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


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.


CONCLUSIONS
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.
Decensi
A
A
Chemoprevention Unit, the Division of Epidemiology and Biostatistics, and the Division of Laboratory Medicine, European Institute of Oncology, Milan, Italy. adecensi@ieo.it
Gandini
S
S
Guerrieri-Gonzaga
A
A
Johansson
H
H
Manetti
L
L
Bonanni
B
B
Sandri
M T
MT
Barreca
A
A
Costa
A
A
Robertson
C
C
Lien
E A
EA
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D008875:Middle Aged; D013629:Tamoxifen / Q000008:administration & dosage* / Q000097:blood*
D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D013629:Tamoxifen