First-Line Chemotherapy Versus CDK4/6 Inhibitors in HR-Positive, HER2-Negative Breast Cancer with Liver Metastases: A Multicenter Real-World Data

<b>Background</b>: Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer frequently involves liver metastases, which are linked to poor outcomes. The optimal first-line treatment strategy in this subgroup remains unclear. <b>Methods</b>: This multicenter, retrospective study evaluated 121 patients with HR-positive, HER2-negative breast cancer and liver metastasis who had not received prior systemic chemotherapy or cyclin-dependent kinase (CDK) 4/6 inhibitors (e.g., palbociclib, ribociclib). Patients were classified based on their initial treatment during the liver metastatic phase (CDK4/6 inhibitors or chemotherapy). Clinical characteristics, treatment patterns, and survival outcomes were assessed. Cox regression analysis identified independent prognostic factors. <b>Results</b>: The median age was 53 years; 62% were postmenopausal. Chemotherapy was administered to 36.4%, and CDK4/6 inhibitors to 63.6% of patients. Most cases (59.5%) were recurrent disease. Baseline characteristics were comparable, except for the use of local liver-directed therapies. Progression-free survival favored CDK4/6 inhibitors (10.9 vs. 4.8 months; <i>p</i> < 0.01), while overall survival favored chemotherapy (42.2 vs. 25.9 months; <i>p</i> = 0.042). In multivariate analysis, initial treatment modality, local liver-directed therapy, hormonal status, and the size of the largest liver lesion were independent predictors of survival. <b>Conclusions</b>: In patients with HR-positive, HER2-negative breast cancer and liver metastasis, first-line chemotherapy was associated with improved overall survival compared to CDK4/6 inhibitors. Local liver-directed therapies contributed to longer survival, while larger liver lesions and endocrine-resistant disease correlated with worse outcomes. These findings support considering chemotherapy as first-line treatment in selected patients with aggressive liver metastatic disease.