Abstract Background: Aromatase inhibitors are effective for breast cancer prevention in postmenopausal women. In the recent MAP.3 study, exemestane significantly reduced invasive breast cancer in postmenopausal women with an elevated risk of developing breast cancer. At 35 months follow up there was no increase risk in cardiovascular events in this study; however, the effects of exemestane use on lipid profiles and cardiovascular health are still unclear. Methods: We conducted a single-arm phase II trial of exemestane in women at increased risk for breast cancer and examined the impact of exemestane on lipid profiles. Postmenopausal women at high risk for invasive breast cancer (e.g., Gail Model risk ≥ 1.7, a history of lobular neoplasia, atypical ductal hyperplasia, DCIS, or stage I/II breast cancer, or BRCA 1/2 mutation) were given exemestane (25 mg orally daily) for 2 years. Fasting serum total cholesterol, HDL, LDL, triglycerides, and homocysteine were collected at baseline, 3, 12, and 24 months after initiation of exemestane therapy. Apolipoprotein A and B were collected at baseline, 3 and 12 months. Wilcoxon sign ranked test was used to analyze if changes from baseline values differed from zero. The Hochberg p-value adjustment was used to account for multiple hypothesis tests. Results: Of the 42 women enrolled in the study, 6 dropped out prior to completing 1 year and 1 dropped out prior to completing 2 years of exemestane therapy. Thirty-one women have completed 2 years of exemestane therapy and the remaining 4 are expected to complete 2 years of therapy by January 2012. On average, participants were 58.5 years old, mostly Caucasian (n = 37; 84.1%), and had a BMI of 29.2 kg/m2. A majority (n = 19) of participants were on lipid-lowering medications (14 were taking a statin) or taking fish oil supplements (n =5) prior to starting on the trial and 1 was started on a statin approximately 10 months after starting the trial. There were no significant differences in mean lipid values for each of the 4 assessment points or in the mean change from baseline at 3, 12, and 24 months between patients who were taking lipid-lowering medications and those were not. In unadjusted analyses, change in HDL from baseline was significantly different from zero and decreased from baseline at 3, 12 and 24 months (−8.0 mg/dL, −8.5 mg/dL, and −9.9 mg/dL; All p-values ≤ .001 before and after applying the Hochberg adjustment). Total cholesterol also significantly decreased from baseline at 3 months (−13.6 mg/dL, p = .002) but was no longer significant at 12 and 24 months (−9.6 mg/dL and −11.4 mg/dL, respectively; p-values = .07). The rest of the lipid panel did not significantly change during follow-up. Discussion: In agreement with previous studies, we found that exemestane causes a significant decrease in HDL and total cholesterol, while leaving the rest of the lipid panel unchanged. Prior studies excluded patients on lipid-lowering medication; half of our participants were taking lipid-lowering medication. It is notable that both women off and on lipid-lowering medication had decreases in HDL. Additional studies are needed to elucidate long-term cardiovascular outcomes in this high risk but otherwise healthy population. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-01.