1130 Background: Obesity and HER2 overexpression are associated with poor prognosis in breast cancer (BC). Recent studies suggest the existence of functional crosstalk between leptin, a hormone correlated with adiposity, and HER2. Specifically, stimulation with leptin can transactivate HER2 and activate its downstream signaling, while chronic exposure to leptin increases HER2 stability in presence or absence of Herceptin. In our study we evaluated if excess adipocity (associated with leptin overexpression) can impact the clinical outcome in HER2-positive patients treated with Herceptin. Methods: We analyzed retrospectively 155 patients with HER2-positive BC treated with Herceptin for early stage or metastatic disease in the period 2003-2008. The patients were grouped into normal, overweight, and obese categories according to Body Mass Index (BMI) following WHO guidelines. Overall survival (OS) and time to progression (TTP) were calculated by the Kaplan-Meier method and comparisons were made using the log-rank test. Results: 103 patients were treated with adjuvant Herceptin. 12.5% of the population relapsed; of these, 31% and 23% were overweight and obese, respectively. Inrelapsed patients, OS and TTP decreased with increased BMI: the median OS for normal, overweight and obese patients was 40, 36.5, and 31 months, respectively (p=ns); median TTP was 11, 8, and 5 months, respectively (p=0.0351). 52 patients received Herceptin for metastatic disease in association with chemotherapy. In this population, 33% and 15% patients were overweight and obese, respectively; median OS was 65 months and TTP 10.5 months. Decreased OS and TTP were associated with increased BMI: median OS for normal weight, overweight and obese patients was 67, 54, and 39 months, respectively (p=0.0010); median TTP was 12, 7.5, and 7 months, respectively (p=0.0442). The negative impact of increasing BMI was confirmed in subgroups differentiated by hormone receptor and menopausal status. Conclusions: The results suggest that obesity is not only a risk factor and an indicator of poor prognosis in BC patients, but also a negative predictive parameter in HER2-positive subjects. Our in vivo data validate in vitro observation that leptin can impair response to Herceptin in BC cells. No significant financial relationships to disclose.