The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L)

K. M. Wasan1,*, P. E. Goss2, P. H. Pritchard3, L. Shepherd4, M. J. Palmer4, S. Liu4, D. Tu4, J. N. Ingle5, M. Heath3, D. DeAngelis3 and E. A. Perez6

1 Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada; 2 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 3 Healthy Heart Program, St Paul's Hospital, Vancouver, BC; 4 National Cancer Institute of Canada, Clinical Trials Group, Queen's Cancer Research Institute, Queen's University, Kingston, ON, Canada; 5 Mayo Clinic, Rochester, MN; 6 Mayo Clinic, Jacksonville, FL, USA

* Correspondence to: Dr K. M. Wasan, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall Vancouver, British Columbia V6T 1Z3, Canada. Tel: +1-604-822-4889; Fax: +1-604-822-3035; Email: kwasan{at}interchange.ubc.ca


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
Background:: The purpose of this study was to evaluate changes in serum lipid parameters {cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein(a) [Lp(a)]}, in postmenopausal women receiving letrozole or placebo after adjuvant tamoxifen for early stage breast cancer (NCIC CTG MA.17L).

Patients and methods:: MA.17L is a substudy of MA.17, a randomized, double-blind, placebo-controlled trial of letrozole 2.5 mg taken daily for 5 years in postmenopausal women with primary breast cancer completing ~5 years of prior adjuvant tamoxifen. Patients consenting to participate in this companion study had blood drawn and lipid parameters (total cholesterol, HDL cholesterol, LDL cholesterol, Lp(a), triglycerides) evaluated at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. It was required that women be non-hyperlipidemic and not taking lipid-lowering drugs at time of entry on this trial.

Results:: Three hundred and forty seven women were enrolled in the study. The letrozole and the placebo groups demonstrated marginally significant differences in the percentage change from baseline in HDL cholesterol at 6 months (P=0.049), in LDL cholesterol at 12 months (P=0.033) and triglycerides at 24 months (P=0.036). All comparisons of lipid parameters at other time points were not significantly different between the two treatment groups. No statistically significant differences in the number of patients exceeding the thresholds defined for the lipid parameters were found between the two treatment groups.

Conclusions:: The MA.17 trial demonstrated a significant improvement in disease-free survival with the use of letrozole as extended adjuvant therapy post tamoxifen. Results from this study suggests that letrozole does not significantly alter serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides or Lp(a) in non-hyperlidiemic postmenopausal women with primary breast cancer treated up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of extended adjuvant letrozole in postmenopausal women following standard tamoxifen therapy.

Key words: letrozole, primary breast cancer, postmenopausal women, serum lipids, tamoxifen


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
Approximately two-thirds of women with breast cancer have tumors which overexpress estrogen (ER) and/or progesterone receptors (PgR) and will benefit from anti-estrogen therapy [1Go, 2Go]. Tumor estrogen deprivation has traditionally been achieved with the use of tamoxifen, a selective estrogen receptor modulator (SERM). Tamoxifen has tissue-specific antagonistic or agonist effects, the latter being responsible for a favorable effect on lipid metabolism in menopausal women. In postmenopausal women after ovarian failure, estrogen is synthesized in peripheral tissues such as fat, skin and muscle by conversion of adrenal androgen precursors to estrogens by the enzyme complex aromatase (estrogen synthase). Inhibitors of aromatase profoundly suppress circulating and tumor concentrations of estrogen and thus offer an alternative way to deprive tumors of this important growth-promoting ligand [2Go–5Go].

Several changes in parameters of lipid metabolism have been noted in women on estrogen replacement therapy including increased high-density lipoprotein (HDL), lower low-density lipoprotein (LDL), lower very-low density lipoprotein (VLDL) cholesterol/triglyceride ratio, increased clearance of LDL via an up-regulated LDL receptor, diminished penetration and degradation of LDL in the arterial wall and inhibition of LDL oxidation [1Go, 6Go–8Go]. Estrogen replacement does not reduce the risk of cardiovascular disease as evidenced by the Women's Health Initiative (WHI) study. Chronic tamoxifen therapy, due to its estrogenic activity, results in a significant decrease in total and LDL cholesterol. Thus, it is anticipated that women completing 5 years of tamoxifen could have an adverse rise in total serum and LDL cholesterol.

Letrozole is one of three third generation aromatase inhibitors, which have been shown to produce clinical remissions of disease in patients with advanced breast cancer. Importantly, letrozole has now also been shown to be highly effective in reducing the risk of recurrent disease when taken after ~5 years of tamoxifen in women with early stage breast cancer. In this extended adjuvant setting, letrozole reduces the risk of breast cancer recurrence by 42%, irrespective of nodal status and prior chemotherapy. These otherwise healthy postmenopausal women are already at risk for cardiovascular disease and thus concern has been raised about the possible effects of chronic estrogen suppression on lipid metabolism.

Because cardiovascular disease is the most common cause of death in postmenopausal women [6Go–8Go], effects on this outcome could play a pivotal role in the risk–benefit analysis of the use of letrozole and possible impact on quality of life in women taking the drug [2Go–5Go]. Our hypothesis in this study was that long-term administration of letrozole in women with primary breast cancer completing five or more years of adjuvant tamoxifen would significantly increase the total and LDL cholesterol levels in the patient in comparison to the baseline levels prior to letrozole administration.

Although there are several studies comparing the clinical efficacy of third generation aromatase inhibitors with other endocrine therapies [3Go–5Go, 9Go, 10Go], consistent findings of the effects of letrozole on serum lipids have yet to be established. Elisaf et al. [5Go] reported an increase in serum total cholesterol (~8% from baseline), LDL cholesterol (~15% from baseline) and apolipoprotein B (~17% from baseline) following 8–16 weeks of therapy in a limited number of postmenopausal women with advanced breast cancer. The authors extrapolated these findings to suggest a significant increase in the atherogenic risk ratios, total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol [5Go]. In contrast, however, studies by Harper-Wynne et al. [3Go] and Heshmati et al. [4Go] found no significant effect on serum lipids (total, HDL or LDL cholesterol) after 3 and 6 months of therapy with letrozole. Thus, further studies with letrozole in a population of women without metastatic breast cancer, a confounding variable, were needed. MA.17 provided a good vehicle for studying these effects because it was a placebo-controlled trial. The limitation, however, was the fact that lipid metabolism would be affected by prior tamoxifen treatment.

The first pre-planned interim analysis of MA.17 showed a highly statistically significant increase in disease-free survival for women treated with letrozole, and on the advice of the Data and Safety Monitoring Committee all the women in the main study, including those participating in MA.17L, had their study medication unblinded. Those on placebo were offered letrozole treatment starting immediately for 5 years [2Go]. At the time of unblinding, only a few patients in this study had been followed for more than 36 months. It was thus decided for the purposes of this report to analyze the changes in serum lipid parameters at 6, 12, 24 and 36 months.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
Study design
A randomized, double-blind, placebo-controlled trial of letrozole in postmenopausal women with primary breast cancer who had completed ~5 years (ranging between 4.5 and 6 years) of adjuvant tamoxifen therapy was conducted [2Go]. As previously reported, women were randomly assigned to receive letrozole (2.5 mg) or placebo orally daily for 5 years and stratified according to the tumor hormone-receptor status (positive or unknown), axillary lymph nodes involved with disease or not, and receipt or not of previous adjuvant systemic chemotherapy [2Go].

Patients were entered into the MA.17 core study if they fulfilled the following criteria: were postmenopausal defined as ≥50 years at the start of adjuvant tamoxifen; <50 years but postmenopausal at the initiation of tamoxifen; <50 years at the start of tamoxifen but having had prior bilateral oophorectomy; premenopausal women <50 years at the start of tamoxifen but who became amenorrheic during chemotherapy or treatment with tamoxifen, and women with postmenopausal luteinizing or follicle stimulating (LH/FSH) levels; prior adjuvant tamoxifen taken for 4.5–6 years; histologically confirmed primary breast cancer; ER- and/or progesterone receptor (PgR)-positive tumors (defined as >10 fmol/mg protein), or positive by immunochemistry; tamoxifen discontinued <3 months prior to enrolment; Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 and life expectancy >5 years. All women had a mandatory chest X-ray and mammogram prior to randomization. Only in patients who were symptomatic or had abnormal blood work did metastatic disease need to be ruled out with imaging. Ineligibility included concurrent use of investigational drugs, and prior concurrent malignancy other than skin cancer or carcinoma in-situ of the cervix. Contraindicated concomitant medications included systemic hormone replacement therapy or SERMS. Intermitted vaginal estrogens were permitted. This MA.17L companion study to assess lipid profile was conducted in centers in both Canada and the USA participating in the core MA.17 protocol [2Go]. Eligible MA.17 patients, who were non-hyperlipidemic and not taking lipid lowering agents, had the option of participating in MA.17L. Patients who agreed to participate had blood drawn in a fasting state and serum lipid levels assessed at baseline, 6 months, 12 months and yearly thereafter until completion of protocol therapy. A final sample was planned for 12 months following completion of the MA.17 protocol treatment. All serum lipid evaluations were done at the Atherosclerosis Specialty Laboratory (Central Laboratory), St Paul's Hospital, Vancouver, British Columbia.

Participating centers and data collection
Clinical data were collected by participating members of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the North Central Cancer Treatment Group (NCCTG) and stored by the operational headquarters of the NCIC CTG in Kingston, Ontario. NCIC CTG was responsible for all data management.

Lipid analysis
Fasting lipid levels were assessed by the Atherosclerosis Specialty Laboratory at St Paul's Hospital in Vancouver, British Columbia in a blinded fashion and transmitted to the NCIC CTG at regular intervals. The atherosclerosis laboratory has been approved and standardized by the Canadian Cholesterol Reference Method Laboratory Network. Lipid measurements {total cholesterol, total triglyceride, HDL cholesterol, LDL cholesterol and lipoprotein(a) [Lp(a)]} were conducted at baseline (prior to drug administration), 6 months and 1, 2 and 3 years following the initiation of letrozole therapy. Total cholesterol, HDL cholesterol and triglyceride levels were determined using an enzymatic assay method previously published [1Go]. Lp(a) was determined using ELISA method previously published [1Go]. All patients had been fasting for a minimum of 16 h before their blood samples were drawn. When serum triglycerides are <4.5 mmol/l the quantity of cholesterol in VLDL has an approximately constant linear relationship with total serum triglyceride concentration. This led to the development of the Friedewald formula [11Go], which permits the calculation of the LDL cholesterol from the HDL cholesterol and the concentrations of total serum cholesterol and triglycerides [11Go], as follows:

LDL cholesterol = total serum cholesterol – [HDL cholesterol + (total triglyceride/5)] mmol/l

This formula is not applicable to non-fasting sera or patients with type III hyperlipoproteinaemia.

Statistical methods
For each lipid parameter, the percentage change at a given time of assessment from the baseline was defined as the ratio (x100%) of the change from baseline, which was calculated as the difference between the measurement at this given time and the baseline measurement, and the baseline measurement itself. Analysis of baseline characteristics was based on all randomized patients who had baseline observations. At each time point after randomization, only the patients who had both the observations at baseline and the time point were included in the analysis. The Wilcoxon rank-sum test was used to compare the percentage changes between the two treatment arms for each of the lipid parameters.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
Randomization and pre-treatment characteristics
The study was closed to accrual in May 2002. Three hundred and forty-seven patients randomized on MA.17 were enrolled in the study, 183 on letrozole and 164 on placebo. Thirty-seven patients (14 on letrozole and 23 on placebo) were deemed ineligible after they were enrolled, 33 because they were hyperlipidemic on baseline sample and four for other minor protocol violations. All patients were analyzed based on intent to treat, regardless of whether they were eligible.

The baseline characteristics of the patients are presented in Table 1. The majority of the patients (91.1%) were white. The median age in both treatment arms was 63 years and most (74%) were <70 years; 89.9% of the patients had a performance status 0; most (79.8%) were 50 years or older when they started prior tamoxifen.


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Table 1. Pretreatment characteristics at baseline (data set: all randomized patients)

 
Five percent of patients had a history of coronary heart disease. A history of the following risk factors for heart disease was collected at baseline but these were not verified in the patient's medical records: hypertension, hypercholesterolemia, diabetes, history of smoking, myocardial infarction, angina requiring coronary artery bypass graft, thromboembolic events and strokes. The median number of baseline risk factors for heart disease was 1, ranging between 0 and 3 (Table 2).


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Table 2. Heart disease and risk factors at baseline (data set: all randomized patients)

 
These characteristics were similar to those of the overall MA.17 population.

Treatment exposures
Tables 3A and B summarize, respectively, the duration of study medication (years), which was defined as the date of randomization to the date of the final dose of study medication, and the concomitant medications taken by the patients during the study. The treatment durations were comparable between the two treatment arms. More patients on placebo received steroids at least once during the study while more patients on letrozole had taken thiazide diuretics.


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Table 3A. Duration of study medication (data set: all treated patients)

 

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Table 3B. Summary of concomitant medications during treatment (data set: all treated patients)

 
Lipid parameters
The mean, standard deviation (SD), and the 95% confidence interval (CI) for the baseline values of the lipid parameters [cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and Lp(a)] and for the percentage changes in them at each time point are presented in Table 4. The two treatment groups demonstrated marginally significant differences in the percentage changes in HDL cholesterol at 6 months, in LDL cholesterol at 12 months and in triglycerides at 24 months, but not at other time points. The number of patients exceeding the threshold defined by the lipid parameters at any one time during the study is summarized in Table 5. No statistically significant differences were found between the two treatment groups in terms of the number of patients reaching the threshold.


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Table 4. Baseline lipid parameters and percentage change in lipid parameters from baseline (data set: all randomized patients)

 

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Table 5. Number of patients exceeding threshold defined by the lipid parameters at any time during the study (data set: all randomized patients)

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
Aromatase inhibitors are becoming widely used in the treatment of both advanced and early stage breast cancer in postmenopausal women. In conjunction with ovarian function suppression they are also now being tested in premenopausal women. Chronic adjuvant endocrine therapy is thus administered to a large number of women, most of whom will not experience recurrence of breast cancer but all of whom are vulnerable to toxicities. Thus, effects of inhibiting estrogen synthesis on general health and quality of life are important. As women age, cardiovascular disease and osteoporosis are particularly common. Both are, in part, estrogen regulated. One possible contributory mechanism of the aromatase inhibitors to cardiovascular risk would be an adverse effect on lipid metabolism.

Estrogen is known to reduce total cholesterol, LDL-cholesterol and Lp(a) and, to a lesser extent, to increase HDL cholesterol levels. Accumulating evidence suggests that estrogens also inhibit LDL oxidation and oxidized LDL is particularly atherogenic. However, the effect on triglycerides is not as clear. Oral estradiol, and especially conjugated estrogens, increase serum triglycerides, whereas estrogens that are delivered by non-oral routes of administration decrease serum triglyceride concentrations [12Go]. Tamoxifen has also been shown to affect lipid levels in a favorable way. Although tamoxifen is used therapeutically for its principal anti-estrogen action, it also possesses some estrogen-like properties, resulting in significant decreases in total and LDL cholesterol serum levels and a concomitant rise in serum HDL cholesterol [1Go, 9Go, 13Go–15Go]. The lipid levels recorded in this study in women completing tamoxifen and receiving no further therapy have not previously been documented.

To address the concern that letrozole might have an adverse effect on lipid metabolism we conducted this companion study in women on letrozole or placebo, randomized in a double blind manner. Of importance in interpreting the results is that all patients were withdrawn from ~5 years of adjuvant tamoxifen just prior to entry on this trial. Thus, our results represent the effects of tamoxifen withdrawal on markers of lipid metabolism in the placebo group of our study. These have not been previously reported. In addition those patients receiving letrozole experienced both the effects of tamoxifen withdrawal and the effects of the aromatase inhibitor on their lipid levels. Our results indicate that both the letrozole-treated and placebo-treated control groups experienced an increase in total and LDL cholesterol and total triglyceride levels compared to baseline throughout the duration of the study. We attribute this ‘rebound effect’ as a result of being taken off tamoxifen following 5 years of therapy [1Go, 13Go–15Go].

The clinical significance of this increase in lipid levels after tamoxifen is uncertain but in part may have been compensated by the beneficial effect previously experienced from tamoxifen. Thus, considering both the positive and negative effect on lipid metabolism, sequencing letrozole after tamoxifen may not have a large net detrimental effect compared to age-matched controls in the general population who had received neither tamoxifen nor the aromatase inhibitor. Our study was not designed to answer that question and this remains to be determined. We did not, however, find any statistically significant difference in lipid levels between the aromatase inhibitor and placebo at 36 months of treatment, although the sample sizes at this time point were small. Our findings are consistent with the results reported by Harper-Wynne et al. [3Go] and Heshmati et al. [4Go] who demonstrated that letrozole had no significant effect on serum lipids (total, HDL or LDL cholesterol) following a much shorter course of therapy (3 and 6 months of therapy, respectively). While failure to affect lipid levels adversely might seem somewhat surprising, it underscores the fact that the true physiologic effects of estrogen on postmenopausal health are not understood, and in particular emphasizes that lowering postmenopausal estrogen levels should not automatically lead to the assumption that it will have the opposite effect of estrogen supplementation. Krag et al. [16Go] reported at ASCO 2004 in New Orleans on the effects of the steroidal aromatase inhibitor exemestane in a placebo-controlled trial in postmenopausal women naïve to prior exposure to tamoxifen. They showed that after 2 years of exemestane therapy, except for a non-significant reduction in HDL cholesterol in the exemestane group, the lipid profile (total cholesterol, LDL cholesterol, triglycerides, ApoAI and ApoB) and homocysteine levels are similar in exemestane and placebo-controlled patients [16Go].

Alteration of lipid levels is only one way in which endocrine therapies may affect cardiovascular risk, and indeed alteration in the coagulation pathway may be more important both for estrogen replacement therapy and for tamoxifen. Tamoxifen has been associated with cardiovascular events more because of venous thromboembolic effects [17Go] than effects on lipid levels. It is conceivable that aromatase inhibitors, by lowering estrogen, may exert an anti-coagulant effect [2Go, 9Go, 10Go] and thereby, if anything, reduce the risk of cardiovascular events [2Go, 9Go, 10Go]. This possibility merits evaluation in future studies of aromatase inhibitors.

This companion trial was reported in conjunction with the results of the main MA.17 study. A recently presented report of a final analysis of this trial reported an improvement in disease-free survival was achieved earlier than anticipated with a hazard rate of 0.58, indicating a 42% reduction in risk of recurrence [18Go]. In addition, a more detailed and mature toxicity evaluation compared with that previously reported showed no difference in the incidence of cardiovascular events between letrozole and placebo. This is reassuring in that if differences were to be caused by letrozole one would expect them to occur early in follow-up, as they did in the hormone replacement studies and in the trials of tamoxifen in healthy women [19Go–21Go]. All of the patients in the MA.17 trial continue to be followed for safety, in spite of the early unblinding of the study, and may contribute data which could help our insight into late cardiovascular events on chronic letrozole administration. In addition, as the optimal duration of giving adjuvant letrozole after tamoxifen has not been established by the MA.17 trial, women completing the initial 5 years of letrozole and remaining free of recurrent breast cancer will be offered re-randomization to a further 5 years of letrozole or placebo. A detailed sub-study of lipid metabolism and other intermediate markers of cardiovascular risk, including the coagulation pathway, are being planned.

It should be noted that women on MA.17 with abnormal lipid parameters at baseline or on lipid-lowering therapy were excluded from this companion study making the sample size smaller than one would like. Future evaluation of such women is also necessary, as from a practical standpoint these women could also be considered for letrozole as adjuvant therapy for early stage breast cancer. A study specifically in these ‘high risk’ women is currently being considered as part of the re-randomization of women on the MA.17 trial.

Furthermore, there is evidence to support that change in plasma lipids alone are not necessarily the only factor associated with modifying the risk of a cardiovascular event. Tamoxifen has been associated with cardiovascular events as a result of venous thromboembolic effects rather than actual through effects on lipid levels [17Go], while the aromatase inhibitors such as letrozole, by lowering estrogen, may act as anti-coagulants [2Go, 9Go, 10Go] and thus protect against cardiovascular events [2Go, 9Go, 10Go].

In conclusion, results from this study do not support the hypothesis that letrozole significantly alters serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides and Lp(a) in non-hyperlidemic postmenopausal women with primary breast cancer treated with letrozole up to 36 months following at least 5 years of adjuvant tamoxifen therapy. These findings further support the tolerability of letrozole and its use as extended adjuvant therapy in postmenopausal women following standard tamoxifen therapy.


    Conflict of interest
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
PEG has received speaker's honoraria from Novartis and industry funding. JNI has received honoraria from Novartis, Pfizer and Taiho consultations. KMW has received research funding from Pfizer, Forbes Medi-Tech Inc., Eisai Inc. and Enzon Pharmaceuticals Inc. EAP has received research funding from Novartis and Pfizer.


    Acknowledgements
 
The authors would like to thank all the women who participated in this study, the investigators of the NCCTG and NCIC CTG and Catherine Elliot and Curtis McMahon who managed the data collected for this trial. This work was supported with a grant co-sponsored from the National Cancer Institute of Canada and Novartis Inc.

Received for publication November 11, 2004. Revision received December 29, 2004. Accepted for publication January 3, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conflict of interest
 References
 
1. Wasan KM, Ramaswamy M, Haley J et al. Administration of long-term tamoxifen therapy modifies the plasma lipoprotein-lipid concentration and lipid transfer protein I activity in postmenopausal women with breast cancer. J Pharm Sci 1997; 86: 876–879.[CrossRef][ISI][Medline]

2. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1793–1802.[Abstract/Free Full Text]

3. Harper-Wynne C, Ross G, Sacks N et al. Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. Cancer Epidemiol Biomarkers Prev 2002; 11: 614–621.[Abstract/Free Full Text]

4. Heshmati HM, Khosla S, Robins SP et al. Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res 2002; 17: 172–178.[ISI][Medline]

5. Elisaf MS, Bairaktari ET, Nicolaides C et al. Effect of letrozole on the lipid profile in postmenopausal women with breast cancer. Eur J Cancer 2001; 37: 1510–1513.[CrossRef][ISI][Medline]

6. Medina RA, Aranda E, Verdugo C et al. The action of ovarian hormones in cardiovascular disease. Biol Res 2003; 36: 325–341.[ISI][Medline]

7. Shlipak MG, Chaput LA, Vittinghoff E 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; 146: 870–875.[CrossRef][ISI][Medline]

8. Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein, and apolipoprotein (a) concentrations: analysis of studies published from 1974–2000. Fertil Steril 2001; 75: 898–915.[CrossRef][ISI][Medline]

9. Buzdar AU. Data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial: Implications for Use of Aromatase Inhibitors in 2003. Clin Cancer Res 2004; 10: 355S–361S.[Abstract/Free Full Text]

10. Atalay G, Dirix L, Biganzoli L et al. 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 2004; 15: 211–217.[Abstract/Free Full Text]

11. Demacker PN, Hijmans AG, Brenninkmeijer BJ et al. Five methods for determining low-density lipoprotein cholesterol compared. Clin Chem 1984; 30: 1797–1800.[Abstract/Free Full Text]

12. Samsioe G. Cardioprotection by estrogens: mechanisms of action-the lipids. Int J Fertil Menopausal Stud 1994; 39 (Suppl 1): 43–49.[Medline]

13. Bonanni B, Johansson H, Gandini S et al. Effect of tamoxifen at low doses on ultrasensitive C-reactive protein in healthy women. J Thromb Haemostasis 2002; 1: 2149–2152.[ISI]

14. Wiseman H, Quinn P, Halliwell B. Tamoxifen and related compounds decrease membrane fluidity in liposomes. Mechanism for the antioxidant action of tamoxifen and relevance to its anticancer and cardioprotective actions? FEBS Lett 1993; 330: 53–56.[CrossRef][ISI][Medline]

15. Guetta V, Lush RM, Figg WD et al. Effects of the antiestrogen tamoxifen on low-density lipoprotein concentrations and oxidation in postmenopausal women. Am J Cardiol 1995; 76: 1072–1073.[CrossRef][ISI][Medline]

16. Krag LE, Geisler J, Lonning PE et al. Lipid and coagulation profile in postmenopausal women with early breast cancer at low risk treated with exemestane: A randomized, placebo-controlled study. Proc Ann Meet Am Soc Clin Oncol 2004; 23: 39 (Abstr 650).

17. Braithwaite RS, Chlebowski RT, Lau J et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003; 18: 937–947.[CrossRef][ISI][Medline]

18. Goss PE, Ingle JN, Martino S et al. Updated analysis of the NCIC CTG MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proc Ann Meet Am Soc Clin Oncol 2004; 23: 87 (Abstr 847).

19. Turgeon JL, McDonnell DP, Martin KA, Wise PM. Hormone therapy: Physiological complexity belies therapeutic simplicity. Science 2004; 304: 1269–1273.[Abstract/Free Full Text]

20. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002; 288: 321–333.[Abstract/Free Full Text]

21. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: Report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst 1998; 90: 1371–1388.[Abstract/Free Full Text]

22. Voetsch B, DeWitt LD, Pessin MS et al. Basilar artery occlusive disease in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2004; 61: 496–504.[Abstract/Free Full Text]

23. Haynes BP, Dowsett M, Miller WR et al. The pharmacology of letrozole. J Steroid Biochem Mol Biol 2003; 87: 35–45.[CrossRef][ISI][Medline]

24. Buzdar AU. Pharmacology and Pharmacokinetics of the Newer Generation Aromatase Inhibitors. Clin Cancer Res 2003; 9: 468S–472S.[Abstract/Free Full Text]