A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated > 25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.