Purpose: Increased body mass index (BMI) is a risk factor for breast cancer and has been associated with poor outcomes in both premenopausal and postmenopausal breast cancer patients. Several retrospective studies have demonstrated higher BMI to be associated with inferior pathological complete response (pCR) to neoadjuvant chemotherapy, yet it remains unclear if this difference is related to chemotherapy underdosing among obese breast cancer patients. We evaluated the association between BMI and response to neoadjuvant chemotherapy (defined by pCR) in the I-SPY2 trial,an adaptive clinical trial platform enrolling biologically high-risk breast cancer patients (triple negative, human epidermal growth factor receptor 2 (HER2) positive and MammaPrint high-risk)that utilizes standard neoadjuvant therapy regimens with treatment based on actual body weight.

Patients and Methods: Of 989 patients enrolled in the I-SPY2 trial, 978 had a recorded baseline BMI prior to treatment and were included in the analysis. Tumor subtypes were defined by hormone receptor and HER2 status. Pretreatment BMI was categorized as obese(BMI30kg/m2), overweight(25BMI<30 kg/m2), and normal or underweight(<25 kg/m2) based on World Health Organization criteria. pCR was defined as elimination of detectable invasive cancer in the breast and lymph nodes(ypT0 and ypN0)at the time of surgery. Logistic regression analysis was used to determine associations between BMI and pCR, and we reported odds ratios(OR) and 95% confidence intervals (CI). Event-free survival (EFS) and overall survival (OS) between different BMI categories were examined using a Cox proportional hazards regression model.

Results: The median age in our study population was 49 years. 35% of patients were normal/underweight, 32%overweight, and 33% obese. Black patients were more likely to be obese(P<0.0001). pCR rates differed significantly by tumor subtype(P0.0001)and tumor stage(P=0.0009). pCR rates were 32.8% in normal/underweight, 31.4% in overweight, and 32.5% in obese patients. In univariable analysis, there was no significant difference in pCR with BMI. In multivariate analysis adjusted for race/ethnicity, age, menopausal status, breast cancer subtype, and clinical stage, there was no significant difference in pCR to neoadjuvant chemotherapy for obese compared with normal/underweight patients (OR=1.1, 95%CI: 0.68-1.63, p=0.83), and for overweight compared with normal/underweight (OR=1,95%CI: 0.64-1.47, p=0.88).We tested for potential interaction between BMI and breast cancer subtype, however, interaction was not significant in the multivariate model (P=0.09).Multivariate Cox regression showed there was no difference in EFS(p=0.81)or OS (p=0.52) between obese, overweight and normal/underweight breast cancer patients with a median follow-up time of 4.0 years.

Conclusions: There was no difference in pCR rates by BMI with actual body weight based neoadjuvant chemotherapy in this biologically high-risk breast cancer population. Only breast cancer subtype and stage showed predictive value for pCR in this high-risk operable breast cancer population receiving neoadjuvant chemotherapy in the I-SPY2 clinical trial.