Association between BMI, vitamin D, and estrogen levels in postmenopausal women using adjuvant letrozole: a prospective study

Mitchell J Elliott,Marguerite Ennis,Dave Warr,Philippe L Bedard,Vuk Stambolic,Pamela J Goodwin,Carol Townsley,Christine Elser,Srikala Sridhar,David W Cescon,Kathleen I Pritchard,Lakshmi Rao,Eitan Amir

doi:10.1038/s41523-020-0166-y

Mitchell J Elliott, Marguerite Ennis + Show 11 more

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https://doi.org/10.1038/s41523-020-0166-y

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Studies have suggested that women with elevated BMI or 25-OH vitamin D levels may derive less benefit from AIs versus tamoxifen. We prospectively investigated whether high BMI or 25-OH vitamin D levels were associated with higher estrogen levels in post-menopausal women receiving standard adjuvant letrozole (2.5 mg/day). Furthermore, we evaluated whether an increased dose of letrozole resulted in lower serum estrogens in women with BMI > 25 kg/m2. Correlation between entry BMI and day 29 serum biomarkers (estrogens, 25-OH vitamin D, insulin, CRP, leptin) was assessed in all patients. On day 29, participants with BMI > 25 kg/m2 switched to letrozole 5 mg/day for 4-weeks and blood was drawn upon completion of the study. The change in serum estrogen levels was assessed in these patients (BMI > 25 kg/m2). 112 patients completed days 1–28. The Pearson correlations of estradiol and estrone with BMI or serum 25-OH vitamin D levels were near zero (−0.04 to 0.07, p = 0.48–0.69). Similar results were obtained for correlation with markers of obesity (insulin, CRP, and leptin) with estradiol and estrone (−0.15 to 0.12; p = 0.11–0.82). Thirty-one patients (BMI > 25 kg/m2) completed the interventional component; Increasing the dose of letrozole did not further reduce estradiol or estrone levels (change 0.1 and 0.4 pmol/L respectively; p = 0.74 and 0.36). There was no observed association between markers of obesity (BMI, insulin, leptin, and CRP), serum 25-OH vitamin D levels and estradiol or estrone levels. Additionally, an increased dose of letrozole did not further reduce estradiol or estrone levels compared to the standard dose.

Highlights

Aromatase inhibitors (AIs: letrozole, anastrozole, and lexemestane) are the recommended endocrine therapy for most postmenopausal women with estrogen receptor positive (ER+) breast cancer
In addition to body mass index (BMI), serum markers such as elevated CRP9, insulin[10], and leptin[11], all play a prominent role in obesity physiology and potentially estrogen receptor signaling
We prospectively investigated whether elevated markers of adiposity (BMI, CRP, insulin, and leptin) or serum 25-OH vitamin D levels were associated with higher estradiol and estrone levels in a population of post-menopausal women using adjuvant letrozole

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Introduction

Aromatase inhibitors (AIs: letrozole, anastrozole, and lexemestane) are the recommended endocrine therapy for most postmenopausal women with estrogen receptor positive (ER+) breast cancer. These agents reduce circulating estradiol and estrone through the inhibition of the enzyme aromatase in adipose tissue, the main source of these hormones in post-menopausal women[1]. A small study in women initiating AI found that both baseline and ontreatment levels of estrogen were greater at higher levels of BMI, suggesting the possibility of inadequate suppression of aromatase by standard dosing of AI therapy[5]. The impact of elevated BMI and its relationship to AI efficacy remains in question and the potential mechanism underlying any such effect requires further study

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