Effect of blood tamoxifen concentrations on surrogate biomarkers in a trial of dose reduction in healthy women

Andrea Decensi, Sara Gandini, Aliana Guerrieri-Gonzaga, Harriet Johansson, Lapo Manetti, Bernardo Bonanni, Maria Teresa Sandri, Antonella Barreca, Alberto Costa, Chris Robertson, Ernst A. Lien

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Tamoxifen administered at 20 mg/d has been shown to decrease breast cancer incidence in at-risk women by 50%, but toxicity may limit its broad use, particularly in postmenopausal women. Because toxicity may be dose-dependent, we studied the biologic activity of low concentrations of tamoxifen to determine the plausibility of a dose reduction. Patients and Methods: We measured the blood concentrations of tamoxifen and its main metabolites in a dose titration study in 105 healthy women (placebo, tamoxifen 10 mg on alternate days, tamoxifen 10 mg/d, and tamoxifen 20 mg/d). Drug levels measured after 2 months of treatment were correlated with the changes in surrogate biomarkers of different diseases, including lipid profile, blood cell count, fibrinogen, antithrombin III, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast cancer. Results: The means (± SD) for tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations (ng/mL) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 ± 15.1 and 43.7 ± 22.5 with 10 mg every other day, 51.2 ± 24.1 and 90.7 ± 48.0 with 10 mg/d, and 136.0 ± 52.7 and 230.6 ± 75.0 with 20 mg/d of tamoxifen. At variance, the biomarker changes were of comparable magnitude at any drug concentration except for platelet count and triglycerides levels, the latter showing a trend to an increase with increasing tamoxifen concentrations. Conclusion: An 80% reduction in blood concentrations does not seem to affect the activity of tamoxifen on biomarkers of cardiovascular or breast cancer risk and may in fact have a more favorable safety profile. Additional studies are warranted to determine the most appropriate dose of this agent.

Original languageEnglish
Pages (from-to)2633-2638
Number of pages6
JournalJournal of Clinical Oncology
Volume17
Issue number9
Publication statusPublished - Sep 1999

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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