PURPOSE: Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations. METHODS: In a 4-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to Exercise Alone, Weight Loss Alone, Exercise plus Weight Loss, or Control for 12-months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). RESULTS: Compared with Control, Exercise Alone increased ICAM-1 (9.3%; 95% CI 1.6 to 16.9) and VCAM-1 (8.6%; 95% CI 2.6 to 14.5), but did not change CRP or SAA. Compared with Control, Weight Loss Alone reduced CRP (-35.2%; 95% CI -49.9 to -20.7), and SAA (-25.6%; 95% CI -39.8 to -11.9), but did not change ICAM-1 or VCAM-1. Compared with Control, Exercise plus Weight Loss reduced CRP (-44.1%; 95% CI -57.1 to -31.1) and SAA (-26.6%; 95% CI -40.5 to -12.6), but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (eg, > 3 mg/L), compared to Control, Weight Loss Alone (0.17; 95% CI 0.04 to 0.30) and Exercise plus Weight Loss (0.31; 95% CI 0.16 to 0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels. CONCLUSIONS: In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death.

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