Exemestane may be less detrimental than letrozole to bone health in women homozygous for the UGT2B17*2 gene deletion
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.
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.
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).
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.
KeywordsHormone receptor positive Breast Cancer Endocrine therapy Bone health UGT2B17
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.
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.
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.
- 1.Parkin DM et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108Google Scholar
- 2.Buzdar AU et al (2008) Summary of aromatase inhibitor clinical trials in postmenopausal women with early breast cancer. Cancer 112(3):700–709Google Scholar
- 3.Coombes RC et al (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane study): a randomised controlled trial. Lancet 369(9561):559–570Google Scholar
- 4.Keating GM (2009) Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. Drugs 69(12):1681–1705Google Scholar
- 5.Robinson A (2009) A review of the use of exemestane in early breast cancer. Ther Clin Risk Manag 5(1):91–98Google Scholar
- 6.Ingle JN (2013) Postmenopausal women with hormone receptor-positive breast cancer: balancing benefit and toxicity from aromatase inhibitors. Breast 22(Suppl 2):S180–S183Google Scholar
- 7.Oesterreich S et al (2015) Associations between genetic variants and the effect of letrozole and exemestane on bone mass and bone turnover. Breast Cancer Res Treat 154(2):263–273Google Scholar
- 8.Chien AJ, Goss PE (2006) Aromatase inhibitors and bone health in women with breast cancer. J Clin Oncol 24(33):5305–5312Google Scholar
- 9.Rabaglio M et al (2009) Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol 20(9):1489–1498Google Scholar
- 10.Goss PE et al (2004) The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 34(3):384–392Google Scholar
- 11.Cheung AM, Tomlinson G, Goss PE (2005) Bone loss with exemestane: is the jury still out? J Clin Oncol 23(36):9433–9434 author reply 9433-5Google Scholar
- 12.Goss PE et al (2007) Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover in healthy postmenopausal women. Breast Cancer Res 9(4):R52Google Scholar
- 13.Lonning PE et al (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23(22):5126–5137Google Scholar
- 14.Wilson W et al (2004) Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15. Genomics 84(4):707–714Google Scholar
- 15.Chen SM et al (2015) Impact of UGT2B17 gene deletion on the pharmacokinetics of 17-hydroexemestane in healthy volunteers. J Clin Pharmacol 56 875–884Google Scholar
- 16.Chew S et al (2011) Homozygous deletion of the UGT2B17 gene is not associated with osteoporosis risk in elderly Caucasian women. Osteoporos Int 22(6):1981–1986Google Scholar
- 17.Giroux S et al (2012) UGT2B17 gene deletion associated with an increase in bone mineral density similar to the effect of hormone replacement in postmenopausal women. Osteoporos Int 23(3):1163–1170Google Scholar
- 18.Yang TL et al (2008) Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am J Hum Genet 83(6):663–674Google Scholar
- 19.Goss PE et al (2013) Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27-a randomized controlled phase III trial. J Clin Oncol 31(11):1398–1404Google Scholar
- 20.Kadakia KC et al (2017) Prospective assessment of patient-reported outcomes and estradiol and drug concentrations in patients experiencing toxicity from adjuvant aromatase inhibitors. Breast Cancer Res Treat 164(2):411–419Google Scholar
- 21.Briot K et al (2010) Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: the ATOLL (articular tolerance of letrozole) study. Breast Cancer Res Treat 120(1):127–134Google Scholar
- 22.Desta Z et al (2011) Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther 90(5):693–700Google Scholar
- 23.Hertz DL et al (2017) Germline genetic predictors of aromatase inhibitor concentrations, estrogen suppression and drug efficacy and toxicity in breast cancer patients. Pharmacogenomics 18(5):481–499Google Scholar