Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer

560 Background: High body mass index (BMI) protects against postmenopausal osteoporotic fracture, mediated in part by higher endogenous levels of oestradiol. Third-generation aromatase inhibitors (AIs) show superior efficacy and tolerability than tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer. We examined the interactions between BMI and bone turnover during treatment with 3 aromatase inhibitors in the LEAP trial, an open, randomized, pharmacodynamic study in postmenopausal women. Methods: Healthy volunteers from the UK and Hungary with normal bone density and BMI between 18 and 34 kg/m2 were randomized to receive A (1 mg/day), L (2.5 mg/day), or E (25 mg/day) orally, once daily for 24 weeks. Effects on bone resorption (log transformed serum C-telopeptide crosslinks, CTX) and bone formation (bone alkaline phosphatase and propeptide of type I procollagen, PINP) were compared. Changes in biochemical markers of bone resorption and formation during treatment were all statistically inter- correlated (p<0.01) with no notable differences between the 3 agents studied, so that the groups were pooled for analysis. Spearman correlation coefficients and the p-values were computed. Results: A total of 90 participants were evaluable at baseline and at 24 weeks (29 A, 29 L, 32 E). As expected, baseline BMI correlated with pre-treatment circulating endogenous oestradiol (r=0.28, p=0.007) and both BMI and oestradiol negatively correlated with baseline serum CTX (r=-0.32, p=0.0025 and r=-0.35, p=0.0007 respectively) and PINP (r=-0.30, p=0.004 and r=-0.26, p=0.016 respectively). Baseline BMI and oestradiol were significantly correlated with the increase in serum CTX (r=0.26, p=0.015 and r=0.23, p=0.032 respectively) and BMI also correlated significantly with the increase in serum PINP (r=0.23, p=0.030). Conclusions: Steroidal and non-steroidal AIs increase bone turnover with the greatest increase in women with high BMI and higher oestradiol levels at baseline. As increased bone turnover is an independent risk factor for fracture, a high BMI may not confer a reduced fracture risk in the setting of AI use in early breast cancer. No significant financial relationships to disclose.

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Abstract P2-13-01: Impact of Body Mass Index (BMI) on the efficacy of aromatase inhibitors to suppress estradiol serum levels in postmenopausal patients with early breast cancer: a prospective proof of principle

10.1158/0008-5472.sabcs12-p2-13-01 ◽

2012 ◽

Author(s):

G Pfeiler ◽

R Königsberg ◽

P Hadji ◽

F Fitzal ◽

M Maroske ◽

...

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Body Mass ◽

Early Breast Cancer ◽

Aromatase Inhibitors ◽

Serum Levels ◽

Proof Of Principle

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Effect of Body Mass Index on Recurrences in Tamoxifen and Anastrozole Treated Women: An Exploratory Analysis From the ATAC Trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.2021 ◽

2010 ◽

Vol 28 (21) ◽

pp. 3411-3415 ◽

Cited By ~ 184

Author(s):

Ivana Sestak ◽

Wolfgang Distler ◽

John F. Forbes ◽

Mitch Dowsett ◽

Anthony Howell ◽

...

Keyword(s):

Breast Cancer ◽

Body Mass Index ◽

Postmenopausal Women ◽

Body Mass ◽

Aromatase Inhibitors ◽

Hormone Receptor ◽

Early Stage ◽

Double Blind ◽

Overweight Women ◽

Hormone Receptor Positive

Purpose Third-generation aromatase inhibitors have been widely used in postmenopausal women for the adjuvant treatment of hormone receptor–positive breast cancer. As aromatase inhibitors work by inhibiting the conversion of androgens to estrogens in adipose tissue, we hypothesized that anastrozole may be more effective in women with a high body mass index (BMI). Patients and Methods The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a double-blind randomized clinical trial in which postmenopausal women with early-stage breast cancer were randomly assigned to receive oral daily anastrozole (1 mg) alone, tamoxifen (20 mg) alone, or the combination in a double-blind fashion. Analyses were based on the 100-month median follow-up for women with hormone receptor–positive breast cancers (estrogen [ER] and/or progesterone [PgR] positive). Here, we investigate the impact of BMI on recurrence and the relative benefit of anastrozole versus tamoxifen according to baseline BMI. Results Overall, women with a high BMI (BMI > 35 kg/m2) at baseline had more recurrences than those women with a low BMI (BMI < 23 kg/m2; adjusted hazard ratio [HR], 1.39; 95% CI, 1.06 to 1.82; Pheterogeneity = .03) and significantly more distant recurrences (adjusted HR, 1.46; 95% CI, 1.07 to 1.61; Pheterogeneity = .01). Overall, the relative benefit of anastrozole versus tamoxifen was nonsignificantly better in thin women compared to overweight women. Conclusion These results confirm the poorer prognosis of obese women with early-stage breast cancer. Recurrence rates were lower for anastrozole than tamoxifen for all BMI quintiles. Our results suggest that the relative efficacy of anastrozole compared to tamoxifen is greater in thin postmenopausal women and higher doses or more complete inhibitors might be more effective in overweight women, but this requires independent confirmation.

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