Background: Weight loss interventions are effective approaches to reduce body weight and alter serum biomarkers in breast cancer survivors, however the impact on breast tissue biomarkers is unknown. The Lifestyle, Exercise and Nutrition (LEAN) study was a randomized trial designed to test the effect of a weight loss intervention on body composition and breast tissue and serum biomarkers. Methods: Fifity-one women with a BMI ³ 25.0 kg/m² diagnosed with breast cancer, who had completed chemotherapy and/or radiation therapy were randomized to weight loss intervention or usual care. Breast tissue biopsies from the unaffected breast, fasting serum samples, and body composition were measured at baseline and 6-months. Ki67, insulin receptor (IR), CD68 and CD163 were measured by Automated Quantitative Analysis (AQUA) method. Mean baseline to 6-month changes were compared using ANCOVA adjusting for baseline values. Results: Pre- and post-intervention biopsies were conducted in 49 and 42 women respectively, with both pre- and post- epithelial tissue available from 25 women; epithelial tissue was unavailable in the remaining 66 women. Women were 56.8 ± 8.9 years old, diagnosed 3.3 + 3.8 years prior, primarily Stage I breast cancer (54%), with a BMI of 32.8 ± 6.0 kg/m². At baseline, breast tissue levels of IR were inversely associated with both percent body fat (r = -0.47, p = .03) and serum insulin levels (r = -0.45, p = .04); serum insulin levels were inversely associated with CD68 (r = -0.47, p = .03). Significant between-group biomarker changes are presented in Table 1. At month 6, loss in percent body fat was associated with increased IR (r = -0.42, p = .05). Increased CD68 breast tissue expression was associated with reductions in serum levels of CRP (r = -0.49, p=0.02). There was no significant effect of the intervention on IR expression or Ki67 (p>0.10). Conclusions: Breast tissue biopsies are feasible to collect in a clinical research setting among breast cancer survivors. A 6-month weight loss intervention led to decreased levels of CD163 in breast tissue and serum levels of leptin, and increased serum levels of adiponectin among breast cancer survivors. At baseline and month 6, changes in breast tissue biomarkers were favorably associated with serum biomarkers and body composition. Future confirmation is required to confirm the added benefit of tissue biomarkers beyond serum as an endpoint for lifestyle interventions among breast cancer survivors. Clinical trial information: NCT02110641