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Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients

  • Epidemiology
  • Published:
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Abstract

Purpose

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations.

Methods

Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures.

Results

Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42–63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05).

Conclusions

Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

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Acknowledgements

This research was supported by Pharmacogenetics Research Network Grant No. U-01 GM61373 (D.A.F.) and Clinical Pharmacology Training Grant No. 5T32-GM08425 (D.A.F.) from the National Institute of General Medical Sciences, National Institutes of Health (NIH), from Grants No. 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 (5T32CA083654-12, PI Jeremy Taylor), the National Institute of General Medical Sciences (GM099143 to J.M.R.) 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 (D.F.H.), Novartis Pharma AG (D.F.H.), the Fashion Footwear Association of New York/QVC Presents Shoes on Sale (D.F.H.). Drugs were supplied by Novartis and Pfizer. We also wish to posthumously recognize David Flockhart, MD, PhD, who co-chaired the COnsortium on BReast cancer phArmacogomics (COBRA) and passed during preparation of this manuscript.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St. Room 3054, Ann Arbor, MI, 48109-1065, USA

    Daniel L. Hertz

  2. Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, USA

    Daniel L. Hertz, Kelley M. Kidwell, Christina L. Gersch, Daniel F. Hayes, N. Lynn Henry & James M. Rae

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

    Kelly A. Speth & Kelley M. Kidwell

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

    Christina L. Gersch, Daniel F. Hayes, N. Lynn Henry & James M. Rae

  5. Indiana University School of Medicine, Indianapolis, USA

    Zeruesenay Desta, Anna Maria Storniolo & Todd C. Skaar

  6. Johns Hopkins School of Medicine, Baltimore, USA

    Vered Stearns

  7. Huntsman Cancer Institute, University of Utah Health Care, Salt Lake City, UT, USA

    N. Lynn Henry

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  1. Daniel L. Hertz
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Correspondence to Daniel L. Hertz.

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Competing interest

DFH and VS have each received research funding from Pfizer and Novartis Pharma AG, including for this study. The authors declare no other competing interest.

Additional information

This work was submitted in preliminary form to 2017 American Society for Clinical Oncology Annual Meeting.

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Hertz, D.L., Speth, K.A., Kidwell, K.M. et al. Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients. Breast Cancer Res Treat 165, 659–668 (2017). https://doi.org/10.1007/s10549-017-4346-x

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