Tamoxifen modulates tumor suppressor gene methylation in breast cells and growth factors in plasma in women at increased risk for breast cancer Free

B32

Background: Tamoxifen reduces the incidence of invasive and in situ breast cancer by 50% in high risk women, but its effects on benign breast tissue biology have not been systematically studied. This randomized, prospective placebo-controlled double-blind Phase IIa trial was designed to identify biomarkers that are modulated by tamoxifen locally in benign breast tissue as well as systemically in plasma. Methods: Between May 2002 and March 2007, 31 premenopausal and 42 postmenopausal women defined as high risk by the Gail model or with a personal history of LCIS were randomized to tamoxifen (20 mg/day) or placebo for 3 months. Blood and breast tissue were collected at baseline and post-treatment. Endpoints included growth hormones and binding proteins in plasma, cytological classifications and tumor suppressor gene methylation in FNA, and proliferation (Ki67) and apoptosis (TUNEL) in tissue cores. Results: Tamoxifen treatment was associated with an increase in SHBG and total estradiol but a reduction in plasma albumin resulting in an increase in free estradiol in the plasma (P=0.003). Levels of IGF1 decreased while IGF2, IGFBP1 and IGFBP3 levels increased. The net effect was a significant decrease in IGF1/IGFBP1 and IGF1/IGFBP3 ratios (P=0.013 and P=0.001). Prolactin levels were not altered during treatment. The three month tamoxifen treatment did not reduce FNA cellularity or the prevalence of cytological atypia. However, promoter methylation of RASSF1A and APC decreased in the tamoxifen group compared to the placebo group (P=0.04). Methylation of cyclin D2, H-cadherin, CST6, HIN-1, and RARβ2 was not affected. There was no reduction in the proliferative index and no increase in apoptosis. Conclusion: Tamoxifen increased total and free estradiol and beneficially modulated IGF/IGFBP ratios in the plasma. Tamoxifen also decreased APC and RASSF1A methylation in benign breast epithelial cells and this effect was independent of IGF modulation. This work was supported by the National Cancer Institute grant: N01-CN-95139.