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).

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 approximately 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.     

The Effect of Exemestane on the Lipidemic Profile of Postmenopausal Early Breast Cancer Patients: Preliminary Results of the TEAM Greek Sub-study

Summary Introduction. Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion sub-protocol to the TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal women with early breast cancer in the adjuvant setting to that of tamoxifen. Patients and methods. In this open-label, randomized, parallel group study, 176 postmenopausal patients with estrogen and/or progesterone receptor positive early breast cancer were randomized to either adjuvant exemestane (25 mg/day; n = 90) or tamoxifen (20 mg/day; n = 86). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglycerides (TRG) were performed at baseline and every 3 months for the first 12 months. Results. Serum triglyceride levels were consistently increased above baseline throughout the study in the tamoxifen arm, while there was a trend towards reduction in the exemestane arm. There was also an overall trend for tamoxifen to decrease the levels of LDL throughout the study period. Exemestane did not demonstrate any other significant change in HDL levels; however, there was a consistent trend for a reduction in total cholesterol in both treatment arms. The atherogenic risk determined by the TC:HDL ratio remained stable in both arms throughout the treatment period. Conclusions. Exemestane appears to have a neutral effect on total cholesterol and HDL levels. Unlike tamoxifen’s positive effect on LDL levels, exemestane does not significantly alter LDL levels. Tamoxifen on the other hand increases triglyceride levels, while exemestane results in a beneficial reduction in TRG levels. These data offer additional information with regard to the safety and tolerability of exemestane in postmenopausal breast cancer patients and support further investigation of its potential usefulness in the adjuvant setting.     

Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.     

Effect of letrozole on plasma lipids, triglycerides, and estradiol in postmenopausal women with metastatic breast cancer

Purpose.

The aromatase inhibitor letrozole effectively treats breast cancer by decreasing estrogen levels in postmenopausal women. The aim of this prospective study was to evaluate the effect of letrozole on plasma lipids, triglyceride lipase (TGL), and estradiol levels in women with metastatic breast cancer (MBC).

Materials and Methods.

Fifty-two postmenopausal women with MBC received letrozole, 2.5 mg/day. Blood samples for assessment of plasma levels of total cholesterol (TC), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, TGL, and estradiol were taken at baseline and after 3, 6, and 12 months of treatment.

Results.

A nonsignificant increase was found in TC and HDL cholesterol levels after 3 months, which returned to baseline levels after 6 months (p = .794 and p = .444, respectively). LDL cholesterol increased nonsignificantly after 6 months and returned to baseline thereafter (p = .886). The mean estradiol level was suppressed from 44 pmol/l before treatment to <18 pmol/l after 6 months (p = .014). No difference was found in the estradiol suppression rate whether baseline levels were >40 or <40 pmol/l.

Conclusion.

Letrozole has a safe effect on the lipid and TGL profiles of postmenopausal women with MBC. Estradiol levels were maximally suppressed within 6 months of treatment. The increased levels of TC during treatment were reversible and returned to normal levels after 3 months.     

Lipid concentrations in postmenopausal women on letrozole after 5?years of tamoxifen: an NCIC CTG MA.17 sub-study

To evaluate changes in serum lipid parameters (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]), in postmenopausal women receiving letrozole after tamoxifen therapy. MA.17L is a sub-study of MA.17, a double-blind, placebo-controlled trial of extended adjuvant letrozole. Eligible postmenopausal women were non-hyperlipidemic and not on lipid-lowering drugs. This analysis considers the 183 patients on the letrozole arm. Lipid parameters evaluated at baseline, 6?months, 12?months, and yearly thereafter until completion of 5?years of letrozole. The median duration of letrozole treatment was 5.0?years with a range from 0.03 to 6.05?years. After 5?year tamoxifen, patients on letrozole experienced significant increases from baseline in total cholesterol, LDL cholesterol, and Lp(a) at all study time points but no statistically significant changes in triglycerides. Specifically, a statistically significant increase was found at 60?months in total cholesterol [mean percentage change from baseline (PC) 5.27; p?=?0.003], HDL cholesterol (mean PC 6.75; p?=?0.003), LDL cholesterol (mean PC 10.02; p?=?0.001), Lp(a) (mean PC 105.95; p?<?0.0001). 103 (56?%) women in the study had clinically significantly elevated levels of Lp(a) (106?% above baseline) after 5?years of therapy. The results were similar after excluding the 21?% of patients who had ever received anti-lipid treatment. Significant increases in total cholesterol, HDL cholesterol, LDL cholesterol, and, most notably, Lp(a) in postmenopausal women were observed following 5?years of adjuvant letrozole treatment and after 5?years of tamoxifen therapy and such patients should have monitoring of their lipid levels in clinical practice.     

Are the effects of tamoxifen on the serum lipid profile modified by apolipoprotein E phenotypes?

BACKGROUND: Tamoxifen has favorable effects on the serum lipid profile. It has been suggested that the apolipoprotein (Apo) E phenotype can influence serum lipid parameters; the ApoE allele 4 (ApoE4) is associated with higher total and low-density lipoprotein (LDL) cholesterol levels. The ApoE phenotype also affects lipid responses to diets or treatment with statins. However, the effect of tamoxifen on the lipid profile in different ApoE phenotypes is unknown. PATIENTS AND METHODS: In the present study, we evaluated the effects of tamoxifen on the serum lipid profile in 11 ApoE4-positive postmenopausal women with breast cancer (phenotypes 3/4 and 4/4) compared with 33 ApoE4-negative women (phenotypes 3/2 and 3/3). Serum lipid parameters [high-density (HDL), LDL and total cholesterol, triglycerides, ApoAI, ApoB and lipoprotein (a)] were measured after an overnight fast before treatment and after 3 and 12 months. ApoE isoforms were determined by isoelectric focusing of delipidated very-low-density lipoproteins (VLDL). RESULTS: During the follow-up period, serum levels of total and LDL cholesterol and ApoB decreased significantly in both groups, but no significant differences were found. Concentrations of serum HDL cholesterol were not significantly different between both groups. However, serum ApoAI levels increased significantly in ApoE4-negative subjects (p = 0.00005), but no significant changes in ApoE4-positive women were observed. Serum triglyceride levels increased by 23.2% (p < 0.05) in ApoE4-positive patients, but they did not change significantly in ApoE4-negative patients. The LDL/HDL cholesterol ratio decreased similarly in the two groups, but the ApoAI/ApoB ratio, which may be a better predictor of cardiovascular events, significantly changed in the ApoE4-negative subjects. Finally, the median level of Lp(a) decreased by 43.4% in the ApoE4-negative patients, whereas it did not change significantly in the ApoE4-positive group. CONCLUSION: In postmenopausal Greek women with breast cancer, the levels of Lp(a) and triglycerides and the ApoAI/ApoB ratio respond more favorably to tamoxifen treatment in ApoE4-negative than in ApoE4-positive patients.     

Extended adjuvant hormonal therapy with exemestane has no detrimental effect on the lipid profile of postmenopausal breast cancer patients: final results of the ATENA lipid substudy

Introduction

Extended adjuvant endocrine therapy for breast cancer with aromatase inhibitors may potentially alter the lipid profile of postmenopausal patients and thus increase the risk of developing cardiovascular disease. In this study, a subprotocol of the ATENA (Adjuvant post-Tamoxifen Exemestane versus Nothing Applied) trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal patients with operable breast cancer, in the adjuvant setting, with that of observation alone after completion of 5 to 7 years of primary treatment with tamoxifen.

Methods

In this open-label, randomized, parallel-group study, 411 postmenopausal patients with operable breast cancer, who had been treated with tamoxifen for 5 to 7 years, were randomized to either 5 additional years of exemestane (25 mg/day; n = 211) or observation only (n = 200). Assessments of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total serum triglycerides (TRG) were performed at baseline and then during each follow-up visit, performed at either 6 or 12 months, according to the center's clinical practice, until completing 24 months in the study.

Results

TC and LDL levels increased significantly across time for both arms; TC increase was more pronounced for the observation arm, and that was sustained up to 24 months. HDL levels decreased significantly across time for the exemestane arm, whereas no significant change was detected across time for the observation arm. Triglyceride levels decreased significantly across time on both arms, with no difference detected in changes from baseline between the exemestane and the observation arms.

Conclusions

Exemestane lacks the beneficial effect of tamoxifen on lipids; however, sequential adjuvant treatment with exemestane in postmenopausal breast cancer patients after cessation of 5 to 7 years of tamoxifen does not appear to alter the lipid profile significantly compared with that of an observational arm.

Trial Registration

ClinicalTrials.gov ID: NCT00810706.     

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'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.     

Lipid changes in breast cancer patients on exemestane treatment: final results of the TEAM Greek substudy

Background: The Greek substudy of the Tamoxifen and ExemestaneAdjuvant Multicenter International trial compared the effectof exemestane on the lipid profile of postmenopausal, breastcancer patients to that of tamoxifen in the adjuvant setting. Patients and methods: Lipidemic profile changes were studiedin 142 postmenopausal patients randomized to receive eitheradjuvant exemestane (n = 77) or tamoxifen (n = 65). Total cholesterol(TC), high-density lipoprotein (HDL), low-density lipoprotein(LDL) and serum triglyceride (TRG) levels were measured at baselineand then every 3 months for the first 12 months of treatmentand at 18 and 24 months. Results: A trend for a reduction in TC was found in both treatmentarms; however, TC and LDL levels were consistently and significantlydecreased in tamoxifen arm only. The mean HDL level was higherfor the tamoxifen arm compared with the exemestane arm acrosstime. No significant trend was detected throughout the studyperiod on TRG levels on either arm. Conclusions: Unlike tamoxifen's beneficial effect on TC andLDL levels, exemestane appears to have a neutral effect on lipidemicprofile of postmenopausal, breast cancer patients. These dataoffer additional information with regard to the safety and tolerabilityof exemestane treatment in the adjuvant setting. Key words: aromatase inhibitors, breast cancer, cholesterol, exemestane, lipids, tamoxifen, TEAM trial Received for publication May 4, 2008. Revision received July 3, 2008. Accepted for publication July 4, 2008.     

Duration of tamoxifen effect on lipidemic profile of postmenopausal breast cancer patients following deprivation of treatment

OBJECTIVE: It was the aim of this study to investigate the effect of tamoxifen withdrawal on markers of lipid metabolism in postmenopausal women with breast cancer who completed tamoxifen therapy and received no further treatment. METHODS: Lipidemic profile changes were studied in 190 postmenopausal patients with operable breast cancer, following cessation of 5-7 years of tamoxifen treatment. Assessments of total cholesterol, high-density lipoprotein, low-density lipoprotein and total serum triglycerides were performed at baseline, 6 months and 12 months. RESULTS: By 6 months, both total cholesterol and low-density lipoprotein levels were significantly increased, and total triglyceride levels were significantly reduced compared with baseline values and maintained to 12 months. There was no significant alteration observed for high-density lipoprotein levels over the study period. CONCLUSION: The beneficial effect of tamoxifen on the lipidemic profile of postmenopausal breast cancer patients seems to be lost in less than 12 months time following cessation of 5-7 years of tamoxifen treatment. A 'rebound effect' on the lipidemic parameters should be expected and those patients should be monitored carefully.     

托瑞米芬和他莫昔芬对血脂影响的对比研究

目的　探讨托瑞米芬 (TOR)在乳腺癌术后辅助治疗中对血脂的影响程度。方法　 10 3例乳腺癌患者分为治疗组和对照组。治疗组包括TOR组和TAM组 ,TOR组口服TOR 60mg/天 ,TAM组口服TAM 2 0mg/天。在内分泌治疗前 ,治疗 3、6、9和 12个月后 ,分别晨取患者空腹静脉血进行血脂检测。结果　TOR治疗组血总胆固醇平均水平下降 11.0 % ,S LDL平均水平下降 11.1% ,血甘油三酯平均水平下降 10 .7% ;TAM治疗组血总胆固醇平均水平下降 9.0 % ,S LDL平均水平下降 17.4% ,而血甘油三酯水平无明显变化 (P =0 .491)。结论　TOR对血脂的影响程度与TAM相近 ,2组血总胆固醇和S LDL平均水平均较治疗前下降。不同的是 ,TOR治疗组血甘油三酯水平下降 ,而TAM治疗组无明显变化。提示TOR可影响与冠心病发病相关的血脂水平。     

Salubrious effect of vitamin C and vitamin E on tamoxifen-treated women in breast cancer with reference to plasma lipid and lipoprotein levels

Tamoxifen, a non-steroidal antiestrogen, has been used in the hormonal treatment for breast cancer. The hepatic estrogenic effect of tamoxifen causes severe triglyceridemia. The combined effect of tamoxifen, vitamin C and vitamin E on plasma lipid and lipoprotein is important, since, vitamin C and vitamin E encumbered the lipid abnormalities instigated by tamoxifen. Therefore supplementation of vitamin C (Celin 500 mg) and vitamin E (Evion 400 mg) for 90 days along with tamoxifen (10 mg twice a day) to postmenopausal breast cancer patients was ventured. In tamoxifen-treated patients, total cholesterol (TC), free cholesterol (FC), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol (LDL) levels were decreased and the triglycerides (TG), ester cholesterol (EC), high density lipoprotein cholesterol (HDL) and very low density lipoprotein cholesterol (VLDL) levels were increased. Combination therapy reduce all the cholesterol level and VLDL, LDL. TG levels were significantly decreased and HDL, EC levels were significantly increased. These results suggested that tamoxifen treatment is the most effective during co-administration of vitamin C and vitamin E in that they reduce the tamoxifen-induced hypertriglyceridemia.     

血脂代谢与胃癌发病风险相关性的病例对照研究

  目的  探讨血脂代谢水平与胃癌发生发展的相关性。  方法  选取2016年3月至2017年6月天津医科大学肿瘤医院诊治的1 072例胃癌患者与同期1 084例健康人群进行病例-对照研究,检测血清总胆固醇（total cholesterol,TC）、甘油三酯（triglyceride,TG）、高密度脂蛋白（high-density lipoprotein,HDL）和低密度脂蛋白（low-density lipoprotein,LDL）水平,采用单因素及多因素分析探讨血脂代谢水平与胃癌发病风险及临床病理特征的关系。  结果  胃癌患者血清中的TG、LDL水平均高于对照组,HDL低于对照组;男性胃癌患者LDL高于对照组,HDL低于对照组;女性胃癌患者血清中的TG、LDL高于对照组,HDL低于对照组（均P < 0.05）。胃癌患者HDL、LDL水平与胃癌的发病风险显著相关;男性中HDL及LDL,女性中TG、HDL及LDL分别与胃癌的发病风险显著相关。胃癌患者中,TG及TC升高常见于远端胃癌及分期较早的患者;HDL降低多见于低、未分化胃癌。男性中,TG升高多见于分期较早的患者;HDL降低多见于低、未分化胃癌。女性中,TC增高更常见于分期较早的患者（均P < 0.05）。  结论  胃癌患者血脂水平高于健康对照组,与胃癌的发病风险显著相关。在胃癌患者中随着疾病的进展,患者肿瘤消耗增多、营养状态持续下降,血脂水平逐渐降低。      

Tamoxifen treatment reverses the adverse effects of chemotherapy-induced ovarian failure on serum lipids

In all, 146 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, 5-year tamoxifen treatment was started after chemotherapy to those 112 patients with hormone-receptor-positive tumours while those with hormone-receptor-negative tumours received no further therapy. The serum lipid levels were followed in both groups. The levels of serum total and low-density lipoprotein (LDL) cholesterol increased significantly after chemotherapy only in patients who developed ovarian dysfunction. Total cholesterol increased +9.5% and LDL cholesterol +16.6% in patients who developed amenorrhoea (P<0.00001 and 0.00001, respectively). The cholesterol levels did not change in patients who preserved regular menstruation after chemotherapy. After 6 months of tamoxifen therapy, the total cholesterol decreased -9.7% and the LDL cholesterol -16.7% from levels after the chemotherapy, while the cholesterol concentrations remained at increased levels in the control group (P=0.001 and P<0.0001, respectively). The high-density lipoprotein cholesterol levels did not change significantly in either tamoxifen or control group. The effects of tamoxifen treatment on serum lipids after chemotherapy have not been studied before. Our current study suggests that adjuvant tamoxifen therapy reverses the adverse effects of chemotherapy-induced ovarian failure on total and LDL cholesterol and even lowers their serum levels below the baseline.     

Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione.

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.     

A randomized,placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated >25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.     

Effects of tamoxifen on serum lipid and apolipoprotein levels in postmenopausal patients with breast cancer

Serum lipids and apolipoprotein levels were measured in twenty postmenopausal women with primary breast cancer, before and three months after tamoxifen therapy (10 mg twice a day). Tamoxifen caused a significant reduction in total serum cholesterol (10%;P < 0.02), and in low-density lipoprotein cholesterol (17%;P < 0.01), and a significant 47 % increase in the subclass 2 of the high density lipoprotein cholesterol (P< 0.01). In addition, tamoxifen caused a 16% increase in apolipoprotein A-I, a 12% decrease in apolipoprotein B (P < 0.05), and a 37% reduction in the serum concentration of lipoprotein(a) (P< 0.01). These results show that tamoxifen brings about an important improvement in serum lipid profile.     

Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats.

PURPOSE: Exemestane (EXE) and letrozole (LET) are third-generation aromatase inhibitors currently prescribed for postmenopausal hormone-dependent breast cancer. The impact on end organs of estrogen depletion in menopausal women is of significant clinical importance. We studied the effects of EXE, its principal metabolite, 17-hydroexemestane (17-H-EXE), and LET on bone and lipid metabolism in ovariectomized (OVX) rats. EXPERIMENTAL DESIGN: OVX rats were treated by weekly intramuscular injection for 16 weeks with 20, 50, and 100 mg/kg EXE, 20 mg/kg 17-H-EXE, and daily oral gavage of 1 mg/kg LET. At the end of the treatment period, bone mineral density (BMD), the bone resorption marker serum pyridinoline, the bone formation marker serum osteocalcin, bone mechanical properties, histomorphometry, and serum lipid concentrations were determined. RESULTS: Lumbar vertebral and femoral BMD, bending strength of the femur, compressive strength of the fifth lumbar vertebra, and trabecular bone volume were significantly higher in OVX animals given EXE and 17-H-EXE than in OVX controls. EXE and 17-H-EXE significantly reduced an ovariectomy-induced increase in serum pyridinoline and serum osteocalcin. EXE and 17-H-EXE given to OVX rats caused significant reductions of serum cholesterol and low-density lipoprotein cholesterol. In contrast, OVX rats treated with LET had BMD, bone biomarkers, mechanical failure properties, and lipid levels similar to those of OVX controls. CONCLUSIONS: EXE and 17-H-EXE significantly prevent bone loss, enhance bone mechanical strength, and lower serum cholesterol and low-density lipoprotein levels in OVX rats. These protective effects on end-organ function are not seen with the nonsteroidal inhibitor LET.     

Changes in serum lipids and lipoproteins in cancer patients during chemotherapy

Summary We studied serum lipid and lipoprotein changes occurring during chemotherapy in 57 patients with chemosensitive cancers, including 18 malignant lymphomas, 18 breast carcinomas, 14 small-cell lung carcinomas, and 7 urothelial-cell carcinomas. Patients who responded favorably to chemotherapy demonstrated a significant increase in serum total cholesterol and LDL cholesterol values, with the singular exception of breastcancer patients, who exhibited a nonsignificant decrease in both of these parameters. Serum levels of free cholesterol and HDL cholesterol did not show any significant changes. Finally, serum triglycerides tended to increase after effective chemotherapy, but this was of statistical significance only in breast-cancer patients. Although our findings were based on a rather small number of patients, they indicate that the lipid and lipoprotein disorders reported in cancer patients are reversible by effective treatment of the tumor, suggesting that these disorders are a secondary phenomenon of malignancy.     

Effects of adjuvant aromatase inhibitor therapy on lipid profiles

How aromatase inhibitors affect lipids is of great interest. Compared with tamoxifen, adjuvant anastrozole and letrozole are associated with increased incidences of hypercholesterolemia, while similar data are lacking for exemestane in the adjuvant setting. No significant differences in lipid profiles occurred with extended adjuvant exemestane compared with placebo, but total cholesterol and low-density lipoprotein levels increased significantly above baseline in both groups over 6 months. Likewise, no significant differences in hypercholesterolemia rates occurred between extended adjuvant letrozole and placebo. A lipid substudy further confirmed that letrozole did not significantly alter serum lipids for 36 months compared with placebo. Thus, although aromatase inhibitors lack the lipid-lowering properties of tamoxifen, no significant worsening of lipid levels occurs with their use. Patients would benefit from lifestyle changes and routine monitoring of serum lipids. Breast cancer therapy trials often report serum lipid parameters, but assessing the quality and overall significance of the data can be difficult. Methodology of data collection varies among trials and the concomitant use of lipid-modifying medication is often not reported. This review discusses the current understanding of the influence of lipid levels on cardiovascular risk in women and presents key findings on the effects of adjuvant aromatase inhibitor therapy on lipid profiles.