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

Purpose: Tamoxifen administered at 20 mg/d has been shown to decrease breas t cancer incidence in at-risk women by 50%, but toxicity may limit its broa d use, particularly in postmenopausal women. Because toxicity may be dose-d ependent, we studied the biologic activity of low concentrations of tamoxif en 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 (place bo, 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 wit h the changes in surrogate biomarkers of different diseases, including lipi d profile, brood cell count, fibrinogen, antithrombin ill, osteocalcin, and insulin-like growth factor I, a promising surrogate biomarker of breast ca ncer. Results: The means (+/- SD) for tamoxifen and N-desmethyltamoxifen (metabol ite 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 we re of comparable magnitude at any drug concentration except for platelet co unt and triglycerides levels, the latter showing a trend to an increase wit h increasing tamoxifen concentrations. Conclusion: An 80% reduction in blood concentrations does not seem to affec t the activity of tamoxifen on biomarkers of cardiovascular or breast cance r risk and may in fact have a more favorable safety profile. Additional stu dies are warranted to determine the most appropriate dose of this agent. (C ) 1999 by American Society of Clinical Oncology.