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

ABSTRACT 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.
    British Journal of Cancer 01/2014; 110(5). DOI:10.1038/bjc.2014.2 · 4.82 Impact Factor
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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.
    British Journal of Cancer 07/2013; 109(3). DOI:10.1038/bjc.2013.367 · 4.82 Impact Factor
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    • "Obesity is a risk factor for breast cancer in postmenopausal women and weight gain after diagnosis of breast cancer is associated with decreased survival and less favourable clinical characteristics such as greater tumour burden, higher grade, and poorer prognosis (Loi et al, 2005; Ellsworth et al, 2011). Jiralerspong et al (2011) reported that in early-stage breast cancer patients, higher BMI was associated with postmenopausal status and survival outcomes were significantly worse in the obese group compared with normal weight patients. "
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    ABSTRACT: Background: Increased adiposity may trigger signalling pathways that induce aromatase expression. As aromatase inhibitors exert their effects by blocking the aromatase enzyme, higher body mass index (BMI) can reduce the effect of aromatase inhibitors. Thus, we aimed to investigate retrospectively the effect of BMI on the efficacy of aromatase inhibitors in hormone receptor-positive postmenopausal patients with breast cancer. Methods: Newly diagnosed hormone receptor-positive breast cancer patients who were postmenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg m−2 were considered as normal weight patients (Arm A, n=102), and patients with a BMI ranging ⩾25 kg m−2 were grouped as overweight and obese patients (Arm B, n=399). Results: In both normal weight and overweight patients, the baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar, and with no statistically significant difference. In normal weight patients disease-free survival (DFS) rate was 93.7% and 77.6%, whereas in overweight and obese patients DFS rate was 96.8% and 85.5% in the first and third years, respectively, (P=0.08). Three year survival rate in Arm A patients was 98.3%, whereas in Arm B was 98.0% (P=0.57). When anastrozole was compared with letrozole in the subgroup analysis no difference with regard to DFS and overall survival was detected. Conclusion: These results, contradictory to the prior results, show that BMI has no worse effect on outcomes of aromatase inhibitors in postmenopausal hormone receptor-positive breast cancer patients. In the subgroup analysis, letrozole and anastrozole had similar survival outcomes.
    British Journal of Cancer 10/2012; 107(11). DOI:10.1038/bjc.2012.473 · 4.82 Impact Factor
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