocrine therapy in the prophylaxis of cardiovascular complications. The objective of this study was to evaluate the role of aspirin in reducing the incidence of breast cancer and to evaluate the impact of its use on morbidity and mortality and reduction of cardiovascular events as adjuvant therapy during breast cancer treatment with selective estrogen receptor modulators. A systematic review was performed using the PRISMA methodology and PICO criteria, based on the MEDLINE, EMBASE and LILACS databases. The original articles of clinical trials, cohort, case-control studies and meta-analyses published from January 1998 to June 2017, were considered. Most studies showed an association between the use of selective estrogen receptor modulators and the increase in thromboembolic events. The studies suggest a protective effect of aspirin for cardiovascular events during its concomitant use with selective estrogen receptor modulators and in the prevention of breast cancer. This systematic review suggests that aspirin therapy combines the benefit of protection against cardiovascular events with the potential reduction in breast cancer risk, and that the evaluation of the benefits of the interaction of endocrine therapy with aspirin should be further investigated.

 Keywords Breast Neoplasms/drug therapy Indicators of Morbidity and Mortality Aspirin Tamoxifen Raloxilene Hydrochloride Cardiovascular Diseases/prevention & control Selective Estrogen Receptor Modulators Introduction

Breast cancer is the most frequently diagnosed tumor in women worldwide, with a significant impact on morbidity and mortality. According to the World Health Organization, it is estimated that more than 1.5 million new cases of breast cancer are annually diagnosed worldwide. Despite advances in treatment, breast cancer mortality is still high, with 570,000 deaths in 2015. The disease, recurrent or metastatic, remains incurable in most cases.1

Chemotherapy and hormone therapy have significantly reduced mortality, but their adverse effects are considerable. Endocrine therapy has revolutionized the treatment of breast cancer patients with positive Estrogen Receptor (ER), although there are cases that develop resistance to this therapy. An appropriate strategy would be the combination of Selective Estrogen Receptor Modulators (SERMs) or another hormonal class with other therapeutic agents, aiming at attaining a synergistic antitumor effect. The use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, has been associated with reduced risk of breast cancer.2,3 This therapy could also antagonize thrombogenic effects in women treated with tamoxifen.

The increasing number of breast cancer survivors is confronted with the shortage of information among clinicians on the subject.

The aim of the present study is to evaluate the role of aspirin in reducing the incidence of breast cancer and to evaluate the impact of its use in reducing cardiovascular events as an adjuvant therapy during the treatment of breast cancer with SERMs.

 Methods

This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology.4 The study included original articles of clinical trials, cohort, case-control studies and meta-analyses published from January 1998 to June 2017, with full-texts in English, Spanish and Portuguese, obtained from the MEDLINE, EMBASE and LILACS databases. The research was performed using the following descriptors: (selective estrogen receptor modulators OR tamoxifen OR raloxifene hydrochloride OR toremifene) AND (platelet aggregation inhibitors OR aspirin) AND (cardiovascular disease) AND (breast CA).

This study was based on the PICO (acronym for Population, Intervention, Control and Outcome) criteria. The objective was to evaluate whether aspirin use implies in the reduction of events, especially cardiovascular events, in women with breast cancer using SERMs. The studies were selected according to the following criteria: use of SERMs in women with breast cancer; regular aspirin use; and evaluation of mortality, metastases, and adverse effects using SERMs and/or aspirin. Case reports, articles with other types of endocrine therapy, and animal experimental models were excluded.

A total of 221 abstracts met the search criteria and other 15 were manually retrieved. A total of 159 duplicated articles were eliminated and 77 abstracts were evaluated. Of these, 57 were selected for the review. We excluded 25 because they did not meet the previously established criteria, resulting in 32 full-text articles, which were evaluated in relation to their scientific quality. Five articles were excluded according to the inclusion/exclusion criteria. A total of 27 articles were analyzed, according to figure 1.

Flowchart of the evaluated studies.

Selective estrogen receptor modulators and reduction of morbidity and mortality in breast cancer

Most breast cancers have positive ER and three main drugs are being used for their treatment and/or prevention, namely: tamoxifen, raloxifene and toremifene. All of these agents are competitive inhibitors of estrogen binding to its receptors, and have mixed agonist and antagonist activity, depending on the target tissue.5 Tamoxifen is the most well-studied SERM and often the drug of choice for breast cancer treatment. Its mechanism of action involves tumor cell growth inhibition through competitive ER inhibition.6

The benefits of tamoxifen have been consolidated through the US Financial Service Task Force (USPSTF) meta-analysis.7 In comparison with placebo, the use of tamoxifen resulted in: reduced risk of invasive breast cancer (Relative Risk – RR = 0.70; 95% Confidence Interval – 95%CI: 0.59-0.82); reduction in the incidence of non-vertebral fractures (RR = 0.66, 95%CI: 0.45-0.98); and no difference in mortality from breast cancer or from all causes. On the other hand, a pro-coagulant effect is described when tamoxifen is added to chemotherapy – especially an increase in thromboembolic events.8,9

Raloxifene differs from tamoxifen because it does not stimulate endometrial tissue, although it exerts the same beneficial effects of tamoxifen on breast tissue. In preclinical studies, raloxifene has been shown to prevent the onset of new breast cancers, as well as prevent the growth of preexisting cancers.10 In the STAR (Study of Tamoxifen and Raloxifene) study,11 19,747 women were randomized to receive 20 mg of tamoxifen or 60 mg/day of raloxifene for 5 years. The results showed that raloxifene had the same efficacy as tamoxifen in the prevention of breast cancer in situ, both with a 50% risk reduction (RR of 1.02, 95%CI: 0.82-1.28). However, raloxifene did not show protection against invasive types of breast cancer, whereas tamoxifen reduced its incidence by around 50%. It was observed that the group treated with raloxifene had an almost 30% reduction in thromboembolic events such as Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) (RR = 0.70, 95%CI: 0.54-0.91). Both groups had the same incidence of cerebrovascular accident, myocardial infarction and fractures.

The MORE (Multiple Outcomes of Raloxifene Evaluation)12 study randomized 7,705 postmenopausal patients who had osteoporosis and had no history of breast or endometrial cancer for the use of placebo or 60 mg/day or 120 mg/day of raloxifene. After 4 years of follow-up, a 72% reduction of breast cancer risk was observed.13 In the CORE (Continuing Outcomes relevant to Evista) study,14 the patients were randomized to either raloxifene 60 mg/day or placebo. A 59% reduction (RR = 0.41, 95%CI: 0.24-0.71) was observed in the incidence of breast cancer and a decrease of 66% (RR = 0.34, 95%CI: 0.18-0.66 ) of ER-positive invasive breast cancer, when compared with the placebo group. When analyzing both studies together, the incidence of invasive breast cancer was reduced by 66% (RR = 0.34, 95% CI: 0.22-0.50) and, for ER-positive cases, 76% (RR = 0.24, 95%CI: 0.15-0.40), relative to the placebo group. No protection was observed against non-invasive cancers.

A significant reduction in the amount of microvessels in breast cancer was observed after treatment with raloxifene 60 mg/day for 28 days in postmenopausal women without previous endocrine treatment.15 There is evidence that the benefits of treatment with SERMs were seen not only during the 5 years of active treatment, as well as 5 years after the end of treatment, indicating a long-term effect on the prevention of breast cancer. Adverse effects, notably the thromboembolic events and endometrial cancer, should be considered when assessing the risk-benefit ratio for each patient.16

Selective estrogen receptor modulators and thromboembolic events

A number of studies have demonstrated that the use of tamoxifen is associated with an increased rate of venous thromboembolic events (VTE) and that there is an additional procoagulant effect when tamoxifen is added to chemotherapy.6,8,9 Raloxifene is also associated with a higher risk of VTE, but with a lower incidence than tamoxifen. The NSABP (National Surgical Adjuvant Breast and Bowel Project) Tamoxifen Prevention Trial9 allocated 13,388 women at high risk of breast cancer to receive tamoxifen or placebo. The incidence of PE and DVT increased in women who received tamoxifen, especially in patients older than 50 years (RR for PE = 3.0, 95%CI: 1.1-11.2, RR for DVT = 1.6; 95%CI: 0.9-2.9). The IBIS-1 (International Breast Cancer Intervention Study)8 allocated 7,154 women at risk for breast cancer to receive tamoxifen or placebo. The use of tamoxifen was associated with an increased risk of developing VTE (Odds Ratio – OR = 2.1, 95%CI: 1.1-4.1). The risk of developing PTE or PE was significantly higher during the 5 years of active treatment with tamoxifen (RR of 2.3; 95%CI 1.4-3.9) but did not persist after its cessation.

A meta-analysis of seven trials and 30,023 patients, which compared outcomes in women with breast cancer assigned to treatment with tamoxifen or an aromatase inhibitor, found a higher rate of VTE in those receiving tamoxifen (2.8% vs. 1.6%).16 An analysis of 13 trials of the NSABP,17 which evaluated the risk of contralateral breast cancer in 20,878 women who received tamoxifen after primary treatment for this disease, found an increased risk of VTE with tamoxifen. The risks of PE, DVT and superficial phlebitis increased two to three-fold in patients treated with tamoxifen, and 11 to 15-fold in patients treated with tamoxifen plus chemotherapy.18 The STAR (Study of Tamoxifen and Raloxifene)11 study suggested a lower incidence of DVT and PE in women receiving raloxifene vs. those treated with tamoxifen. This study randomized 19,747 women at risk for breast cancer to raloxifene and tamoxifen use for 5 years.

 Selective estrogen receptor modulators and cerebrovascular accident

In the EBCTCG (Early Breast Cancer Trialists' Collaborative Group)6 meta-analysis, which compared 21,457 women to receive tamoxifen or placebo, there was an increase in cerebrovascular accident (CVA) rates, but without statistical significance. In a case-control study of 11,045 women with breast cancer, the risk of CVA was not increased by the use of tamoxifen.19 In a meta-analysis that evaluated the use of tamoxifen in primary or secondary prevention in 39,601 breast cancer patients, the frequency of ischemic CVA was higher in those who received tamoxifen than in the controls.20 Tamoxifen was associated with an increased risk of CVA, but with a low absolute risk.

In the RUTH (Raloxifene Use for The Heart) study,21 raloxifene was associated with an increased risk of fatal CVA when compared with placebo. The IBIS-1 study22 did not show statistical significance between the treatment groups (tamoxifen vs. placebo) regarding cerebrovascular or cardiovascular events. A sub-analysis of the MORE12 study suggested that in women at high risk for arterial events, raloxifene reduced the incidence of coronary events and CVA. However, after 8 years of treatment, the incidence of cardiovascular, coronary, or cerebrovascular events did not significantly differ between the raloxifene and placebo groups. In the STAR study,11 the risk of CVA was similar in the raloxifene and tamoxifen groups.

 Selective estrogen receptor modulators and lipid profile

There is evidence of changes in the lipid profile with the use of SERMs. The reduction of serum total cholesterol and low-density lipoprotein cholesterol (LDL-c) levels is a consensus. However, an increase in serum triglyceride levels has also been reported. Sawada and Sato23 reported that tamoxifen reduced total and LDL cholesterol levels, as well as significantly increased triglycerides. Atalay et al.24 did not find a significant effect of tamoxifen on total cholesterol or high-density lipoprotein-cholesterol (HDL-c) but reported a borderline increase in triglycerides. Taken together, these studies suggest that although tamoxifen consistently lowers LDL-c levels, the effects on HDL-c are mild, and tamoxifen use increases serum triglyceride levels. Changes in the lipid profile associated with the use of tamoxifen are summarized in Table 1.

Tamoxifen and lipid profile
Changes Total cholesterol LDL-c HDL-c Triglycerides
Tamoxifen Reduction Reduction Mild alteration Increase

LDL-c: low-density lipoprotein cholesterol; HDL-c: high-density lipoprotein cholesterol.

 Selective estrogen receptor modulators and coronary artery disease

Even after consolidation of the clinical use of tamoxifen, there is no definitive evidence of its effect on coronary 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) study21 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

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.

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 tamoxifen was not associated with a reduced risk of myocardial infarction for the observed 137 cases of myocardial infarction.27 Another case-control study demonstrated that women with 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 Group30 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 reversed with 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 therapy may improve tamoxifen efficacy. Cheng et al.42 carried out a study that showed that aspirin not only inhibits the growth of the MCF-7 RE-positive breast cancer cell line, but also has a potential function to overcome resistance to tamoxifen in MCF-7/TAM cell lines. The concomitant action of aspirin makes cells more sensitive to tamoxifen, indicating that aspirin can regulate proteins to overcome tamoxifen resistance.

The RUTH21 study evaluated the effects of antiplatelet therapy concomitant with the use of raloxifene regarding the risk of VTE. The increased risk of VTE with raloxifene when compared to placebo was not different between the women who used antiplatelet agents and those who did not use it.43 The key findings of the abovementioned studies are summarized in Table 3.

Aspirin and selective estrogen receptor modulators (SERMs)
Author, year Type of study Patients (n) SERMs and/or aspirin Main Conclusions
Holmes et al.,40 2008 Clinical trial 30 Tamoxifen or aromatase inhibitor + ASA ASA attenuated the increase in VEGF associated with tamoxifen
Holmes et al.,44 2010 Prospective Cohort 4,164 ASA Reduction in the recurrence and death from breast cancer
Holmes et al.,41 2013 Clinical trial 12 Tamoxifen + ASA Reduction in VEGF and increase in TSP-1
Holmes et al.,45 2014 Case-control 27,426 ASA There is no benefit during end-stage illness
Yang et al.,46 2017 Retrospective Cohort 148,739 ASA Reduction in breast cancer risk in diabetics
Fraser et al.,47 2014 Cohort 4,627 ASA Reduction in death risk from all causes
Jhonson et al.,48 2002 Prospective Cohort 27,616 ASA Reduction in breast cancer risk
Harris et al.,53 1999 Prospective Cohort 32,505 ASA/ibuprofen Reduction in breast cancer risk
Duvernoy et al.,43 2010 (RUTH Trial) Clinical trial 10,101 Raloxifene + ASA Did not change the risk of VTE

ASA: acetylsalicylic acid; VEGF: vascular endothelial growth factor; TSP-1: thrombospondin 1; VTE: venous thromboembolism.

 Aspirin and Cancer Prevention

A prospective observational study of 4,164 women with breast cancer showed that, among women who were alive at least 1 year after the breast cancer diagnosis, the use of aspirin was associated with a reduction in the risk of recurrence and death from breast cancer.44 Contrarily, another study with 27,426 women with breast cancer showed that there was no association between aspirin use and death from breast cancer.45

A retrospective cohort study was carried out in Taiwan with 148,739 diabetic women, of which 27,378 used aspirin at a dose ranging from 75 mg to 165 mg/day, which were compared to women who did not use aspirin. Overall, aspirin use reduced the risk of breast cancer by 18% (Hazard Ratio – HR= 0.82, 95%CI: 0.71-0.94). Specifically, a cumulative dose of aspirin > 88,900mg was observed to reduce the risk of breast cancer by 47% .46 A cohort in Scotland identified 4,627 women with breast cancer throughout 11 years. The use of aspirin after the diagnosis was identified in 1,035 women (22.4%). Most of them used a 75 mg dose/day. It was concluded that low-dose aspirin was associated with reduced risk of death from all causes and breast cancer.47 Another cohort, with 27,616 postmenopausal women, identified 938 cases of breast cancer in 6 years of follow-up, meaning a RR of 0.71 (95% CI: 0.58-0.87) for those who took aspirin at least six times a week, when compared with those who did not use the medication.48 Evidence from case-control and cohort studies suggest an approximately 10% reduction in the risk of breast cancer for aspirin use.49,50 Similar results were found with other NSAIDs and Cycloxygenase-2 inhibitors (COX-2).51

Rothwell et al.52 analyzed seven randomized trials for the regular use of aspirin with a minimum duration of 4 years to determine the effect of aspirin on the risk of death from cancer. Daily aspirin reduced death rates from several types of cancer during and after the studies. The benefit increased with treatment duration and was consistent in all the different studied populations.

Harris et al.53 found 393 cases of breast cancer in 32,505 patients after 5 years of follow-up. This study reported a 50% reduction in the incidence of breast cancer using ibuprofen (p < 0.01) and 40% with regular aspirin use (p < 0.05), suggesting that other NSAIDs may also be effective in breast cancer prophylaxis.

Aspirin emerged as the most likely NSAID for use in chemoprevention due to its benefits also in preventing cardiovascular events. Other NSAIDs have also been studied as adjuvants in the chemoprevention of several types of cancer, especially colorectal, breast and stomach neoplasms, although these drugs do not offer cardioprotection.54 Mortality reduction is more evident in colon cancer, probably in prostate and possibly also in breast neoplasms.55,56

Discussion

The clinical trials mentioned in this review report an increase in VTE with the use of SERMs and, regarding cerebrovascular and coronary events, the results were discordant. The currently used treatment, consisting of chemotherapy and hormone therapy, has reduced breast cancer mortality, but morbidity and mortality are still high, with considerable side effects and high financial costs. There are great expectations regarding new treatments, with low toxicity and cost reduction.

Aspirin has been incorporated into clinical practice for over 100 years at a low cost, making it attractive as a potential adjunct treatment. The observational studies included in this review suggest a reduction in the risk of breast cancer in patients regularly taking aspirin. Randomized clinical trials are required to assess the impact of aspirin use on breast cancer prevention, whether associated with endocrine therapy or disease-free survival in breast cancer patients.

Aspirin use is a consensus for the secondary prevention of myocardial infarction and ischemic CVA in patients with pre-existing cardiovascular disease and for primary prevention in high-risk groups. Current indications for the prophylactic use of aspirin are based on cardiovascular risk, considering the side effects, especially gastrointestinal bleeding, of which incidence increases with age. Other potential benefits of using aspirin need to be proven in the context of cancer.

 Conclusion

Breast cancer is the most frequently diagnosed tumor in women worldwide, with a significant impact on morbidity and mortality. Although there are controversies in the analyzed studies, considering the possible benefits regarding breast cancer prevention and reduction in cardiovascular events, this systematic review suggests that therapy with selective estrogen receptor modulators and aspirin should be better investigated, and emphasizes the need for randomized trials. Future studies should address issues such as dose, age at the start, duration, efficacy, and safety of a clearly defined treatment regimen.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is a research product in Cardio-oncology of the Master submitted by Andréa de Melo Leite, from Universidade Federal Fluminense.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

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Cuzick J Sestak I Bonanni B Costantino JP Cummings S DeCensi A SERM Chemoprevention of Breast Cancer Overview Group Selective estrogen receptor modulators in prevention of breast cancer an updated meta-analysis of individual participant data Lancet 2013 381 9880 1827 1834 16 Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103(17):1299-309. Amir E Seruga B Niraula S Carlsson L Ocaña A Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients a systematic review and meta-analysis J Natl Cancer Inst 2011 103 17 1299 1309 17 McCaskill-Stevens W, Wilson J, Bryant J, Mamounas E, Garvey L, James J, et al. Contralateral breast cancer and thromboembolic events in African American women treated with tamoxifen. J Natl Cancer Inst. 2004;96(23):1762-9. Erratum in: J Natl Cancer Inst. 2005;97(1):71. McCaskill-Stevens W Wilson J Bryant J Mamounas E Garvey L James J Contralateral breast cancer and thromboembolic events in African American women treated with tamoxifen J Natl Cancer Inst 2004 96 23 1762 1769 Erratum in: J Natl Cancer Inst. 2005;97(1):71 18 Onitilo AA, McCarty CA, Wilke RA, Glurich I, Engel JM, Flockhart DA, et al. Estrogen receptor genotype is associated with risk of venous thromboembolism during tamoxifen therapy. Breast Cancer Res Treat. 2009;115(3):643-50. Onitilo AA McCarty CA Wilke RA Glurich I Engel JM Flockhart DA Estrogen receptor genotype is associated with risk of venous thromboembolism during tamoxifen therapy Breast Cancer Res Treat 2009 115 3 643 650 19 Geiger AM, Fischberg GM, Chen W, Bernstein L. Stroke risk and tamoxifen therapy for breast cancer. J Natl Cancer Inst. 2004;96(20):1528-36. Geiger AM Fischberg GM Chen W Bernstein L Stroke risk and tamoxifen therapy for breast cancer J Natl Cancer Inst 2004 96 20 1528 1536 20 Bushnell CD, Goldstein LB. Risk of ischemic stroke with tamoxifen treatment for breast cancer: a meta-analysis. Neurology. 2004;63(7):1230-3. Bushnell CD Goldstein LB Risk of ischemic stroke with tamoxifen treatment for breast cancer a meta-analysis Neurology 2004 63 7 1230 1233 21 Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D, Kornitzer M, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355(2):125-37. Barrett-Connor E Mosca L Collins P Geiger MJ Grady D Kornitzer M Raloxifene Use for The Heart Trial Investigators Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women N Engl J Med 2006 355 2 125 137 22 Cuzick J, Forbes JF, Sestak I, Cawtohorn S, Hamed H, Holli K, et al; International Breast Cancer Intervention Study I Investigators. Long-term results of tamoxifen prophylaxis for breast cancer - 96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99(4):272-82. Cuzick J Forbes JF Sestak I Cawtohorn S Hamed H Holli K International Breast Cancer Intervention Study I Investigators Long-term results of tamoxifen prophylaxis for breast cancer - 96-month follow-up of the randomized IBIS-I trial J Natl Cancer Inst 2007 99 4 272 282 23 Sawada S, Sato K. Effect of anastrozole and tamoxifen on serum lipid levels in Japanese postmenopausal women with early breast câncer. [abstract]. Breast Cancer Res Treat. 2003;82(Suppl 1):S31-S32. Sawada S Sato K Effect of anastrozole and tamoxifen on serum lipid levels in Japanese postmenopausal women with early breast câncer abstract Breast Cancer Res Treat 2003 82 Suppl 1 S31 S32 24 Atalay G, Dirix L, Biganzoli L, Beex L, Nooij M, Cameron D, et al. The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, "Randomised phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients". Ann Oncol. 2004;15(2):211-7. Atalay G Dirix L Biganzoli L Beex L Nooij M Cameron D The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer a companion study to EORTC Trial 10951, "Randomised phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients". Ann Oncol 2004 15 2 211 217 25 Cano A, Hermenegildo C, Oviedo P, Tarín JJ. Selective estrogen receptor modulators and risk for coronary heart disease. Climacteric. 2007;10(2):97-111. Cano A Hermenegildo C Oviedo P Tarín JJ Selective estrogen receptor modulators and risk for coronary heart disease Climacteric 2007 10 2 97 111 26 Reis SE, Costantino JP, Wickerham DL, Tan-Chiu E, Wang J, Kavanah M. Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. J Natl Cancer Inst. 2001;93(1):16-21. Reis SE Costantino JP Wickerham DL Tan-Chiu E Wang J Kavanah M Cardiovascular effects of tamoxifen in women with and without heart disease breast cancer prevention trial J Natl Cancer Inst 2001 93 1 16 21 27 Geiger AM, Chen W, Bernstein L. Myocardial infarction risk and tamoxifen therapy for breast cancer. Br J Cancer. 2005;92(9):1614-20. Geiger AM Chen W Bernstein L Myocardial infarction risk and tamoxifen therapy for breast cancer Br J Cancer 2005 92 9 1614 1620 28 Bradbury BD, Lash TL, Kaye JA, Jick SS. Tamoxifen-treated breast carcinoma patients and the risk of acute myocardial infarction and newly-diagnosed angina. Cancer. 2005;103(6):1114-21. Bradbury BD Lash TL Kaye JA Jick SS Tamoxifen-treated breast carcinoma patients and the risk of acute myocardial infarction and newly-diagnosed angina Cancer 2005 103 6 1114 1121 29 Nordenskjold B, Rosell J, Rutqvist LE, Malmström PO, Bergh J, Bengtsson NO, et al. Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. J Natl Cancer Inst. 2005;97(21):1609-10. Nordenskjold B Rosell J Rutqvist LE Malmström PO Bergh J Bengtsson NO Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy results from a randomized trial J Natl Cancer Inst 2005 97 21 1609 1610 30 Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet. 2005;365(9472):1687-717. Early Breast Cancer Trialist' Collaborative Group Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival an overview of the randomized trials Lancet 2005 365 9472 1687 1717 31 Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11(2):123-34. Gay LJ Felding-Habermann B Contribution of platelets to tumour metastasis Nat Rev Cancer 2011 11 2 123 134 32 Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, Arepally GM, et al; 2009 Platelet Colloquium Participants. Platelet functions beyond hemostasis. J Thromb Haemost. 2009;7(11):1759-66. Smyth SS McEver RP Weyrich AS Morrell CN Hoffman MR Arepally GM 2009 Platelet Colloquium Participants Platelet functions beyond hemostasis J Thromb Haemost 2009 7 11 1759 1766 33 Dobrydneva Y, Weatherman RV, Trebley JP, Morrell MM, Fitzgerald MC, Fichandler CE, et al. Tamoxifen stimulates calcium entry into human platelets. J Cardiovasc Pharmacol. 2007;50(4):380-90. Dobrydneva Y Weatherman RV Trebley JP Morrell MM Fitzgerald MC Fichandler CE Tamoxifen stimulates calcium entry into human platelets J Cardiovasc Pharmacol 2007 50 4 380 390 34 Shah VP, Chegini HA, Vishneski SR, Weatherman RV, Blackmore PF, Dobrydneva Y. Tamoxifen promotes superoxide production in platelets by activation of PI3kinase and NADPH oxidase pathways. Thromb Res. 2012;129(1):36-42. Shah VP Chegini HA Vishneski SR Weatherman RV Blackmore PF Dobrydneva Y Tamoxifen promotes superoxide production in platelets by activation of PI3kinase and NADPH oxidase pathways Thromb Res 2012 129 1 36 42 35 Johnson KE, Forward JA, Tippy MD, Ceglowski JR, El-Husayni S, Kulenthirarajan R, et al. Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis. Arterioscler Thromb Vasc Biol. 2017;37(4):664-74. Johnson KE Forward JA Tippy MD Ceglowski JR El-Husayni S Kulenthirarajan R Tamoxifen Directly Inhibits Platelet Angiogenic Potential and Platelet-Mediated Metastasis Arterioscler Thromb Vasc Biol 2017 37 4 664 674 36 Boudreau N, Myers C. Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment. Breast Cancer Res. 2003;5(3):140-6. Boudreau N Myers C Breast cancer-induced angiogenesis multiple mechanisms and the role of the microenvironment Breast Cancer Res 2003 5 3 140 146 37 Jayachandran M, Miller VM. Human platelets contain estrogen receptor a, caveolin-1 and estrogen receptor associated proteins. Platelets. 2003;14(2):75-81. Jayachandran M Miller VM Human platelets contain estrogen receptor a, caveolin-1 and estrogen receptor associated proteins Platelets 2003 14 2 75 81 38 Khetawat G, Faraday N, Nealen ML, Vijayan, KV, Bolton E, Noga SJ, et al. Human megakaryocytes and platelets contain the estrogen receptor b and androgen receptor (AR): testosterone regulates AR expression. Blood. 2000;95(7):2289-96. Khetawat G Faraday N Nealen ML Vijayan KV Bolton E Noga SJ Human megakaryocytes and platelets contain the estrogen receptor b and androgen receptor (AR) testosterone regulates AR expression Blood 2000 95 7 2289 2296 39 Moro L, Reineri S, Piranda D, Pietrapiana D, Lova P, Bertoni A, et al. Nongenomic effects of 17b-estradiol in human platelets: potentiation of thrombin-induced aggregation through estrogen receptor b and Src kinase. Blood. 2005;105(1):115-21. Moro L Reineri S Piranda D Pietrapiana D Lova P Bertoni A Nongenomic effects of 17b-estradiol in human platelets potentiation of thrombin-induced aggregation through estrogen receptor b and Src kinase Blood 2005 105 1 115 121 40 Holmes CE, Huang JC, Pace TR, Howard AB, Muss HB. Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer. Clin Cancer Res. 2008;14(10):3070-6. Holmes CE Huang JC Pace TR Howard AB Muss HB Tamoxifen and aromatase inhibitors differentially affect vascular endothelial growth factor and endostatin levels in women with breast cancer Clin Cancer Res 2008 14 10 3070 3076 41 Holmes CE, Jasielec J, Levis JE, Skelly J, Muss HB. Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy. Clin Transl Sci. 2013;6(5):386-90. Holmes CE Jasielec J Levis JE Skelly J Muss HB Initiation of aspirin therapy modulates angiogenic protein levels in women with breast cancer receiving tamoxifen therapy Clin Transl Sci 2013 6 5 386 390 42 Cheng R, Liu YJ, Cui JW, Yang M, Liu XL, Li P, et al. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast câncer cells. Oncotarget. 2017;8(18):30252-64. Cheng R Liu YJ Cui JW Yang M Liu XL Li P Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast câncer cells Oncotarget 2017 8 18 30252 30264 43 Duvernoy CS, Yeo AA, Wong M, Cox DA, Kim HM. Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial. J Womens Health (Larchmt). 2010;19(8):1459-65. Duvernoy CS Yeo AA Wong M Cox DA Kim HM Antiplatelet therapy use and the risk of venous thromboembolic events in the Raloxifene Use for the Heart (RUTH) trial J Womens Health (Larchmt) 2010 19 8 1459 1465 44 Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE, et al. Aspirin intake and survival after breast cancer. J Clin Oncol. 2010;28(9):1467-72. Holmes MD Chen WY Li L Hertzmark E Spiegelman D Hankinson SE Aspirin intake and survival after breast cancer J Clin Oncol 2010 28 9 1467 1472 45 Holmes MD, Olsson H, Pawitan Y, Holm J, Lundholm C, Andersson TM, et al. Aspirin intake and breast cancer survival - a nation-wide study using prospectively recorded data in Sweden. BMC Cancer. 2014 Jun 2;14:391-2. Holmes MD Olsson H Pawitan Y Holm J Lundholm C Andersson TM Aspirin intake and breast cancer survival - a nation-wide study using prospectively recorded data in Sweden BMC Cancer 2014 06 02 14 391 392 46 Yang YS, Kornelius E, Chiou JY, Lai YR, Lo SC, Peng CH, et al. Low-dose aspirin reduces breast cancer risk in women with diabetes: a Nationwide Retrospective Cohort Study in Taiwan. J Womens Health (Larchmt). 2017;26(12):1278-84. Yang YS Kornelius E Chiou JY Lai YR Lo SC Peng CH Low-dose aspirin reduces breast cancer risk in women with diabetes a Nationwide Retrospective Cohort Study in Taiwan J Womens Health (Larchmt) 2017 26 12 1278 1284 47 Fraser DM, Sullivan FM, Thompson AM, McCowan C. Aspirin use and survival after the diagnosis of breast cancer: a population-based cohort study. Br J Cancer. 2014;111(3):623-7. Fraser DM Sullivan FM Thompson AM McCowan C Aspirin use and survival after the diagnosis of breast cancer a population-based cohort study Br J Cancer 2014 111 3 623 627 48 Johnson TW, Anderson KE, Lazovich D, Folsom AR. Association of aspirin and nonsteroidal anti-inflammatory drug use with breast cancer. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1586-91. Johnson TW Anderson KE Lazovich D Folsom AR Association of aspirin and nonsteroidal anti-inflammatory drug use with breast cancer Cancer Epidemiol Biomarkers Prev 2002 11 12 1586 1591 49 Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol. 2012;23(6):1403-15. Bosetti C Rosato V Gallus S Cuzick J La Vecchia C Aspirin and cancer risk a quantitative review to 2011 Ann Oncol 2012 23 6 1403 1415 50 Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 2012;13(5):518-27. Algra AM Rothwell PM Effects of regular aspirin on long-term cancer incidence and metastasis a systematic comparison of evidence from observational studies versus randomised trials Lancet Oncol 2012 13 5 518 527 51 Li Y, Brasky TM, Nie J, Ambrosone CB, McCann SE, Shields PG, et al. Use of nonsteroidal anti-inflammatory drugs and survival following breast cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2012;21(1):239-42. Li Y Brasky TM Nie J Ambrosone CB McCann SE Shields PG Use of nonsteroidal anti-inflammatory drugs and survival following breast cancer diagnosis Cancer Epidemiol Biomarkers Prev 2012 21 1 239 242 52 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomized trials. Lancet. 2011;377(9759):31-41. Rothwell PM Fowkes FG Belch JF Ogawa H Warlow CP Meade TW Effect of daily aspirin on long-term risk of death due to cancer analysis of individual patient data from randomized trials Lancet 2011 377 9759 31 41 53 Harris RE, Kasbari S, Farrar WB. Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer. Oncol Rep. 1999;6:71-3. Harris RE Kasbari S Farrar WB Prospective study of nonsteroidal anti-inflammatory drugs and breast cancer Oncol Rep 1999 6 71 73 54 Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10(5):501-7. Cuzick J Otto F Baron JA Brown PH Burn J Greenwald P Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement Lancet Oncol 2009 10 5 501 507 55 Elwood PC, Morgan G, Pickering JE, Galante J, Weightman AL, et al. Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies. PLoS One. 2016;11(4):e0152402. Elwood PC Morgan G Pickering JE Galante J Weightman AL Aspirin in the treatment of cancer reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies PLoS One 2016 11 4 e0152402 56 Chen WY, Holmes MD. Role of aspirin in breast câncer survival. Curr Oncol Rep. 2017;19(7):48. Chen WY Holmes MD Role of aspirin in breast câncer survival Curr Oncol Rep 2017 19 7 48 48 Artigo de Revisão Terapia Antiplaquetária em Pacientes com Câncer de Mama em Uso de Terapia Hormonal: Mitos, Evidências e Potencialidades – Revisão Sistemática Leite Andréa de Melo 1 2 Macedo Ariane Vieira Scarlatelli 3 Jorge Antonio José Lagoeiro 1 Martins Wolney de Andrade 1 Programa de Pós-graduação em Ciências Cardiovasculares da Universidade Federal Fluminense (UFF), Niterói, RJ - Brasil Rede D'Or São Luiz, Rio de Janeiro, RJ – Brasil Grupo Oncoclínicas do Brasil, Belo Horizonte, MG – Brasil Correspondência: Andréa de Melo Leite Rua Marques do Paraná, 303. CEP 24030-215, Niterói, RJ - Brasil E-mail: andreamelo@cardiol.br, andreamelocardiologia@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa e Obtenção de dados: Leite AM, Martins WA; Análise e interpretação dos dados: Leite AM, Macedo AVS, Jorge AJL, Martins WA; Redação do manuscrito: Leite AM; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Macedo AVS, Jorge AJL, Martins WA.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Resumo

O câncer de mama é o tumor mais frequentemente diagnosticado em mulheres de todo o mundo, com impacto importante na morbimortalidade. A quimioterapia e a terapia hormonal reduziram significativamente a mortalidade, mas os efeitos adversos são consideráveis. A aspirina está incorporada à prática clínica há mais de 100 anos, com baixo custo, tornando-a particularmente atraente como potencial agente na prevenção do câncer de mama e auxiliar durante o tratamento endócrino, na profilaxia de complicações cardiovasculares. Objetivou-se avaliar o papel da aspirina na redução da incidência do câncer de mama e avaliar o impacto de seu uso na morbimortalidade e na redução de eventos cardiovasculares como terapia adjuvante durante o tratamento do câncer de mama com moduladores seletivos do receptor do estrogênio. Procedeu-se à revisão sistemática utilizando-se a metodologia PRISMA e os critérios PICO, nas bases MEDLINE, EMBASE e LILACS. Foram considerados os artigos originais do tipo ensaio clínico, coorte, caso-controle e metanálises, publicados no período de janeiro de 1998 até junho de 2017. Na maioria dos estudos, houve relação entre o uso dos moduladores seletivos do receptor do estrogênio e o aumento de eventos tromboembólicos. Os estudos sugerem efeito protetor da aspirina para eventos cardiovasculares em uso concomitante aos moduladores seletivos do receptor do estrogênio e na prevenção do câncer de mama. Esta revisão sistemática sugere que o tratamento com aspirina combina o benefício da proteção contra eventos cardiovasculares com a potencial redução do risco de câncer de mama, e que a avaliação dos benefícios da interação da terapia endócrina com a aspirina deve ser melhor investigada.

 Palavras-chave Neoplasias da Mama/tratamento farmacológico Indicadores de Morbimortalidade Aspirina Tamoxifeno Cloridrato de Raloxifeno Doenças Cardiovasculares/prevenção & controle Moduladores Seletivos do Receptor Estrogênio Introdução

O câncer de mama é o tumor mais frequentemente diagnosticado em mulheres de todo o mundo, com impacto importante na morbimortalidade. De acordo com a Organização Mundial da Saúde, estima-se que mais de 1,5 milhão de novos casos de câncer de mama sejam diagnosticados anualmente em todo o mundo. Apesar dos avanços no tratamento, a mortalidade por câncer de mama ainda é alta, com 570 mil óbitos em 2015. A doença, recorrente ou metastática, permanece incurável na maioria dos casos.1

A quimioterapia e a terapia hormonal reduziram significativamente a mortalidade, porém os efeitos adversos são consideráveis. A terapia endócrina revolucionou o tratamento de pacientes com câncer de mama com Receptor de Estrogênio (RE) positivo, embora existam casos de desenvolvimento de resistência a esta terapia. Uma estratégia adequada seria a combinação dos Moduladores Seletivos de Receptores de Estrogênio (MSRE) ou outra classe hormonal com outros agentes terapêuticos, visando à realização do efeito antitumoral sinérgico. O uso de Anti-Inflamatórios Não Esteroidais (AINEs), incluindo a aspirina, tem sido associado à redução do risco de câncer de mama.2,3 Esta terapia poderia também antagonizar os efeitos trombogênicos em mulheres tratadas com tamoxifeno.

O número crescente de sobreviventes de câncer de mama é confrontado com a escassez de informação entre os clínicos sobre o tema.

O objetivo do presente estudo é avaliar o papel da aspirina na redução da incidência do câncer de mama e avaliar o impacto de seu uso na redução de eventos cardiovasculares, como terapia adjuvante durante o tratamento do câncer de mama com MSRE.

 Métodos

Esta revisão sistemática foi conduzida conforme a metodologia Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).4 A pesquisa incluiu artigos originais do tipo ensaio clínico, coorte, caso-controle e metanálises publicados no período de janeiro de 1998 até junho de 2017, com textos na íntegra, em inglês, espanhol e português, nas bases de dados MEDLINE, EMBASE e LILACS. A pesquisa foi realizada com os seguintes descritores: (selective estrogen receptor modulators OR tamoxifen OR raloxifene hydrochloride OR toremifene) AND (platelet aggregation inhibitors OR aspirin) AND (cardiovascular disease) AND (breast CA).

Este estudo baseou-se nos critérios PICO (acrônimo para População, Intervenção, Controle e Resultados). Objetivou-se avaliar se o uso da aspirina implica na redução de eventos, especialmente os eventos cardiovasculares em mulheres com câncer de mama em uso de MSRE. Os estudos foram selecionados conforme os seguintes critérios: uso de MSRE em mulheres com câncer de mama; uso regular de aspirina; e avaliação de mortalidade, metástases e efeitos adversos com uso de MSRE e/ou aspirina. Foram excluídos relatos de caso, artigos com outros tipos de terapia endócrina e modelos experimentais animais.

Preencheram os critérios de pesquisa 221 resumos, outros 15 foram recuperados manualmente. Foram eliminados 159 artigos em duplicata entre as bases de dados. Foram avaliados 77 resumos. Destes, foram selecionados 57. Foram excluídos 25 por se apresentarem fora dos critérios previamente estabelecidos, resultando em 32 artigos de texto completo, os quais foram avaliados em relação à qualidade científica. Cinco artigos foram excluídos conforme os critérios de inclusão/exclusão. Foram analisados 27 artigos, conforme a figura 1.

Fluxograma dos estudos avaliados.

Moduladores seletivos do receptor do estrogênio e redução da morbimortalidade no câncer de mama

A maioria dos cânceres de mama apresenta RE positivo e três principais medicamentos estão em uso para seu tratamento e/ou prevenção, a saber: tamoxifeno, raloxifeno e toremifeno. Todos estes agentes são inibidores competitivos da ligação de estrogênio a seus receptores, e têm atividade mista agonista e antagonista, dependendo do tecido-alvo.5 O tamoxifeno é o MSRE mais bem estudado e, frequentemente, o medicamento de escolha para o tratamento do câncer de mama. Seu mecanismo de ação envolve a inibição do crescimento das células tumorais por inibição competitiva do RE.6

Os benefícios do tamoxifeno foram consolidados por meio da metanálise da US Financial Service Task Force (USPSTF).7 Em comparação com o placebo, o uso do tamoxifeno resultou em: redução no risco de câncer de mama invasivo (Risco Relativo - RR de 0,70; Intervalo de Confiança de 95% - IC95% 0,59-0,82); redução na incidência de fraturas não vertebrais (RR de 0,66; IC95% 0,45-0,98); e ausência de diferença na mortalidade por câncer de mama ou por todas as causas. Por outro lado, está descrito um efeito pró-coagulante quando o tamoxifeno é adicionado à quimioterapia - em especial um aumento de eventos tromboembólicos.8,9

O raloxifeno difere do tamoxifeno por não estimular o tecido endometrial, apesar de exercer as mesmas propriedades benéficas do tamoxifeno sobre o tecido mamário. Em estudos pré-clínicos, o raloxifeno mostrou prevenir o surgimento de novos cânceres mamários, assim como impedir o crescimento de cânceres preexistentes.10 No estudo STAR (Study of Tamoxifen and Raloxifen),11 19.747 mulheres foram randomizadas para receber 20 mg ao dia de tamoxifeno ou 60 mg ao dia de raloxifeno por 5 anos. Os resultados demonstraram que o raloxifeno apresenta a mesma eficácia que o tamoxifeno na prevenção do câncer de mama in situ, ambos com diminuição de risco de 50% (RR de 1,02; IC95% 0,82-1,28). Porém, o raloxifeno não apresentou proteção contra os tipos invasores de câncer de mama, enquanto que o tamoxifeno reduziu sua incidência em torno de 50%. Foi observado que o grupo tratado com raloxifeno apresentou quase 30% a menos de eventos tromboembólicos como Trombose Venosa Profunda (TVP) e Embolia Pulmonar (EP) (RR de 0,70; IC95% 0,54-0,91). Os dois grupos apresentaram a mesma incidência de acidente vascular cerebral (AVC), infarto do miocárdio e fraturas.

O estudo MORE (Multiple Outcomes of Raloxifen Evaluation)12 randomizou 7,705 pacientes pós-menopáusicas, que tinham osteoporose e não apresentavam história de câncer de mama ou de endométrio para o uso de placebo ou 60 mg ao dia ou 120 mg ao dia de raloxifeno. Após 4 anos de seguimento, observou-se redução em 72% no risco de câncer de mama.13 No estudo CORE (Continuing Outcomes relevant to Evista),14 as pacientes foram randomizadas para o uso de raloxifeno 60 mg ao dia ou placebo. Foram observadas redução de 59% (RR de 0,41; IC95% 0,24-0,71) na incidência de câncer de mama e diminuição de 66% (RR de 0,34; IC95% 0,18-0,66) de câncer de mama invasor RE positivo, quando comparadas com o grupo placebo. Na análise dos dois estudos em conjunto, a incidência de câncer de mama invasor foi reduzida em 66% (RR de 0,34; IC95% 0,22-0,50) e, para os casos RE positivos, em 76% (RR de 0,24; IC95% 0,15-0,40), em relação ao grupo placebo. Não foi observada proteção frente aos cânceres não invasivos.

Foi observada redução significativa da quantidade de microvasos no câncer de mama após tratamento com raloxifeno 60 mg ao dia, por 28 dias, em mulheres após menopausa sem tratamento endócrino prévio.15 Existem evidências de que os benefícios do tratamento com MSRE foram vistos não somente durante os 5 anos ativos de tratamento, como também nos 5 anos após o término do tratamento, indicando efeito a longo prazo na prevenção do câncer de mama. Os efeitos adversos, notadamente os eventos tromboembólicos e o câncer de endométrio, devem ser levados em consideração ao avaliar a relação risco-benefício para cada paciente.16

Moduladores seletivos do receptor do estrogênio e eventos tromboembólicos

Uma série de estudos demonstrou que o uso de tamoxifeno está associado à taxa aumentada de eventos Tromboembólicos Venosos (TEV) e que existe um efeito pró-coagulante adicional quando o tamoxifeno é adicionado à quimioterapia.6,8,9 O raloxifeno também está associado ao maior risco de TEV, porém com menor incidência que o tamoxifeno. O NSABP (National Surgical Adjuvant Breast and Bowel Project) Tamoxifen Prevention Trial9 alocou 13.388 mulheres com alto risco de câncer de mama para receber tamoxifeno ou placebo. As incidências de EP e TVP aumentaram nas mulheres que receberam tamoxifeno, especialmente nas pacientes com mais de 50 anos de idade (RR para EP de 3,0; IC95% 1,1-11,2; RR para TVP de 1,6; IC95% 0,9-2,9). O IBIS-1(International Breast Cancer Intervention Study)8 alocou 7.154 mulheres em risco de câncer de mama para receber tamoxifeno ou placebo. O uso de tamoxifeno foi associado a um risco aumentado de desenvolver TEV (Razão de Chance – RC 2,1; IC95% 1,1-4,1). O risco de desenvolver TEP ou EP foi significativamente maior durante os 5 anos de tratamento ativo com tamoxifeno (RR de 2,3; IC95% 1,4-3,9), mas não se manteve após sua interrupção.

Uma metanálise de sete ensaios clínicos e 30.023 pacientes, que comparou resultados em mulheres com câncer de mama designadas para tratamento com tamoxifeno ou um inibidor de aromatase, encontrou maior taxa de TEV naqueles que receberam tamoxifeno (2,8% vs. 1,6%).16 Uma análise de 13 ensaios do NSABP,17 que avaliou o risco de câncer de mama contralateral em 20.878 mulheres que receberam tamoxifeno após o tratamento primário para esta doença, encontrou risco aumentado de TEV com uso de tamoxifeno. Os riscos de EP, TVP e flebite superficial aumentaram duas a três vezes nas pacientes tratadas com tamoxifeno, e 11 a 15 vezes nas pacientes tratadas com tamoxifeno mais quimioterapia.18 O STAR (Study of Tamoxifen and Raloxifene)11 sugere menor incidência de TVP e EP em mulheres que recebem raloxifeno vs. as tratadas com tamoxifeno. Este estudo randomizou 19.747 mulheres com risco de câncer de mama para uso do raloxifeno e tamoxifeno por 5 anos.

 Moduladores seletivos do receptor do estrogênio e acidente vascular cerebral

Na metanálise EBCTCG (Early Breast Cancer Trialists' Collaborative Group),6 que comparou 21.457 mulheres para receberem tamoxifeno ou placebo, houve aumento de AVC, porém sem significância estatística. Em estudo caso-controle de 11.045 mulheres com câncer de mama, o risco de AVC não foi aumentado pelo uso de tamoxifeno.19 Em metanálise que avaliou o uso de tamoxifeno na prevenção primária ou secundária em 39.601 pacientes com câncer de mama, a frequência de AVC isquêmico foi maior naqueles que receberam tamoxifeno do que nos controles.20 O tamoxifeno esteve associado a um aumento do risco de AVC, porém com risco absoluto pequeno.

No estudo RUTH (Raloxifene Use for The Heart),21 o raloxifeno foi associado a um risco aumentado de AVC fatal em comparação com o placebo. O IBIS-122 não demonstrou significância estatística entre os grupos de tratamento (tamoxifeno vs. placebo) nos eventos cerebrovasculares ou cardiovasculares. Subanálise do estudo MORE12 sugeriu que, em mulheres com alto risco para eventos arteriais, o raloxifeno reduziu a incidência de eventos coronários e AVC. Porém, após 8 anos de tratamento, a incidência de eventos cardiovasculares, coronarianos ou cerebrovasculares não diferiu significativamente entre os grupos tratados com raloxifeno e placebo. No estudo STAR,11 o risco de AVC foi semelhante nos grupos raloxifeno e tamoxifeno.

 Moduladores seletivos do receptor do estrogênio e perfil lipídico

Existem evidências de mudanças no perfil lipídico com o uso de MSRE. A redução do nível sérico de colesterol total e Lipoproteína de Baixa Densidade-Colesterol (LDL-c) é um consenso. No entanto, também foi relatado aumento do nível sérico de triglicerídeos. Sawada e Sato,23 relataram que o tamoxifeno reduziu os níveis de colesterol total e de LDL, assim como o aumento significativo dos triglicerídeos. Atalay et al.,24 não encontraram efeito significativo do tamoxifeno sobre o colesterol total ou Lipoproteína de Alta Densidade-Colesterol (HDL-c), mas relataram aumento limítrofe dos triglicerídeos. Em conjunto, estes estudos sugerem que, embora o tamoxifeno tenha reduzido a LDL-c de forma consistente, os efeitos sobre a HDL-c são discretos, e o uso do tamoxifeno aumenta o nível sérico de triglicerídeos. As alterações no perfil lipídico associadas ao uso do tamoxifeno estão resumidas na Tabela 1.

Tamoxifeno e perfil lipídico
Alterações Colesterol total LDL-c HDL-c Triglicerídeos
Tamoxifeno Redução Redução Alteração Discreta Aumento

LDL-c: lipoproteína de baixa densidade-colesterol; HDL-c: lipoproteína de alta densidade colesterol.

 Moduladores seletivos do receptor do estrogênio e doença arterial coronariana

Mesmo após a consolidação do uso clínico do tamoxifeno, não há evidência definitiva sobre seu efeito na Doença Arterial Coronariana (DAC). As evidências sugerem discreto efeito protetor do tamoxifeno para a morte por DAC. Existe controvérsia sobre os efeitos dos MSRE na aterosclerose e suas complicações (Tabela 2). A publicação do estudo RUTH (Raloxifene Use for The Heart)21 confirmou efeito neutro para o raloxifeno. As evidências disponíveis na literatura mundial sugerem efeitos neutros ou discretos benefícios do uso dos MSRE no risco cardiovascular global.25

Eventos associados ao uso dos moduladores seletivos de receptor do estrogênio (MSRE)
Estudo, ano Tipo de estudo Pacientes (n) MSRE avaliado/ comparação Câncer de mama TEV AVC DAC
STAR / Vogel et al.11 / 2006 Ensaio clínico 19.747 em pós‑menopausa Tamoxifeno e raloxifeno Redução do risco em 50% (in situ – tamoxifeno e raloxifeno e invasor – tamoxifeno) Aumento, raloxifeno < tamoxifeno em 30% Redução (tamoxifeno e raloxifeno) Aumento (tamoxifeno e raloxifeno)
MORE / Cauley et al.13 / 2001 Ensaio clínico 7.705 em pós-menopausa Raloxifeno e placebo Redução do risco em 72% após 4 anos Aumento Neutro Neutro
CORE / Martino et al.14 / 2004 Ensaio clínico 5.213 em pós-menopausa Raloxifeno e placebo Redução do risco em 59% Aumento
NSABP / Fisher et al.9 / 1998 Ensaio clínico 13.388 com risco de câncer de mama Tamoxifeno e placebo Redução do risco em 49% Aumento Aumento Neutro
IBIS-1 / Cuzick et al.8 / 2002 Ensaio clínico 7.152 com risco de câncer de mama Tamoxifeno e placebo Redução do risco 32% Aumento neutro neutro
RUTH / Barret-Connor et al.21 / 2006 Ensaio Clínico 10.101 em pós-menopausa Raloxifeno e placebo Redução do risco de câncer inavasor 55% Aumento de 44% Aumento de 49% Neutro

TEV: tromboembolismo venoso; AVC: acidente vascular cerebral; DAC: doença arterial coronariana.

No NSABP,26 13.388 mulheres com maior risco de câncer de mama foram distribuídas para receber tamoxifeno 20 mg ao dia ou placebo. O acompanhamento cardiovascular estava disponível para 13.194 mulheres, das quais 1.048 tinham DAC clinicamente manifesta. As taxas de eventos cardiovasculares não foram significativamente diferentes entre as mulheres que receberam tamoxifeno e as que receberam placebo, independentemente da doença preexistente. Estudo caso-controle de mulheres diagnosticadas com câncer de mama encontrou que o uso de tamoxifeno não esteve associado ao risco reduzido de infarto do miocárdio para os 137 casos de infarto observados.27 Outro estudo de caso-controle demonstrou que as mulheres com câncer de mama que receberam tamoxifeno tiveram risco reduzido de angina pectoris ou infarto do miocárdio (RC 0,4; IC95%, 0,2-0,7) em comparação com as pacientes que não receberam.28

Nordenskjold et al.,29 relataram redução significativa da mortalidade por DAC em mulheres que receberam 5 anos vs. 2 anos de tamoxifeno, com dose superior de 40 mg ao dia. O estudo conduzido pelo Early Breast Cancer Trialists’ Collaborative Group30 relatou redução na mortalidade por DAC em mais de 15 mil mulheres randomizadas para receber aproximadamente 5 anos de tamoxifeno vs. placebo, porém sem significância estatística (120 vs. 132 mortes; p = 0,06).

 Moduladores seletivos do receptor do estrogênio e aspirina

O câncer pode levar a um estado de hipercoagulabilidade, anormalidades plaquetárias e eventos tromboembólicos. As plaquetas podem contribuir com o processo de metástase pela promoção de angiogênese e pela liberação do Fator de Crescimento do Endotélio Vascular (VEGF).31,32 As plaquetas e os componentes da cascata de coagulação envolvem as células tumorais, o que impede a lise por células natural killer, permitindo a propagação de metástases.

O tamoxifeno aumenta rapidamente o cálcio livre em plaquetas humanas.33,34 Jhonson et al.,35 demonstraram que o tamoxifeno e seu metabólito 4-hidroxitoxiferaxifeno alteraram a função plaquetária, com redução do potencial angiogênico e metastático. As proteínas angiogênicas são liberadas durante o processo de ativação plaquetária, e a deposição de plaquetas é observada na localização do tumor.36 As formas alfa e beta do RE foram encontradas na membrana plaquetária.37,38 Alguns estudos sugeriram que o estradiol, bem como os metabólitos do tamoxifeno, pode aumentar a agregação plaquetária, sugerindo que a ocupação do RE pode influenciar na liberação de proteínas intraplaquetárias, como o VEGF e a endostatina, quando as plaquetas são estimuladas no ambiente tumoral.39

Holmes et al.,40 realizaram estudo que avaliou as concentrações de VEGF e endostatina antes e após tamoxifeno ou inibidores da aromatase em 30 mulheres com câncer de mama. A terapia com tamoxifeno resultou em aumento das concentrações de VEGF nas plaquetas, mas sem alteração no VEGF plasmático. O uso de aspirina atenuou o aumento de VEGF associado ao tamoxifeno e reduziu os níveis séricos de VEGF. Os dados deste estudo sugerem que a terapia antiplaquetária pode interferir nos níveis de proteína angiogênica em mulheres tratadas com terapia endócrina.

Mulheres com câncer de mama, que usaram tamoxifeno e 45 dias de aspirina, tiveram redução dos níveis intraplaquetários de VEGF, além de aumento dos níveis séricos e intraplaquetários do fator antiangiogênico trombospondina-1.41 Estas alterações se reverteram com a descontinuação da aspirina. Neste estudo, foi utilizada a dose de 325 mg ao dia. A aspirina diminuiu os efeitos pró-angiogênicos do tamoxifeno, sugerindo que a terapia antiplaquetária pode melhorar a eficácia do tamoxifeno. Cheng et al.,42 conduziram estudo que demonstrou que a aspirina não só inibe o crescimento da linha celular de câncer de mama RE-positivo MCF-7, como também possui função potencial para superar a resistência ao tamoxifeno nas linhas celulares MCF-7/TAM. A ação concomitante da aspirina faz com que as células se tornem mais sensíveis ao tamoxifeno, indicando que a aspirina pode regular proteínas, para superar a resistência ao tamoxifeno.

O estudo RUTH21 avaliou os efeitos da terapia antiplaquetária concomitante ao uso de raloxifeno no risco de TEV. O aumento do risco de TEV com o raloxifeno em comparação com o placebo não foi diferente entre as mulheres que usaram agentes antiplaquetários e aquelas que não usaram.43 As principais conclusões dos estudos citados estão sumarizadas na Tabela 3.

Aspirina e moduladores seletivos de receptores de estrogênio (MSRE)
Autor, ano Tipo de estudo Pacientes (n) MSRE e/ou aspirina Principais Conclusões
Holmes et al.,40 2008 Ensaio clínico 30 Tamoxifeno ou inibidor da aromatase + AAS AAS atenuou o aumento de VEGF associado ao tamoxifeno
Holmes et al.,44 2010 Coorte prospectiva 4.164 AAS Redução de recorrência e morte por câncer de mama
Holmes et al.,41 2013 Ensaio clínico 12 Tamoxifeno + AAS Redução de VEGF e aumento de TSP-1
Holmes et al.,45 2014 Caso-controle 27.426 AAS Não há beneficio durante doença terminal
Yang et al.,46 2017 Coorte retrospectiva 148.739 AAS Redução de risco de câncer de mama em diabéticos
Fraser et al.,47 2014 Coorte 4.627 AAS Redução do risco de morte por todas as causas
Jhonson et al.,48 2002 Coorte prospectiva 27.616 AAS Redução de risco de câncer de mama
Harris et al.,53 1999 Coorte prospectiva 32.505 AAS/ ibuprofeno Redução de risco de câncer de mama
Duvernoy et al.,43 2010 (RUTH Trial) Ensaio clínico 10.101 Raloxifeno + AAS Não alterou o risco de TEV

AAS: ácido acetilsalicílico; VEGF: fator de crescimento do endotélio vascular; TSP-1: trombospondina-1; TEV: tromboembolismo venoso.

 Aspirina e prevenção do câncer

Estudo prospectivo observacional com 4.164 mulheres com câncer de mama, demonstrou que, entre as mulheres que vivem pelo menos 1 ano após o diagnóstico de câncer de mama, o uso de aspirina foi associado com redução no risco de recorrência e morte por câncer de mama.44 De modo oposto, outro estudo, com 27.426 mulheres com câncer de mama, demonstrou que não houve associação entre o uso de aspirina e a morte por câncer de mama.45

Um estudo de coorte retrospectivo foi realizado em Taiwan com 148.739 mulheres diabéticas, das quais 27.378 com uso de aspirina entre 75 mg e 165 mg ao dia foram comparadas com mulheres sem o uso de aspirina. Em geral, o uso de aspirina reduziu o risco de câncer de mama em 18% (Hazard Ratio - HR de 0,82; IC95% 0,71-0,94). Especificamente, observou-se dose cumulativa de aspirina superior a 88.900 mg para reduzir o risco de câncer de mama em 47%.46 Uma coorte na Escócia identificou 4.627 mulheres com câncer de mama ao longo de 11 anos. O uso da aspirina após o diagnóstico foi identificado em 1.035 mulheres (22,4%). A maioria usou a dose de 75 mg ao dia. Concluiu-se que a aspirina em baixa dose esteve associada à redução do risco de morte por todas as causas e câncer de mama.47 Outra coorte, com 27.616 mulheres na pós-menopausa, identificou 938 casos de câncer de mama em 6 anos de seguimento, traduzindo RR de 0,71 (IC95% 0,58-0,87) para aquelas que fizeram uso de aspirina no mínimo seis vezes por semana, quando comparadas com as que não usaram esta medicação.48 Evidências de estudos de caso-controle e coorte sugerem redução do risco de câncer de mama em cerca de 10% para a aspirina.49,50 Resultados semelhantes foram encontrados com outros AINEs e inibidores da Ciclo-Oxigenase 2 (COX-2).51

Rothwell et al.,52 analisaram sete ensaios randomizados para o uso regular de aspirina com duração mínima de 4 anos para determinar o efeito da aspirina sobre o risco de morte por câncer. A aspirina diária reduziu mortes devido a vários tipos de câncer durante e após os estudos. O benefício aumentou com a duração do tratamento e foi consistente em todas as diferentes populações estudadas.

Harris et al.,53 encontraram 393 casos de câncer de mama em 32.505 pacientes após 5 anos de seguimento. Este estudo relatou redução de 50% na incidência de câncer de mama com uso de ibuprofeno (p < 0,01) e de 40% com uso regular de aspirina (p < 0,05), sugerindo que outros AINEs também podem ser efetivos na profilaxia do câncer de mama.

A aspirina emergiu como o AINE mais provável para uso em quimioprevenção pelos benefícios também na prevenção de eventos cardiovasculares. Outros AINEs são também estudados como adjuvantes na quimioprevenção de diversos tipos de câncer, especialmente o colorretal, de mama e de estômago, embora estes medicamentos não ofereçam cardioproteção.54 A redução na mortalidade é mais evidenciada no câncer de colón, provavelmente no de próstata e, possivelmente, também no de mama.55,56

Discussão

Os ensaios clínicos citados nesta revisão relataram aumento de TEV com o uso de MSRE e, em relação aos eventos cerebrovasculares e coronarianos, os resultados foram discordantes. A terapêutica atualmente empregada com quimioterapia e terapia hormonal tem reduzido a mortalidade por câncer de mama, porém a morbimortalidade ainda é alta, com efeitos colaterais consideráveis e elevados custos financeiros. Existe grande expectativa por novos tratamentos com baixa toxicidade e redução de custos.

A aspirina está incorporada à prática clínica há mais de 100 anos, com baixo custo, tornando-a atraente como um potencial tratamento adjuvante. Os estudos observacionais incluídos nesta revisão sugerem redução de risco de câncer de mama nas pacientes em uso regular de aspirina. Ensaios clínicos randomizados são necessários para avaliar o impacto do uso de aspirina na prevenção do câncer de mama, seja na associação com a terapia endócrina, ou na sobrevida sem doença, em pacientes com câncer de mama.

O uso da aspirina é consensual para a prevenção secundária de infarto do miocárdio e do AVC isquêmico em pacientes com doença cardiovascular preexistente e para prevenção primária em grupos de alto risco. As indicações atuais para o uso profilático da aspirina são baseadas no risco cardiovascular diante dos efeitos colaterais, especialmente sangramento gastrintestinal, cuja incidência aumenta com a idade. Outros benefícios potenciais do uso da aspirina precisam ser comprovados no contexto do câncer.

 Conclusão

O câncer de mama é o tumor mais frequentemente diagnosticado em mulheres de todo o mundo, com impacto importante na morbimortalidade. Embora existam controvérsias entre os estudos analisados, considerando os possíveis benefícios na prevenção do câncer de mama e na redução de eventos cardiovasculares, esta revisão sistemática sugere que a terapêutica com moduladores seletivos de receptores de estrogênio e aspirina deve ser melhor investigada, e ressalta a necessidade da realização de estudos randomizados. Estudos futuros devem abordar questões como dose, idade para início, duração, eficácia e segurança de um regime de tratamento claramente definido.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é produto de pesquisa em Cardio-oncologia do Mestrado de Andréa de Melo Leite pela Universidade Federal Fluminense.

Aprovação ética e consentimento informado

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.