EFFECT OF TAMOXIFEN ON ENDOMETRIAL PROLIFERATION

Purpose: An increase in the incidence of endometrial cancer and a pote ntial increase in related mortality has been associated with the admin istration of 20 mg tamoxifen, the dose adopted in breast cancer chemop revention trials, thus urging studies on intermediate markers of risk. Patients and Methods: Thirty-three women who received 20 mg tamoxifen as adjuvant breast cancer treatment underwent endometrial biopsy. Sam ples were divided for histologic examination, including a quantitative analysis of stromal:epithelial ratio, and an assessment of DNA ploidy and proliferation by flow cytometry, Results were compared with 37 sy mptomatic subjects. Results: All histograms were DNA diploid, Compared with controls, a significant increase in the risk of proliferation as measured by the hyperdiploid fraction was associated with tamoxifen d uration (less than or equal to 36 months: cumulative odds ratio = 16.5 , 95% confidence interval, 1,85 to 146.5; > 36 months: cumulative odds ratio = 28.2, 95% confidence interval, 2.56 to 310.6, P for trend < . 05). Tamoxifen-induced risk was significantly reduced by the extent of menopausal status, No cases of cancer or epithelial hyperplasia were observed in the tamoxifen group, whereas seven cases of epithelial hyp erplasia without atypia were observed in the control group. The effect of tamoxifen on proliferation was associated with an increase in the stromal component. Conclusion: Tamoxifen at 20 mg/d exerts a time-depe ndent proliferative effect on the endometrium, particularly in premeno pausal and early postmenopausal women. This effect appears to be media ted by the stromal component, which accounts for the discrepancy betwe en flow cytometry and histology. Our study provides preliminary eviden ce that the DNA flow cytometric hyperdiploid fraction may be a useful tool for monitoring endometrial cell proliferation in women exposed to tamoxifen. (C) 1996 by American Society of Clinical Oncology.