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
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.