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Background: The ATAC trial is a randomised double blind trial to assess the efficacy of anastrozole and tamoxifen alone or in combination as adjuvant therapy for early breast cancer. The endometrial sub-protocol was designed to examine the effect of these treatments on the endometrium. Methods: Endometrial biopsies were taken at baseline and after 1 year’s treatment. The expression of oestrogen receptor a (ER), progesterone receptor (PR), Ki-67 and Bcl-2 were compared in samples classified as inactive/atrophic from postmenopausal women at baseline (n= 93) and after 1 year’s treatment (n = 60). Results: Women treated with Tamoxifen for 1 year showed no change in expression of ER in either the stromal or epithelial compartments. Expression of PR and Ki-67 were increased in both the stroma and glands when compared to baseline (p <0.05). Bcl-2 expression was decreased in the stromal compartment only (p <0.05). Treatment with Anastrozole demonstrated no significant change to ER or PR expression in the glands or stroma after 1 year of treatment. Ki-67 expression was decreased in the glands after 1 year of treatment with Anastrozole. 81% of samples were classed as negative compared to 50% at baseline (p <0.05). This decrease was not observed in the stroma. Bcl-2 expression was also decreased in the glands (p <0.05) with 52% of glands classified as negative after 1 year of treatment compared to 19% at baseline. Discussion: Treatment for 1 year with Anastrozole appears to have a quiescent effect on the endometrium of postmenopausal women reducing proliferation, increasing the level of apoptosis whilst leaving ER and PR expression unaffected. The lack of a stimulatory effect of Anastrozole on the endometrium is thought to be due to its ability to reduce circulating estrogen levels. The decline in Bcl-2 suggests that the estrogen suppression brought about by Anastrozole has the downstream effect of regulating Bcl-2, which in turn may act to protect the endometrium against malignant changes. Tamoxifen significantly increased the activity of the endometrium. The rise of PR and Ki-67 are indicative of estrogenic pathway activity commonly observed in Tamoxifen treated endometrium and is a feature of its partial estrogen activity. The observed increased in Bcl-2 expression within the stroma may be as a response to the increase in proliferation. The absence of changes to Bcl-2 expression within the glandular compartment is not yet understood. In conclusion, Anastrozole appears to have a down regulating effect on the endometrium possibly exerted by reducing the level of circulating estrogens. Tamoxifen stimulates the postmenopausal endometrium to proliferate and express increased numbers of PR, increasing the potential for malignant change.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]