Suppression of Plasma Estrogen Levels by Letrozole and Anastrozole Is Related to Body Mass Index in Patients With Breast Cancer

Royal Marsden Hospital, London, United Kingdom.
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2012; 30(24):2977-80. DOI: 10.1200/JCO.2012.42.0273
Source: PubMed


To investigate whether suppression of plasma estradiol and estrone sulfate levels by the aromatase inhibitors (AIs) anastrozole and letrozole is related to body mass index (BMI) in postmenopausal women with early estrogen receptor (ER) -positive breast cancer. Recent studies have reported that the AI anastrozole has lower effectiveness than tamoxifen in women with high BMI. This effect with high BMI might hypothetically be a result of reduced inhibition of aromatase and suppression of plasma estrogen levels and might be overcome by the use of an increased dose of anastrozole or, alternatively, the use of a more potent AI such as letrozole.
Plasma estradiol and estrone sulfate levels from a highly sensitive radioimmunoassay were available for 44 postmenopausal patients who received anastrozole (1 mg per day) for 3 months followed by letrozole (2.5 mg per day) for 3 months or the opposite sequence. Correlations between the estrogen suppression by each AI and BMI were assessed.
Baseline values of estradiol and estrone sulfate were significantly correlated with BMI (r = 0.57; P < .001, and r = 0.38; P = .006, respectively). Levels of estrogen in patients receiving treatment were greater at higher levels of BMI with both AIs, but although this was significant with letrozole (r = 0.35; P = .013, and r = 0.30; P = .035 for estradiol and estrone sulfate, respectively), it was not with anastrozole. Suppression of both estrogen types was greater with letrozole across the full range of BMIs in this study.
The suppressed levels of plasma estradiol and estrone sulfate in postmenopausal women with early ER-positive breast cancer treated with the AIs anastrozole and letrozole are related to BMI.

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    • "30 ; P ¼ 0 . 035 for oestradiol and ES , respectively ) but no correlation in the same group when treated with anastrozole ( Folkerd et al , 2012 ) . Mean ES concentrations , during letrozole treatment , were lower in the o25 kg m À 2 group ( 13 pM l À 1 ) , but similar among 25 – 29 , 30 – 35 and 435 BMI groups ( mean 22 , 35 and 25 pM l À 1 , respectively ) . "
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    ABSTRACT: Background: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. Methods: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. Results: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0–67.2, n=150) when BMI was <25.0 kg m−2; 65.6 (57.8–74.6, n=154) when 25.0–29.9 kg m−2; 59.3 (47.1–74.6, n=50) when 30.0–34.9 kg m−2; and 43.3 (23.0–81.7, n=16) when ⩾35.0 kg m−2. No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. Conclusions: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.
    Full-text · Article · Jan 2014 · British Journal of Cancer
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    • "Furthermore, our prospective data are in line with the retrospective analysis by Folkerd et al, 2012. who demonstrated that estradiol levels during AI treatment are related to BMI (Folkered et al, 2012). "
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    ABSTRACT: Background:Body mass index (BMI) has an impact on survival outcome in patients treated with aromatase inhibitors (AIs). Obesity is associated with an increased body aromatisation and may be a cause of insufficient estradiol depletion.Methods:Sixty-eight postmenopausal oestrogen receptor-positive patients with early breast cancer were prospectively included in this study. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were analysed immediately in the clinical routine lab and in a dedicated central lab before (T1) and 3 months after start with aromatase inhibitors (T2).Results:A total of 40 patients were normal or overweight (non-obese: BMI 18.5–29.9 kg m−2) and 28 were obese (BMI⩾30 kg m−2). Aromatase inhibitors significantly suppressed estradiol serum levels (T1: 19.5 pg ml−1, T2: 10.5 pg ml−1, P<0.01) and increased FSH serum levels (T1: 70.2 mIU ml−1, T2: 75.7 mIU ml−1, P<0.05). However, after 3 months of AI treatment, estradiol levels of obese patients were nonsignificantly higher compared with non-obese patients (12.5 pg ml−1 vs 9.0 pg ml−1, P=0.1). This difference was reflected by significantly lower FSH serum levels in obese compared with non-obese patients (65.5 mIU ml−1 vs 84.6 mIU ml−1, P<0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine as well as in the dedicated central lab.Conclusion:Aromatase inhibitors are less efficient at suppressing estradiol serum levels in obese when compared with non-obese women.
    Full-text · Article · Sep 2013 · British Journal of Cancer
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    • "This observation can be interpreted as the result of a 'minor' reduction in estradiol serum levels in overweight and obese patients by anastrozole, which on the one hand causes noticeable side effects, but on the other hand does not lower estradiol serum levels enough to impact on clinical outcome. Recently, Folkerd et al (2012) showed a retrospective analysis of the ALIQUOT study that indeed oestrogen serum levels are lowered in overweight and obese patients but not to the same low level when compared with normal weight patients. "
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    ABSTRACT: Background: We investigated whether body mass index (BMI) can be used as a predictive parameter indicating patients who benefit from extended aromatase inhibitor (AI) treatment. Methods: The ABCSG-6a trial re-randomised event-free postmenopausal hormone receptor-positive patients from the ABCSG-6 trial to receive either 3 additional years of endocrine therapy using anastrozole vs nil. In this retrospective analysis, we investigated the prognostic and predictive impact of BMI on disease outcome and safety. Results: In all, 634 patients (177 normal weight, 307 overweight, and 150 obese) patients were included in this analysis. Normal weight patients with additional 3 years of anastrozole halved their risk of disease recurrence (disease-free survival (DFS) HR 0.48; P=0.02) and death (HR 0.45; P=0.06) and had only a fifth of the risk of distant metastases (HR 0.22; P=0.05) compared with normal weight patients without any further treatment. In contrast, overweight+obese patients derived no benefit from additional 3 years of anastrozole (DFS HR 0.93; P=0.68; distant recurrence-free survival HR 0.91; P=0.78; and OS HR 0.9; P=0.68). The possible predictive impact of BMI on extended endocrine treatment could be strengthened by a Cox regression interaction model between BMI and treatment (P=0.07). Conclusion: Body mass index may be used to predict outcome benefit of extended AI treatment in patients with receptor-positive breast cancer.
    Full-text · Article · Jul 2013 · British Journal of Cancer
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