title: Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Robarge
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Zereunesay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nguyen
authors.affiliation: Center for Computational Biology and Bioinformatics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hertz
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Rae
authors.affiliation: Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Storniolo
authors.affiliation: Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr #3362, Salt Lake City, UT, 84112, USA. lynn.henry@hci.utah.edu.
authors.forename: N Lynn
authors.initials: NL
authors.lastname: Henry
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D004967:Estrogens / Q000097:blood*; D005260:Female; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000008:administration & dosage; D017698:Postmenopause; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000730:Androstadienes; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; C056516:exemestane
keywords: Breast cancer; Estradiol; Estrone; Estrone sulfate; Exemestane; Letrozole