The present study aimed to analyze the clinical outcomes of treatment with CDK4/6 inhibitors (CDK4/6i) in a cohort of patients with metastatic estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, focusing on progression-free survival (PFS), overall survival (OS), and time on treatment (TOT). This evidence concerns the gene ESR1 and breast carcinoma.