Prognostic Impact of Early Metabolic Response on Interim 18F-FDG PET/CT in HR+/HER2− Metastatic Breast Cancer Treated with CDK4/6 Inhibitors

<i>Background and objectives</i>: Early biomarkers that can reliably predict treatment outcomes during CDK4/6 inhibitor therapy remain an unmet clinical need in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). Metabolic changes on ^18F-FDG PET/CT may precede radiologic response and provide insight into tumor biology and early treatment resistance. <i>Methods</i>: This two-center retrospective study included 203 patients with HR+/HER2- MBC who received first-line CDK4/6 inhibitors (ribociclib or palbociclib) plus endocrine therapy between 2018 and 2024. Baseline and interim ^18F-FDG PET/CT scans performed after 2-4 cycles were evaluated. Early metabolic response was defined as a ≥30% reduction in SUVmax on the most metabolically active lesion, consistent with PERCIST 1.0. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and multivariable Cox models. ROC analysis assessed the discriminative performance of ΔSUVmax for predicting disease progression. <i>Results</i>: Among 203 patients, 153 (75.4%) achieved a ≥30% SUVmax reduction. Responders had significantly longer PFS (median 44.4 vs. 4.8 months; <i>p</i> < 0.001) and OS (median not reached vs. 32.0 months; <i>p</i> < 0.001). Metabolic response remained independently associated with improved PFS (HR 0.24; 95% CI 0.15-0.37; <i>p</i> < 0.001) and OS (HR 0.37; 95% CI 0.20-0.67; <i>p</i> = 0.001) after adjustment for tumor grade, endocrine resistance, and visceral disease involvement. Non-responders demonstrated more aggressive baseline features, including higher rates of liver (34.0% vs. 15.0%) and brain metastasis (10.0% vs. 1.3%), as well as lower progesterone receptor expression (median 30% vs. 60%). <i>Conclusions</i>: Early metabolic response assessed by SUV-max on interim ^18F-FDG PET/CT is independently associated with substantially improved PFS and OS in HR+/HER2- MBC receiving treatment with CDK4/6 inhibitors. Although the predictive accuracy of ΔSUVmax alone was modest, the strong survival gradient suggests meaningful prognostic value. Prospective studies with standardized imaging time points and comprehensive metabolic metrics are warranted to define the role of PET-guided treatment adaptation.