background In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy — but not tamoxifen therapy of longer duration — prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. methods We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. results A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast — 75 in the letrozole group and 132 in the placebo group — with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P ≤ 0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. conclusions As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.

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A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer

Background The aromatase inhibitor letrozole is a more effective treatment for metastatic breast cancer and more effective in the neoadjuvant setting than tamoxifen. We compared letrozole with tamoxifen as adjuvant treatment for steroid-hormone-receptor-positive breast cancer in postmenopausal women. Methods The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five years of treatment with various adjuvant endocrine therapy regimens in postmenopausal women with hormone-receptor-positive breast cancer: letrozole, letrozole followed by tamoxifen, tamoxifen, and tamoxifen followed by letrozole. This analysis compares the two groups assigned to receive letrozole initially with the two groups assigned to receive tamoxifen initially; events and follow-up in the sequential-treatment groups were included up to the time that treatments were switched. Results A total of 8010 women with data that could be assessed were enrolled, 4003 in the letrozole group and 4007 in the tamoxifen group. After a median follow-up of 25.8 months, 351 events had occurred in the letrozole group and 428 events in the tamoxifen group, with five-year disease-free survival estimates of 84.0 percent and 81.4 percent, respectively. As compared with tamoxifen, letrozole significantly reduced the risk of an event ending a period of disease-free survival (hazard ratio, 0.81; 95 percent confidence interval, 0.70 to 0.93; P=0.003), especially the risk of distant recurrence (hazard ratio, 0.73; 95 percent confidence interval, 0.60 to 0.88; P=0.001). Thromboembolism, endometrial cancer, and vaginal bleeding were more common in the tamoxifen group. Women given letrozole had a higher incidence of skeletal and cardiac events and of hypercholesterolemia. Conclusions In postmenopausal women with endocrine-responsive breast cancer, adjuvant treatment with letrozole, as compared with tamoxifen, reduced the risk of recurrent disease, especially at distant sites. (ClinicalTrials.gov number, NCT00004205.)

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer

Subclinical thyroid disease (SCTD) is defined as serum free T4 and free T3 levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine t...

The clinical significance of subclinical thyroid dysfunction.

Until recently, tamoxifen, a nonsteroidal antiestrogen, was the mainstay of endocrine treatment of breast cancer. However, new aromatase inhibitors that are many times more potent and specific than the first such agent, aminoglutethimide, are changing the management of breast cancer in postmenopausal women. This review discusses the role of aromatase inhibitors such as letrozole, anastrozole, and exemestane in the treatment of breast cancer.

Aromatase Inhibitors in Breast Cancer

Tamoxifen, given for 5 years after surgery for hormone-dependent breast cancer, prolongs disease-free survival and overall survival. No added effect is noted with more than 5 years of treatment. This study, enrolling postmenopausal women who had been treated for early-stage breast cancer, was intended to show whether letrozole improves the outcome after tamoxifen therapy is withdrawn. Letrozole is an aromatase inhibitor that suppresses estrogen production. Using a randomized, double-blind design, 5187 women who had taken adjuvant tamoxifen therapy for 4.5 to 6 years were assigned to receive 2.5 mg letrozole or placebo orally each day for 5 years. All participants were age 50 and older when tamoxifen therapy began, and all had a tumor that was positive for estrogen receptors and/or progesterone receptors. After a median follow up of 2.4 years, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the other breast, 75 in the letrozole-treated group and 132 in placebo recipients. The estimated 4-year disease-free survival rates were 93% and 87%, respectively. The hazard ratio for cancer in the letrozole group was 0.57. Women with negative lymph nodes did at least as well as those with node-positive disease when given letrozole. Overall survival rates were 96% in the letrozole group and 94% in placebo patients, with a hazard ratio in the former group of 0.76. Hot flashes, arthritislarthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding occurred more often in the placebo group. Comparable numbers of patients (4.5% and 3.6%, respectively) discontinued treatment because of toxic effects. A trend was noted toward more frequent newly diagnosed osteoporosis in patients given letrozole. The investigators concluded that letrozole should be considered for postmenopausal women with hormone receptor-positive breast cancer who have completed 5 years of tamoxifen therapy. The optimal duration of letrozole treatment remains to be determined.

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Estimation of LDL cholesterol based on the Friedewald formula and on apo B levels.

Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.

Increased activity of platelet‐activating factor acetylhydrolase in low‐density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia

OBJECTIVE —The study was to determine whether being the macrosomic offspring of a mother without detected glucose intolerance during pregnancy has an impact on lipid profile, glucose homeostasis, and blood pressure during childhood. RESEARCH DESIGN AND METHODS —Plasma total, HDL, and LDL cholesterol; triglycerides; apolipoprotein (Apo) A-1, -B, and -E; lipoprotein (a); fasting glucose and insulin; homeostasis model assessment of insulin resistance (HOMA-IR) index; blood pressure; BMI; and detailed anthropometry were evaluated in 85 children aged 3–10 years old, born appropriate for gestational age (AGA; n = 48) and large for gestational age (LGA; n = 37) of healthy mothers. RESULTS —At the time of the assessment, body weight, height, skinfold thickness, BMI, waist circumference, and blood pressure did not differ between the LGA and AGA groups with the exception of head circumference ( P P P P P CONCLUSIONS —Children born LGA of mothers without confirmed impaired glucose tolerance during pregnancy show higher insulin concentrations than AGAs.

https://care.diabetesjournals.org/content/diacare/29/6/1197.full.pdf

Lipid profile, glucose homeostasis, blood pressure, and obesity-anthropometric markers in macrosomic offspring of nondiabetic mothers.

Thyroid disorders are known to influence lipoprotein metabolism. In the current study we examined the incidence of thyroid function abnormalities in patients attending our outpatient lipid clinic. ...

C. Tzallas

Papers

Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.

Estimation of LDL cholesterol based on the Friedewald formula and on apo B levels.

Increased activity of platelet‐activating factor acetylhydrolase in low‐density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia

Lipid profile, glucose homeostasis, blood pressure, and obesity-anthropometric markers in macrosomic offspring of nondiabetic mothers.

The incidence of thyroid function abnormalities in patients attending an outpatient lipid clinic.