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Breast Cancer Res Treat. 2015 Nov;154(2):263-73. doi: 10.1007/s10549-015-3608-8. Epub 2015 Nov 4.

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

Author information

1
Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, Magee Womens Research Institute, University of Pittsburgh Cancer Institute (UPCI), 204 Craft Avenue, Pittsburgh, PA, 15261, USA. oesterreichs@upmc.edu.
2
Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
3
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
4
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
5
BioMedical Imaging Laboratory, Wright State University, Dayton, OH, 45435, USA.
6
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
7
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA.
8
Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA.

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.

KEYWORDS:

Aromatase inhibitors; Bone health; Breast cancer; Pharmacogenomics; Polymorphism

PMID:
26536870
PMCID:
PMC4807610
DOI:
10.1007/s10549-015-3608-8
[Indexed for MEDLINE]
Free PMC Article

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