# Association Between Body Mass Index and Clinical Outcomes of CDK4/6 Inhibitors in HR+/HER2− Metastatic Breast Cancer: A Real-World Cohort Study

## TL;DR

The study finds that body mass index (BMI) in metastatic breast cancer patients treated with CDK4/6 inhibitors is not clearly linked to survival outcomes when categorized as normal or overweight, but a U-shaped pattern suggests risks at extreme BMI levels.

## Contribution

This study reveals a non-linear relationship between BMI and survival outcomes in metastatic breast cancer patients treated with CDK4/6 inhibitors, challenging dichotomous BMI categorization.

## Key findings

- Dichotomized BMI categories were not independently associated with progression-free or overall survival.
- Non-linear modeling showed increased risk at both low and high BMI extremes.
- Propensity score matching confirmed no significant survival differences between BMI groups.

## Abstract

Background: Body mass index (BMI) has been widely investigated as a potential prognostic factor in breast cancer; however, its clinical relevance in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer treated with CDK4/6 inhibitors remains controversial, particularly in contemporary real-world settings. This study aimed to evaluate the association between baseline BMI and clinical outcomes, including survival and treatment-related toxicity, in a real-world cohort. Methods: This single-centre retrospective observational cohort study included patients with HR+/HER2− metastatic breast cancer treated with endocrine therapy and a CDK4/6 inhibitor (palbociclib or ribociclib) in the metastatic setting between January 2018 and May 2025. Patients were categorised by baseline BMI (<25 vs. ≥25 kg/m2). Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan–Meier method and Cox proportional hazards models. To minimise confounding, propensity score matching (PSM) with a 1:3 nearest-neighbour algorithm was performed. Non-linear associations between continuous BMI and survival outcomes were explored using restricted cubic spline analyses. Treatment-related adverse events were evaluated according to CTCAE v5.0. Results: A total of 456 patients were included; 321 (70.4%) had a BMI ≥ 25 kg/m2, and 135 (29.6%) had a BMI < 25 kg/m2. Propensity score matching produced a balanced cohort of 220 patients. The reduction in sample size after matching reflects the need to achieve close baseline comparability between groups. In the matched cohort, no statistically significant differences in PFS (log-rank p = 0.55) or OS (log-rank p = 0.31) were observed across BMI categories. BMI was not an independent predictor of PFS or OS in multivariable analyses. However, restricted cubic spline modelling revealed a non-linear relationship between continuous BMI and survival outcomes, with increased risk at extreme BMI values, underscoring the limitations of dichotomous BMI categorisation. Conclusions: In this real-world cohort of patients with HR+/HER2− metastatic breast cancer treated with CDK4/6 inhibitors, dichotomised BMI categories were not independently associated with survival outcomes. However, modelling BMI as a continuous variable revealed a non-linear (U-shaped) relationship, with increased risk at both the low and high ends of the BMI distribution. These findings suggest that the prognostic impact of BMI is non-linear and may be obscured by simple dichotomous categorisation.