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Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer

The Pharmacogenomics Journal volume 17, pages 521–527 (2017)Cite this article

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Abstract

Discovery of clinical and genetic predictors of exemestane pharmacokinetics was attempted in 246 postmenopausal patients with breast cancer enrolled on a prospective clinical study. A sample was collected 2 h after exemestane dosing at a 1- or 3-month study visit to measure drug concentration. The primary hypothesis was that patients carrying the low-activity CYP3A4*22 (rs35599367) single-nucleotide polymorphism (SNP) would have greater exemestane concentration. Additional SNPs in genes relevant to exemestane metabolism (CYP1A1/2, CYP1B1, CYP3A4, CYP4A11, AKR1C3/4, AKR7A2) were screened in secondary analyses and adjusted for clinical covariates. CYP3A4*22 was associated with a 54% greater exemestane concentration (P<0.01). Concentration was greater in patients who reported White race, had elevated aminotransferases, renal insufficiency, lower body mass index and had not received chemotherapy (all P<0.05), and CYP3A4*22 maintained significance after adjustment for covariates (P<0.01). These genetic and clinical predictors of exemestane concentration may be useful for treatment individualization in patients with breast cancer.

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Acknowledgements

This research was supported by Pharmacogenetics Research Network Grant No. U-01 GM61373 (to DAF) and Clinical Pharmacology Training Grant No. 5T32-GM08425 (to DAF) from the National Institute of General Medical Sciences, National Institutes of Health (NIH), Grant Nos. M01-RR000042 (University of Michigan), M01-RR00750 (Indiana University) and M01-RR00052 (Johns Hopkins University) from the National Center for Research Resources (NCRR), a component of the NIH, the Breast Cancer Research Foundation (BCRF) (N003173 to JMR and DFH), the National Cancer Institute (5T32CA083654), the National Institute of General Medical Sciences (GM099143 to JMR) and the National Institutes of Health through the University of Michigan’s Cancer Center Support Grant (P30 CA046592) by the use of the following Cancer Center Core: University of Michigan DNA Sequencing Core. In addition, these studies were supported by grants from Pfizer (to DFH), Novartis Pharma AG (to DFH) and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale (to DFH). Drugs were supplied by Novartis and Pfizer.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

    D L Hertz

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

    K M Kidwell & N J Seewald

  3. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

    C L Gersch, D F Hayes, N L Henry & J M Rae

  4. Department of Medicine, Indiana University, Bloomington, IN, USA

    Z Desta, D A Flockhart, A-M Storniolo & T C Skaar

  5. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    V Stearns

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Correspondence to D L Hertz.

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Competing interests

Dr Stearns has received research funding from Abbvie, Celgene, Merck, Novartis, Medimmune, Pfizer and Puma. NLH had research funding from AstraZeneca, Eli Lilly, BioMarin Pharmaceuticals, Celldex Pharmaceuticals, and Sanofi Aventis. VS had research funding from Abbvie, Abraxis (Celgene), Medimmune, Merck, Novartis, Pfizer, Puma. DFH has consulted for Pfizer and Lilly Oncology, and had research funding from Janssen R&D, Puma Biotechnology, Pfizer, and Astra Zeneca. DFH also has personal financial interest in Oncimmune and Inbiomotion and has royalties from Janssen R&D. DAF had research funding from Pfizer and Novartis and sat on the Scientific Board for Quest Diagnostics. The other authors declare no conflict of interest.

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This work was presented in part at the 2015 San Antonio Breast Cancer Symposium.

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Hertz, D., Kidwell, K., Seewald, N. et al. Polymorphisms in drug-metabolizing enzymes and steady-state exemestane concentration in postmenopausal patients with breast cancer. Pharmacogenomics J 17, 521–527 (2017). https://doi.org/10.1038/tpj.2016.60

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