Timing of central nervous system metastases occurrence in patients with metastatic breast cancer treated with CDK 4/6 inhibitors: A single institution real-world analysis.

e13068 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are standard first-line treatment for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Patients with CNS metastases in HR+/HER2- MBC remain underrepresented in clinical trials, and a major unmet clinical need despite advances in systemic therapy; real-world data (RWD) are needed to better understand their patterns of occurrence. Methods: Data were extracted from medical records of HR+/HER2- MBC patients treated with CDK4/6i at the University Hospital Centre Zagreb from April 2018 to December 2025. Patients were stratified by timing of CNS metastases development: at baseline, during CDK4/6i treatment, or in later lines (after progression on CDK4/6i therapy). Median real-world progression-free survival (rwPFS) was estimated using the Kaplan-Meier method. Results: Among 442 HR+/HER2- MBC patients, 49 (11%) developed CNS metastases (radiologically and/or histologically confirmed) during the course of metastatic disease. Median rwPFS in 14 patients with baseline CNS metastases treated with CDK4/6i was 12.5 months (95% CI, 6-22 months). Median rwPFS in 17 patients who developed CNS metastases during CDK4/6i therapy was 30 months (95% CI, 25-50 months). Among them, 10 patients had isolated CNS progression and continued CDK4/6i beyond CNS progression, achieving a median rwPFS of 7 months (95% CI, 6-13 months), while 7 patients had both systemic and CNS progression and subsequently received chemotherapy. In patients with baseline CNS metastases abemaciclib was the most frequently used CDK4/6i, and ribociclib in those who developed CNS metastases during CDK4/6i therapy. In 18 patients who developed CNS metastases in later lines, after progression on CDK4/6i therapy, median rwPFS on CDK4/6i was 18 months (95% CI, 12-25 months), 56% progressed within 12 months. Conclusions: Favourable median rwPFS was observed in patients with CNS metastases treated with CDK4/6i, whether present at baseline or developed during therapy. Continuation of CDK4/6i beyond CNS progression, may in isolated cases provide meaningful disease control. These findings are consistent with PFS reported in pivotal randomized trials. Further research is needed to identify biomarkers predictive of CNS progression. Clinicopathological and molecular characteristics of patients with CNS metastases. Baseline CNSmetastases (n=14) CNS progression duringCDK4/6i therapy (n=17) CNS metastases after progression on CDK4/6i therapy (n=18) Lobular tumour histology, n(%) 6 (43%) 4 (24%) 5 (28%) PIK3CA mt, n(%) 5 (35%) 4 (24%) 5 (28%) PR negative, n(%) 3 (21%) 10 (59%) 7 (39%) HER2 low (1+ or 2+), n(%) 4 (29%) 5 (29%) 5 (28%) gBRCA 1 or 2 mt, n(%) 0 2 (12%) 1 (5%) Median rwPFS months, (95% CI) 12.5 (6-22) 30 (25-50) 18 (12-25)