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

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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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Acknowledgments

We thank the patients who participated in the study, and the treating physicians, research nurses, and data managers at the three sites. This study was supported in part by a Pharmacogenetics Research Network Grant # U-01 GM61373 (DAF) and Clinical Pharmacology training grant: 5T32-GM08425 (DAF) from the National Institute of General Medical Sciences, National Institutes of Health (NIH), Bethesda, MD, and by grant numbers M01-RR000042 (UM), M01-RR00750 (IU), and M01-RR00052 (JHU) from the National Center for Research Resources (NCRR), and by R01-GM-099143 (JR, SO). The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH. In addition, these studies were supported by grants from Pfizer, Inc. (DFH), Novartis Pharma AG (DFH), the Fashion Footwear Association of New York/QVC Presents Shoes on Sale™ (DFH), and BCRF. Study medication was provided by Pfizer, Inc. and Novartis Pharma AG. Authors’ roles: Study design: SO, NLH, TCS, VS, DFH, DAF. Study conduct and data collection: ATN, TCS, TNH, SP, MP, AMS, VS. NLH. Data analysis: KMK, LL, JD. Data interpretation: SO, NLH, TCS, VS, DFH, DAF, CHP, ATN, JMR, ZD. Drafting manuscript: SO, NLH. Revising manuscript content and approving final version of manuscript: All co-authors. SO, NLH, VS, DFH, and DAF take responsibility for the integrity of the data analysis.

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Authors and Affiliations

  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

    Steffi Oesterreich

  2. Breast Oncology Program, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA

    N. Lynn Henry, Catherine H. Van Poznak, James M. Rae & Daniel F. Hayes

  3. Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA

    Kelley M. Kidwell

  4. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Todd C. Skaar, Jessica Dantzer, Lang Li, Anne T. Nguyen, Zeruesenay Desta, Santosh Philips & David A. Flockhart

  5. BioMedical Imaging Laboratory, Wright State University, Dayton, OH, 45435, USA

    Thomas N. Hangartner

  6. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Munro Peacock

  7. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, 46202, USA

    Anna M. Storniolo

  8. Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21231, USA

    Vered Stearns

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  1. Steffi Oesterreich
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  2. N. Lynn Henry
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Correspondence to Steffi Oesterreich.

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Conflict of Interest

NLH received research funding from AstraZeneca. DFH received research funding during the conduct of this trial from Novartis and Pfizer, and currently receives research funding from Veridex and Janssen Diagnostics. DAF receives research funding from Novartis and Pfizer and is a member of the Scientific Advisory Board for Quest Diagnostics, Inc. VS receives research funding from Abbott, Abraxis, Merck, Novartis, and Pfizer. JMR received a research grant from Pfizer. TNH receives research funding from Shire. TCS, JD, LL, KMK, CVP, CG, ATN, ZD, SO, SP, JSC, and AMS reported no conflicts of interest.

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Steffi Oesterreich and Henry N. Lynn share first authorship.

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Oesterreich, S., Henry, N.L., Kidwell, K.M. et al. Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. Breast Cancer Res Treat 154, 263–273 (2015). https://doi.org/10.1007/s10549-015-3608-8

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  • DOI: https://doi.org/10.1007/s10549-015-3608-8

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