Purpose: To evaluate the usefulness of serum cyclin D1, CDK4, and CDK6 as biomarkers of treatment response and progression-free survival (PFS) in metastatic breast cancer (MBC). Methods: In a single-center prospective observational study, 74 women with hormone-receptor-positive (HR+)/ human epidermal growth receptor-2 (HER2)-negative metastatic breast cancer were recruited from the Oncology Hospital, Medical City in Baghdad, Iraq. The patients were treated with oral Palbociclib (125 mg) for 21 days, then continued with Letrozole (2.5 mg) for 7 days, and completed six treatment cycles. The candidates were divided into two groups based on therapeutic response: Group 1 responded to the palbociclib plus letrozole combination therapy, and Group 2 did not. Serum cyclin D1, CDK 4, and CDK 6 levels were measured using enzyme-linked immunosorbent assay (ELISA) after the 6th cycle. Treatment response was evaluated using RECIST 1.1 criteria. The study was designed and reported in alignment with STROBE guidelines. Results: Serum cyclin D1 levels were higher in responders than non-responders (p = 0.070). Importantly, higher cyclin D1 levels were significantly associated with longer progression-free survival (PFS; p = 0.027). In contrast, serum CDK4 and CDK6 levels did not differ between groups and showed no predictive or prognostic value for PFS. Conclusion: Serum cyclin D1 has demonstrated prognostic relevance in palbociclib-treated MBC, supporting its role as a pharmacodynamic biomarker of CDK 4/6 inhibitors. These findings highlight the limitations of circulating intracellular kinase proteins and support further investigation of dynamic, tumor-derived biomarkers for treatment monitoring.
