Obesity, chemotherapy dosing, and toxicity: Results from the Optimal Breast Cancer Chemotherapy Dosing study.

547 Background: ASCO guidelines state that most cytotoxic drugs should be dosed according to full body surface area (BSA) without limiting the dose on the basis of obesity. This approach is supported by a lack of evidence to suggest that patients with obesity, when fully-dosed, experience higher risk of toxicity. Indeed, historical evidence suggests that obese, fully-dosed patients may experience lower risk of neutropenia than normal weight patients. However, questions remain regarding the representativeness of historical trial data on which this evidence is based. We examined this issue in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study. Methods: The OBCD Study is a real-world cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at Kaiser Permanente Northern California and Kaiser Permanente Washington between 2004-2019. Among women receiving the full dose of chemotherapy at treatment initiation (≥90% of intended dose, n = 7,644), we examined risk of toxicities in women with obesity (BMI ≥30 kg/m 2 ) compared to non-obese women (BMI 18.5- < 30 kg/m 2 ). We examined hematologic (neutropenia, anemia, thrombocytopenia) and non-hematologic (nephrotoxicity, hepatotoxicity, neuropathy, and cardiotoxicity) toxicities. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression, adjusted for covariates including prevalent comorbid conditions. Secondary analyses examined associations pertaining to specific BMI groups and also stratified by administration schedule (standard vs dose-dense). Results: Fully-dosed patients with obesity experienced lower risk of neutropenia (HR: 0.80; 95% CI: 0.73-0.88) and any hematologic toxicity (HR: 0.83; 95% CI: 0.75-0.91) but increased risk of neuropathy (HR: 1.34; 95% CI: 1.18-1.52), cardiotoxicity (HR: 2.30; 95% CI: 1.13-4.67), and non-hematologic toxicities overall (HR: 1.31; 95% CI: 1.15-1.48). The strength of these associations increased with increasing BMI category. The inverse association between obesity and hematologic toxicity was evident for standard administration schedules (HR: 0.54; 95% CI: 0.45-0.66) but not dose-dense schedules. However, the positive association between obesity and non-hematologic toxicities persisted regardless of administration schedule. Conclusions: Women with obesity given the full BSA-determined chemotherapy dose are less likely to experience neutropenia than fully-dosed non-obese women. Importantly, this holds among patients with more severe obesity, but not when restricted to newer dose-dense administration schedules. Findings also suggest that fully-dosed patients with obesity may experience higher risks for neuropathy and cardiotoxicity. These findings highlight the importance of better understanding the risks and benefits of dosing strategies as treatments and patient populations continue to evolve.