Background: In 2014, an ASPO position statement was released calling for action regarding cancer survivors’ needs for weight management. Reduction of body weight is hypothesized to affect several cancer-related biological pathways. Methods: The Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) trial is the largest weight loss trial completed to date among breast cancer survivors. In it, 692 stage Ic-IIIc breast cancer survivors were randomized to an intensive, group-based weight loss intervention with 26 contacts over one year or to a non-intensive intervention with two contacts over the same time period. Results recently reported in JCO showed significantly greater weight loss in the intensive intervention arm compared to the non-intensive arm. A pilot study exploring baseline to 6-month changes in gene methylation and expressed biomarkers was undertaken in 30 chemo-naïve, post-menopausal, non-Hispanic white women who participated in this study. Results: Several significant differences in mean change scores (standard error) between the intensive vs. non-intensive groups were noted, i.e., insulin: -4.19(0.80) vs. 0.42 (1.01)/p = 0.0016; c-peptide: -0.49(0.14) vs. 0.40(0.19)/p = 0.0009; leptin: -15.73(1.79) vs. 2.53(1.78)/p < 0.0001; adiponectin:leptin ratio: 0.67(0.15) vs. 0.010(0.064)/p = 0.0007; homeostasis model of insulin resistance (HOMA-IR): 20.00(4.65) vs. 9.57(5.00)/p = 0.0003; sex hormone binding globulin 20.45(4.61) vs. 8.65(8.00)/p = 0.023; and Follistatin-Related Protein-3 (FSTL3): 0.48(0.19) vs. -0.88(0.55)/p = 0.0497. While effects were in the direction hypothesized for c-reactive protein, interleukin-6, vascular endothelial growth factor, and tumor necrosis factor no significant differences were noted. Significant differences in DNA methylation also were noted for genes encoding for Follistatin Related Protein (corresponds to FSTL3), and those on hormonal/growth pathways (e.g., AMOTL1, ESR, EGR3), inflammatory pathways (e.g., TNFRS10A/TRAIL-R1, C14orf106), and metabolic pathways (e.g., ZBED3, GABRA). Conclusions: While results are based on a small sample and not corrected for multiple testing, they provide evidence that weight loss affects several biomarkers and pathways that impact cancer and which warrant further investigation. Clinical trial information: NCT01112839