ASSESSMENT OF HORMONE DEPENDENCE OF COMEDO DUCTAL CARCINOMA IN-SITU OF THE BREAST

Background: Ductal carcinoma in situ (DCIS) represents 20%-30% of brea st cancers detected by clinical screening (i.e., mammography), More th an 50% of DCIS lesions may be estrogen receptor negative and, therefor e, hormone independent, However, the role of estrogen in the natural h istory of DCIS is unknown, Purpose: A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth, Methods: Specimens of breast tissue were collect ed from 52 women during diagnostic or therapeutic surgical procedures, Portions of each specimen were randomly selected and analyzed by hist ology and thymidine labeling (to measure cell proliferation), The rema inder of each specimen was implanted into five to 18 athymic BALB/c nu /nu mice (depending on the amount of tissue available), with eight pie ces of approximately 2 mm x 2 mm x 1 mm implanted at different locatio ns on the back of each mouse, Half of the mice received implants conta ining estrogen (2 mg 17 beta-estradiol), and the other half received p lacebo implants, Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specifi c for the Ki-67 nuclear antigen, Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens, Seru m 17 beta-estradiol levels in the mice were measured by radioimmunoass ay, Results: Initial levels of cell proliferation were approximately 1 0-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versu s 1.9%, respectively; two-sided P < .001), Xenografts from the majorit y of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation, Estrogen treatment of the xen ograft-bearing mice had no effect on the high level of cell proliferat ion observed in estrogen receptor-negative, comedo DCIS specimens (two -sided P =.89), In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001), Howe ver, even with estrogen treatment, cell proliferation levels in estrog en receptor-positive DCIS specimens did not reach those seen in estrog en receptor-negative DCIS specimens, Conclusion and Implication: Estro gen receptor-negative, comedo DCIS lesions appear to be estrogen indep endent; therefore, antiestrogen (e.g., tamoxifen) therapy may not bene fit patients with comedo DCIS.