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Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer

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Abstract

Purpose

Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients.

Methods

In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs.

Results

The ranges of baseline estrogen concentrations were <LLOQ–361 pg/mL for E2, <LLOQ–190 pg/mL for E1, and 8.3–4060 pg/mL for E1S. For E2, the frequency of suppression below the LLOQ was not statistically significantly different between AIs (exemestane: 89.0%, letrozole: 86.9%, p = 0.51). However, patients on letrozole were more likely to achieve suppression below the LLOQ of both E1 (exemestane: 80.1%, letrozole: 90.1%, p = 0.005) and E1S (exemestane: 17.4%, letrozole: 54.9%, p = 4.34e−15). After 3 months of AI therapy, the ranges of estrogen concentrations were <LLOQ–63.8 pg/mL, <LLOQ–36.7 pg/mL, and <LLOQ–1090 pg/mL for E2, E1, and E1S, respectively. During treatment, 16 patients had an increased concentration compared to the baseline concentration of at least one estrogen.

Conclusions

Letrozole had greater suppression of plasma E1 and E1S than exemestane, though the response was highly variable among patients. Additional research is required to examine the clinical relevance of differential estrogen suppression.

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Acknowledgements

This study was supported in part 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 Number W81XWH-10-1-0349 (JDR)], Pfizer (DFH), Novartis Pharma AG (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 patients with breast cancer and the research nurse coordinators at each of the clinical trial sites. Finally, we express our gratitude to and respect for DAF, who provided tremendous expertise and leadership for this project prior to his untimely death.

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Authors and Affiliations

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

    Jason D. Robarge, Zereunesay Desta, Anne T. Nguyen, David A. Flockhart & Todd C. Skaar

  2. Center for Computational Biology and Bioinformatics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Lang Li

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

    Daniel Hertz, James M. Rae & Daniel F. Hayes

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

    Anna M. Storniolo

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

    Vered Stearns

  6. Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr #3362, Salt Lake City, UT, 84112, USA

    N. Lynn Henry

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  1. Jason D. Robarge
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  2. Zereunesay Desta
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Corresponding author

Correspondence to N. Lynn Henry.

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Conflicts of interest

NLH received research funding from AstraZeneca, Eli Lilly, BioMarin Pharmaceuticals, Celldex Pharmaceuticals, and Sanofi Aventis. VS received research funding from Abbvie, Celgene, Medimmune, Merck, Novartis, Pfizer, and Puma. DFH worked as a consultant for Lilly Oncology, and received research funding from Merrimack, Lilly, Janssen R&D, Puma Biotechnology, Pfizer, and Astra Zeneca. DFH also has personal financial interest in Oncimmune and Inbiomotion and received royalties from Janssen R&D. DAF received research funding from Pfizer and Novartis and sat on the Scientific Board for Quest Diagnostics. The rest of the authors have no conflicts of interest to declare (JDR, ZD, ATN, LL, DLH, JMR, AMS, TCS).

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Todd C. Skaar, N. Lynn Henry: co-senior authors.

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Robarge, J.D., Desta, Z., Nguyen, A.T. et al. Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer. Breast Cancer Res Treat 161, 453–461 (2017). https://doi.org/10.1007/s10549-016-4077-4

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  • DOI: https://doi.org/10.1007/s10549-016-4077-4

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