Abstract PS1-12-21: Association of weight changes compared to baseline with time on CDK 4/6 inhibitor in women with de novo Stage IV HR+HER2- breast cancer

Abstract Background and objectives: Overweight and obesity are associated with worse outcomes in breast cancer, while weight loss can delay the onset of endocrine therapy resistance in pre-clinical models. Weight gain is a common side-effect of endocrine therapy. We explored if weight loss delays resistance to endocrine therapy with CDK 4/6 inhibitors (CDK4/6i) in women with de novo hormone-receptor positive (HR+) /HER2- metastatic breast cancer. Methods: We analyzed patients with de novo HR+/HER2- metastatic breast cancer treated at MD Anderson Cancer Center with CDK4/6 inhibitors and endocrine therapy from January 2015 to December 2024 who experienced disease progression. Body weight and BMI were tracked at baseline (CDK4/6i initiation) and 3, 6, and 12 months from CDK4/6 inhibitor start. Mixed-effects models assessed associations between treatment duration and weight/BMI change. Cox proportional hazards models evaluated factors associated with overall survival (OS). Results: Among 488 patients who progressed on CDK 4/6i and endocrine therapy, palbociclib was the most used drug (86.3%). 80 (16.4%) experienced weight gain and 48 (9.8%) experienced weight loss at 12 months compared to baseline. Similar proportions were observed for change in BMI. Mixed-effects univariate and multivariate models showed that increases in absolute weight and BMI from baseline over time were associated with longer CDK4/6i therapy duration (p=0.010 and p=0.005, respectively) (Table 1). In univariate Cox analysis, longer CDK4/6i use was associated with improved OS (HR 0.50, 95% CI 0.44-0.57, p0.001), while higher tumor grade and presence of BRCA mutations correlated with poorer OS. Conclusion: Contrary to our hypothesis, absolute weight and BMI increase from baseline was associated with longer CDK 4/6i use in de novo HR+/HER2- breast cancer. Weight trends and tumor biology may offer prognostic insight and warrant further study in prospective settings. Citation Format: D. Kizub, S. Pasyar, M. V. Phan, J. Sukumar, A. K. Arun, A. Singareeka Raghavendra. Association of weight changes compared to baseline with time on CDK 4/6 inhibitor in women with de novo Stage IV HR+HER2- breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-21.