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

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...

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Bibliographic Details
Published in:Breast cancer research and treatment 2015-11, Vol.154 (2), p.263-273
Main Authors: Oesterreich, Steffi, Henry, N. Lynn, Kidwell, Kelley M., Van Poznak, Catherine H., Skaar, Todd C., Dantzer, Jessica, Li, Lang, Hangartner, Thomas N., Peacock, Munro, Nguyen, Anne T., Rae, James M., Desta, Zeruesenay, Philips, Santosh, Storniolo, Anna M., Stearns, Vered, Hayes, Daniel F., Flockhart, David A.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alleles
Androstadienes - pharmacology
Androstadienes - therapeutic use
Antineoplastic Agents, Hormonal - pharmacology
Antineoplastic Agents, Hormonal - therapeutic use
Aromatase Inhibitors - pharmacology
Aromatase Inhibitors - therapeutic use
Biomarkers
Bone and Bones - drug effects
Bone and Bones - metabolism
Bone density
Bone Density - drug effects
Bone Density - genetics
Bone Remodeling - drug effects
Bone Remodeling - genetics
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Cancer research
Cancer therapies
Female
Genetic Association Studies
Genetic Variation
Genetics
Genotype
Humans
Medicine
Medicine & Public Health
Middle Aged
Nitriles - pharmacology
Nitriles - therapeutic use
Oncology
Polymorphism, Single Nucleotide
Postmenopause
Preclinical Study
Triazoles - pharmacology
Triazoles - therapeutic use
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Summary: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.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-015-3608-8