REVIEWComparative assessment of lipid effects of endocrine therapy for breast cancer: Implications for cardiovascular disease prevention in postmenopausal women
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.
References (74)
- et al.
Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham population
Am Heart J
(1986) - et al.
Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence
Prev Med
(1991) - et al.
Anastrozole (Arimidex™) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results
Eur J Cancer
(2003) - et al.
Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men
Lancet
(1986) - et al.
Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols
Am J Cardiol
(1980) - et al.
High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport
Atherosclerosis
(1996) - et al.
Current and future treatment of hyperlipidemia: the role of statins
Am J Cardiol
(1998) - et al.
Hypertriglyceridemia as a cardiovascular risk factor
Am J Cardiol
(1998) Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome
Am J Cardiol
(1998)- et al.
Lipid changes on hormone therapy and coronary heart disease events in the Heart and Estrogen/progestin Replacement Study (HERS)
Am Heart J
(2003)
Anastrozole therapy and lipid profile: an update
Eur J Cancer Suppl
Effect of letrozole on the lipid profile in postmenopausal women with breast cancer
Eur J Cancer
The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, ‘Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients’
Ann Oncol
Effects of anastrozole on the lipid profile in postmenopausal breast cancer patients—a preliminary study
Eur J Cancer Suppl
Failure to demonstrate myocardial ischaemia in patients with angina and normal coronary arteries. Evaluation by continuous coronary sinus pH monitoring and lactate metabolism
Eur Heart J
Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk
J Natl Cancer Inst
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial
JAMA
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women
JAMA
Tamoxifen for early breast cancer: an overview of the randomised trials
Lancet
Estrogens and antiestrogens
Adjuvant tamoxifen in breast cancer treatment in postmenopausal women: occurrence of thromboembolic complications
Oncol Rep
Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors
J Natl Cancer Inst
Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study
J Natl Cancer Inst
Tamoxifen and risk of idiopathic venous thromboembolism
Br J Clin Pharmacol
Acquired tamoxifen resistance in human breast cancer—potential mechanisms and clinical implications
Anticancer Drugs
Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer
J Clin Oncol
Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment
J Clin Oncol
Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial
J Clin Oncol
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group
J Clin Oncol
Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study
J Clin Oncol
Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma
Cancer
Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group
J Clin Oncol
Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group
Cancer
Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group
J Clin Oncol
Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate
J Clin Oncol
Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group
J Clin Oncol
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