title: Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover.
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.
authors.affiliation: 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.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
authors.forename: N Lynn
authors.initials: NL
authors.lastname: Henry
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Kidwell
authors.affiliation: Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Van Poznak
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dantzer
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: BioMedical Imaging Laboratory, Wright State University, Dayton, OH, 45435, USA.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Hangartner
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Philips
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000730:Androstadienes / Q000494:pharmacology* / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D015519:Bone Density / Q000187:drug effects* / Q000235:genetics*; D016723:Bone Remodeling / Q000187:drug effects* / Q000235:genetics*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D015415:Biomarkers; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; C056516:exemestane
keywords: Aromatase inhibitors; Bone health; Breast cancer; Pharmacogenomics; Polymorphism