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Effect of Blood Tamoxifen Concentrations on Surrogate Biomarkers in a Trial of Dose Reduction in Healthy Women

From the Chemoprevention Unit, the Division of Epidemiology and Biostatistics, and the Division of Laboratory Medicine, European Institute of Oncology, Milan; the Department of Endocrinology, University of Genoa, Genoa, Italy; and the Department of Pharmacology, University of Bergen, Bergen, Norway.

Address reprint requests to Andrea Decensi, MD, Chemoprevention Unit, European Institute of Oncology, via Ripamonti, 435; 20141 Milan, Italy; email adecensi{at}ieo.it

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.

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