Retention Of 4-Hydroxytamoxifen And Levels Of Estradiol In The Breast Of High-Risk Women.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5431 Objective: Evaluate the formation and retention of 4-hydroxytamoxifen (4-HT) in the breast and determine the relation to estradiol and tamoxifen levels in serum and breast fluid. Background: Tamoxifen is an orally effective estrogen receptor (ER) modulator, reducing the incidence of ER+ breast cancer by approximately 70%; however 30% of ER+ cancers and essentially no ER- cancers are not prevented. There are no published data on variability of formation and retention of the active metabolite of tamoxifen in ductal lavage fluid (DLF) or the concomitant levels of estradiol that may compete for the ER. Methods: Twenty patients with Gail scores of >1.7 were offered tamoxifen for prophylaxis, 20 mg/day. Both women who accepted tamoxifen, and those who declined, were recruited to the study. DLF was collected before treatment and after approximately 6 mo. Blood was collected at the time of ductal lavage. DLF was lyophilized and reconstituted to 4 ml and total protein concentration was measured. Estradiol was measured by ELISA in serum and DLF; tamoxifen and 4-hydroxytamoxifen were measured by HPLC-mass spectrometry. Results: 13 women accepted TAM therapy. The concentrations of 4-HT in DLF varied from undetectable to 0.81 ng/ml with a CV of 53.6%; those of tamoxifen varied from undetectable to 9.4 ng/ml with a CV of 42.8%. The ratio of 4-HT to tamoxifen in serum was 0.048, and in DLF was 0.124. The correlation of DLF TAM with DLF 4-HT was 0.90, whereas that between serum tamoxifen and DLF 4-HT was 0.49.. The correlation of serum and DLF 4-HT was 0.42. DLF estradiol concentrations were negatively correlated with DLF 4-HT, r = -0.50, but DLF androstenedione and DHEA were not correlated with DLF 4-HT, -0.09 and -0.07, respectively. Tamoxifen treatment increased estradiol levels in the DLF from 20.9 to 77.6 pg/mg protein (p = 0.03 by Wilcoxon’s test) over 6 mo. Conclusions: The concentrations of 4-HT and tamoxifen in DLF are highly variable with undetectable levels in some samples. The higher correlation of DLF 4-HT with DLF tamoxifen and the higher ratio of 4-HT to tamoxifen imply that DLF 4-HT is primarily formed from tamoxifen in the breast. The increase in estradiol in DLF is consistent with previous data on serum levels but the negative correlation of DLF 4-HT with DLF estradiol suggests that, to some degree, 4-HT is competing with estradiol for binding sites in the breast. These data are consistent with the hypothesis that ineffective prophylactic treatment may be related to inadequate inhibition of estrogen action at the level of the breast in some women.