Elsevier

The Breast

Volume 15, Issue 3, June 2006, Pages 301-312
The Breast

REVIEW
Comparative assessment of lipid effects of endocrine therapy for breast cancer: Implications for cardiovascular disease prevention in postmenopausal women

https://doi.org/10.1016/j.breast.2005.08.033Get rights and content

Summary

Cardiovascular disease (CVD) is the leading cause of death in the developed world for both men and women. Women experience significant alterations in lipid profiles during the years following menopause, including a reduction in plasma high-density lipoprotein cholesterol and an elevation of plasma low-density lipoprotein cholesterol, and are at an increased risk of CVD. These changes are due in part to the reduction in estrogen production following the onset of the menopause. Therefore, agents that have anti-estrogenic effects, such as most endocrine therapies for breast cancer, may increase the risk of CVD.

Tamoxifen, historically the standard endocrine therapy, has an overall beneficial effect on lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect and patients treated with tamoxifen did not experience fewer cardiovascular events compared with those receiving placebo. Indeed, a number of studies have shown that tamoxifen may have a detrimental effect, with a significantly increased risk of venous thromboembolic events, pulmonary embolism and stroke.

The third-generation aromatase inhibitors (AIs) have demonstrated an improvement in efficacy and tolerability over previous treatments. Since they have a different mechanism of action to tamoxifen, they are not anticipated to exert the same impact on lipid profiles. Clinical trials with anastrozole demonstrated no clinically relevant impact on lipid profiles in postmenopausal patients with advanced breast cancer. However, as lipid profiles are surrogate endpoints, the most appropriate endpoint is the incidence of cardiovascular events in long-term studies. This is of particular relevance in the treatment of early breast cancer, where endocrine agents may be used in the adjuvant setting for periods of 5 years or more. Long-term adjuvant anastrozole treatment resulted in significantly fewer thromboembolic and cerebrovascular events and a similar incidence of ischemic cardiovascular events compared with tamoxifen. The effects of the other AIs on lipid levels are variable, and any correlation with cardiovascular events is currently unknown.

Introduction

Cardiovascular disease (CVD), principally heart disease and stroke, is the leading cause of death in the developed world. In the US approximately 950,000 people die of CVD each year, making it responsible for more than 40% of all deaths.1 In women, the risk of cardiovascular morbidity and mortality increases dramatically in the postmenopausal setting compared with the premenopausal.2 This increase in risk is due to changes in lipid metabolism, including a reduction of plasma high-density lipoprotein cholesterol (HDL-C) and elevation of low-density lipoprotein cholesterol (LDL-C).3, 4 It has been suggested that these alterations in lipid metabolism may be at least partially because of the dramatic decrease in the production of estrogen associated with the onset of menopause. The so-called “metabolic syndrome” (obesity, glucose intolerance, low serum HDL-C, high serum triglycerides, hypertension) has been associated with increased risk of breast cancer in postmenopausal women.5 Hormone or estrogen replacement therapy was postulated to exert a cardioprotective effect in postmenopausal women as a result of restoring plasma lipid profiles back to premenopausal levels. However, although hormone replacement therapy (HRT) has been shown to be associated with reduced risk of CVD in observational studies, results from randomized controlled trials, the Women's Health Initiative (WHI) for primary prevention of heart disease,6 and the Heart and Estrogen/progestin Replacement Study (HERS) for secondary prevention7 were contradictory, with no benefit, or even an increased CVD risk.

The association between the decrease in estrogen levels at menopause and an increase in CVD presents an obvious parallel with many of the endocrine agents used in the treatment of postmenopausal women with breast cancer. Many of these agents exhibit anti-estrogenic effects and, as a result, may have a detrimental effect on lipid profiles, and an unfavorable impact upon cardiovascular risk. The potential influence of endocrine therapy upon the risk of CVD is important, since an increasing number of women are receiving hormonal therapy for many years, and will go on to live for a prolonged period of time after the cessation of treatment. It is necessary to consider whether these women, although cured of their breast cancer or living with their disease, have an altered risk of CVD.

This review focuses on the effects that endocrine therapies used to treat postmenopausal women with breast cancer have on lipid profiles, and how changes in lipid levels may influence the risk of developing CVD. The effect that endocrine agents have on cardiovascular risk is of particular importance to postmenopausal women, both in the adjuvant setting, where endocrine therapies may be given for periods of 5 years or longer, and the treatment of advanced disease, where patients may receive sequential treatment with a series of endocrine agents.

Section snippets

Background to endocrine therapy

The major purpose of endocrine therapy for women with breast cancer is to remove the growth-stimulatory effects of estrogens on tumor cells. In postmenopausal women, the two most commonly used strategies are inhibition of endogenous estrogen production, as in the case of aromatase inhibitors (AIs), or interference with estrogen signaling by binding to the cognate receptor protein, as with the selective estrogen receptor (ER) modulators or ER antagonists.

Risk factors for cardiovascular disease

Over the past 40 years, a wealth of data derived from large-scale epidemiological studies, such as the Framingham Heart Study, have indicated that elevation of total cholesterol is an important risk factor for the development of CVD.39, 40 In prospective studies, low levels of HDL-C (which largely comprises apolipoprotein [apo] A-I and apo A-II) have proved to be the lipid risk factor most correlated with an increased risk of coronary heart disease (CHD).41, 42 Low levels of serum HDL-C are

Effects of tamoxifen on lipid profiles and cardiovascular events

A number of studies have demonstrated that tamoxifen has a favorable effect on lipid profiles in postmenopausal women with reductions in both total cholesterol and LDL-C levels,54, 55, 56, 57 an effect which may be attributed to its partial agonist activity at the level of the ER. The long-term effects of tamoxifen on lipid profiles have also been investigated in the adjuvant setting.56 Five years of adjuvant tamoxifen therapy resulted in a significant reduction from baseline compared with

Menopause, hormone replacement therapy and cardiovascular disease

The question of why HRT for menopausal women produces seemingly favorable changes in lipid profile, yet does not lead to preventative action on CVD, is an intriguing one. As a result, it is important to briefly consider some of the other factors that may be involved in determining risk of CVD. These will raise some important questions that may have a wider bearing on our understanding of an association between endocrine therapy for breast cancer and risk of CVD. Indeed, while lipid profiles are

Conclusions

Although the relationship between lipid changes and cardiovascular events is unclear, there is concern that antiestrogen therapies for breast cancer may affect a woman's risk of developing CVD.

Despite tamoxifen's favorable impact on lipid profiles overall, these benefits do not translate into a cardioprotective effect.8 Indeed, tamoxifen treatment increases the risk of thromboembolic and ischemic cerebrovascular events, reinforcing the importance of cardiovascular events as a clinical endpoint.

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