Background: Results of a clinical trial recently completed in the Unit
ed States indicate that administration of tamoxifen (20 mg/day) to wom
en at risk can reduce breast cancer incidence by approximately 50% but
is associated with an increased risk of developing endometrial cancer
and venous thromboembolic events. Since these adverse effects may be
dose related, we investigated the effect of tamoxifen on several bioma
rkers when the drug was given at doses lower than those currently in u
se. Methods: In two sequential experiments, 127 healthy hysterectomize
d women aged 35-70 years were randomly assigned to one of the followin
g four treatment arms: placebo (n = 31) or tamoxifen at 20 mg/day (n =
30) (first experiment); or tamoxifen at 10 mg/day (n = 34) or tamoxif
en at 10 mg/alternate days (n = 32) (second experiment). Baseline and
2-month measurements of the following parameters were compared: 1) tot
al cholesterol (primary end point) and other surrogate markers of card
iovascular disease, e.g., low-density lipoprotein cholesterol, high-de
nsity lipoprotein cholesterol, triglycerides, and lipoprotein(a); 2) b
lood cell count; 3) fibrinogen; 4) antithrombin III; 5) osteocalcin; a
nd, 6) in a subgroup of 103 women, insulin-like growth factor-I (IGF-I
), a possible surrogate marker for breast cancer. Resuits: After adjus
tment for the baseline values, there were reductions in circulating le
vels of total cholesterol and IGF-I of the same magnitude in all three
tamoxifen treatment arms. A similar pattern was observed for most of
the other parameters. In the placebo arm, fibrinogen level, which show
ed a decrease, was the only parameter exhibiting change, Conclusions:
Up to a 75% reduction in the conventional dose of tamoxifen (i.e., 20
mg/day) does not affect the activity of the drug on a large number of
biomarkers, most of which are surrogate markers of cardiovascular dise
ase. This study was hypothesis generating, and larger studies are warr
anted to assess the efficacy of tamoxifen at low doses.