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

被引:70
作者
Decensi, A
Gandini, S
Guerrieri-Gonzaga, A
Johansson, H
Manetti, L
Bonanni, B
Sandri, MT
Barreca, A
Costa, A
Robertson, C
Lien, EA
机构
[1] Ist Europeo Oncol, Chemoprevent Unit, Div Epidemiol & Biostat, I-20141 Milan, Italy
[2] Ist Europeo Oncol, Div Lab Med, I-20141 Milan, Italy
[3] Univ Genoa, Dept Endocrinol, Genoa, Italy
[4] Univ Bergen, Dept Pharmacol, Bergen, Norway
关键词
D O I
10.1200/JCO.1999.17.9.2633
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 me 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, brood cell count, fibrinogen, antithrombin ill, 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/mt) were dose-related, being, respectively, 0 and 0 with placebo, 26.8 +/- 15.1 and 43.7 +/- 22.5 with 10 me 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. (C) 1999 by American Society of Clinical Oncology.
引用
收藏
页码:2633 / 2638
页数:6
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