Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer

Lønning, Per Eystein; Geisler, Jürgen; Krag, L. E.; Erikstein, Bjørn; Bremnes, Yngve; Hagen, Anne Irene; Schlichting, Ellen; Lien, Ernst A.; Øfjord, Erik Snorre; Paolini, Jolanda; Polli, Anna; Massimini, Giorgio

doi:10.1200/jco.2005.07.097

Cited by 267 publications

(154 citation statements)

References 43 publications

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“…The increase in LDL-C may therefore be at least partially explained by the loss of the positive action of tamoxifen. The decrease in HDL-C in the exemestane group is in line with previous studies, and may be explained by a direct action of exemestane and/or by the interruption of tamoxifen therapy (Atalay et al, 2004;Lonning et al, 2005;Markopoulos et al, 2005;Esteva and Hortobagyi, 2006). The Intergroup Exemestane Study found a trend toward more frequent myocardial infarction in patients treated with exemestane than in those treated with tamoxifen (Coombes et al, 2004).…”

Section: Discussionsupporting

confidence: 89%

Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids

et al. 2006

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Recent studies have shown that administering the aromatase inhibitor exemestane after 2 -3 years of tamoxifen therapy significantly improves disease-free survival in postmenopausal women with primary breast cancer in comparison with standard 5-year tamoxifen treatment. Although many of the adverse effects associated with exemestane and tamoxifen have been analysed, there are no comparative data concerning body weight and body composition. The aim of this randomised study was to evaluate the longitudinal changes in body composition and lipid profiles in postmenopausal women switched from tamoxifen to exemestane. In total, 60 overweight or obese postmenopausal patients were enrolled. Their anthropometric data, body composition, including fat mass (FM) and fat-free mass (FFM), and lipid profiles, caloric intake and physical activity were assessed 1 week before randomisation, and 6 and 12 months later. In all, 55 patients (27 on tamoxifen and 28 on exemestane) completed the 1-year study period. Fat mass had significantly decreased by month 12 in the exemestane, but not in the tamoxifen group; the between-group difference was statistically significant (Po0.01). The FFM/FM ratio had significantly increased in the exemestane group, but not the tamoxifen group; the between-group difference was statistically significant (Po0.05). Triglycerides and high-density lipoprotein cholesterol significantly decreased (Po0.01; Po0.05), and low-density lipoprotein cholesterol significantly increased (Po0.01) in the exemestane group at the end of the 1-year study period. Our findings suggest that switching patients to adjuvant exemestane treatment after at least 2 years of tamoxifen therapy may be associated with an advantage over continuing adjuvant tamoxifen treatment in terms of body composition.

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Section: Discussionsupporting

confidence: 89%

Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids

et al. 2006

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“…One of these preclinical studies also evaluated the nonsteroidal AI letrozole, but in contrast, found no benefit of letrozole on bone or lipid profiles (16). In a clinical study investigating the effects of 2 years of exemestane on bone compared with placebo without prior tamoxifen therapy in patients with surgically resected breast cancer at low risk for recurrence, exemestane did not enhance BMD loss in lumbar spine and only modestly enhanced BMD loss in the femoral neck compared with the placebo group (17). Interestingly, in this study, exemestane promoted bone metabolism by increasing levels of both bone resorption and formation markers (17).…”

Section: Introductionmentioning

confidence: 99%

“…In a clinical study investigating the effects of 2 years of exemestane on bone compared with placebo without prior tamoxifen therapy in patients with surgically resected breast cancer at low risk for recurrence, exemestane did not enhance BMD loss in lumbar spine and only modestly enhanced BMD loss in the femoral neck compared with the placebo group (17). Interestingly, in this study, exemestane promoted bone metabolism by increasing levels of both bone resorption and formation markers (17). However, a clear-cut advantage of exemestane versus the nonsteroidal AIs on bone safety has not been shown in humans, possibly because all other clinical studies compared the AI to tamoxifen (9,12,18) or the AI to placebo with prior tamoxifen therapy (10,11).…”

Section: Introductionmentioning

confidence: 99%

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

Ariazi

Leitão

Oprea

et al. 2007

Molecular Cancer Therapeutics

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Aromatase inhibitors (AI) are being evaluated as longterm adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor A (ERA) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the nonaromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane downregulated ERA protein levels at high concentrations in a cell type -specific manner similarly as 17B-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17B-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERA. Molecular modeling also indicated that 17-hydroexemestane interacted with ERA and AR through selective recognition motifs employed by 17B-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs.

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“…These include patients who do not have pathological prognostic factors which predict a higher and earlier relapse rate, such as higher histological grade, presence of vascular invasion, tumour size and number of positive axillary nodes [24], and biological molecular markers such Cerb2, Ki67, CYP-2D6, level of oestrogen receptor positivity and progesterone receptor negativity [24,25]. However, even if patients have a good prognosis, patients may also be better off on anastrozole if they have a history of thromboembolic disease or risk of uterine carcinoma [24][25][26]. More recently, the roles played by quality of life, tolerance and patient preference also have important implications on the choice of adjuvant drug [5].…”

Section: Discussionmentioning

confidence: 99%

Comparing the cost of adjuvant anastrozole with the benefits of managing less patients with relapsed breast cancer

Thomas

Williams

Glen

et al. 2009

Breast Cancer Res Treat

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Prescribing anastrozole instead of tamoxifen increases initial adjuvant drug costs but there is an eventual saving as fewer patients will relapse. The effect of this saving depends on an accurate understanding of the cost of breast cancer relapse. We identified 232 patients relapsing between March 2000 and 2005. Seventy-seven were randomly selected for analysis of their entire hospital and community management costs from the date of relapse until death, or the end of the evaluation period (01/01/07). The mean cost per patient was £25,186 (95% CI £13,705-£33,821). The median survival from time of relapse was 40.07 months (range 0.5-73 months) and median total cost per patient was £31,402.62. Equating this figure with the difference in relapse rate (4.1%), initial drug cost (£4,773) gives an extra cost of £17,244/life year saved. This was the first adjuvant cost effectiveness analysis which included the community management activity of a subsequent relapse.

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Effects of Exemestane Administered for 2 Years Versus Placebo on Bone Mineral Density, Bone Biomarkers, and Plasma Lipids in Patients With Surgically Resected Early Breast Cancer

Cited by 267 publications

References 43 publications

Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids

Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

Comparing the cost of adjuvant anastrozole with the benefits of managing less patients with relapsed breast cancer

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