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01-11-2015 | Preclinical study

Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover

Authors: Steffi Oesterreich, N. Lynn Henry, Kelley M. Kidwell, Catherine H. Van Poznak, Todd C. Skaar, Jessica Dantzer, Lang Li, Thomas N. Hangartner, Munro Peacock, Anne T. Nguyen, James M. Rae, Zeruesenay Desta, Santosh Philips, Anna M. Storniolo, Vered Stearns, Daniel F. Hayes, David A. Flockhart

Published in: Breast Cancer Research and Treatment | Issue 2/2015

Abstract

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (−3.2 %) compared to exemestane-treated patients (−1.0 %) (p = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane (p = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

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Title: Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover
Authors: Steffi Oesterreich
N. Lynn Henry
Kelley M. Kidwell
Catherine H. Van Poznak
Todd C. Skaar
Jessica Dantzer
Lang Li
Thomas N. Hangartner
Munro Peacock
Anne T. Nguyen
James M. Rae
Zeruesenay Desta
Santosh Philips
Anna M. Storniolo
Vered Stearns
Daniel F. Hayes
David A. Flockhart
Publication date: 01-11-2015
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2015
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-015-3608-8

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