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Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion

  • Landry K. KamdemEmail author
  • Jingyue Xi
  • Brandi L. Clark
  • Bryana J. Gregory
  • Kelley M. Kidwell
  • Ana-Maria Storniolo
  • Vered Stearns
  • Daniel F. Hayes
  • Christina L. Gersch
  • James M. Rae
  • N. Lynn Henry
  • Daniel L. Hertz
Preclinical study

Abstract

Purpose

UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer.

Methods

Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2.

Results

Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05).

Conclusion

UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.

Keywords

Hormone receptor positive Breast Cancer Endocrine therapy Bone health UGT2B17 

Notes

Author contributions

Data were collected by the NIH-supported Consortium on Breast Cancer Pharmacogenetics (COBRA) including DFH, AMS, VS, JMR, and NLH, LKK, BLC, and BJG carried out UGT2B17 genotyping. All authors had full access to the data. LKK, JX, and KMK performed statistical analysis. KMK supervised the statistical analysis. LKK and DLH interpreted the data and drafted the manuscript. All authors discussed the results and reviewed and approved the manuscript.

Funding

This work was supported in part by the Arkansas INBRE program, supported by grant funding from the National Institute of Health (NIH), National Institute of General Medical Sciences (NIGMS) (P20GM103429), by the National Institutes of Health (Grant Numbers U-01GM61373 (DAF), 5T32-GM08425 (DAF, JDR), M01-RR000042 (UM), M01-RR00750 (IU), and M01-RR00052 (JHU)), the Department of Defense (Grant Numbers W81XWH-10-1-0349 (JDR), Pfizer (DFH), Novartis Pharma AG (DFH)), Breast Cancer Research Foundation (Grant Number N003171 (JMR, DFH)) and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale™ (DFH). Study medication was provided by Pfizer, Inc. and Novartis Pharma AG. We would like to thank the participating breast cancer patients and the research nurse coordinators at each of the clinical trial sites.

Compliance with ethical standards

Conflict of interest

VS has received research funding from Novartis and Pfizer. DFH has consulted for Pfizer and received research funding from Pfizer. NLH is the local principal investigator for two Pfizer-sponsored clinical trials. The remaining authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Supplementary material

10549_2019_5158_MOESM1_ESM.pptx (184 kb)
Consort diagram describing patient flow from trial enrollment to each analysis. Supplementary material 1 (PPTX 184 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Landry K. Kamdem
    • 1
    Email author
  • Jingyue Xi
    • 2
  • Brandi L. Clark
    • 1
  • Bryana J. Gregory
    • 1
  • Kelley M. Kidwell
    • 2
  • Ana-Maria Storniolo
    • 3
  • Vered Stearns
    • 4
  • Daniel F. Hayes
    • 5
  • Christina L. Gersch
    • 5
  • James M. Rae
    • 5
    • 6
  • N. Lynn Henry
    • 7
  • Daniel L. Hertz
    • 8
  1. 1.Department of Pharmaceutical SciencesHarding University College of PharmacySearcyUSA
  2. 2.Department of BiostatisticsUniversity of Michigan School of Public HealthAnn ArborUSA
  3. 3.Melvin and Bren Simon Cancer CenterIndiana University School of MedicineIndianapolisUSA
  4. 4.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  5. 5.Department of Internal MedicineUniversity of MichiganAnn ArborUSA
  6. 6.Department of PharmacologyUniversity of MichiganAnn ArborUSA
  7. 7.Huntsman Cancer InstituteSalt Lake CityUSA
  8. 8.Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborUSA

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