Efficacy and Safety of CDK4/6 Inhibitor Therapy in Patients Aged 80 Years and Older with HR+/HER2- Metastatic Breast Cancer: A Multicenter Real-World Analysis

Purpose: The management of metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer in elderly patients, particularly those aged 80 years and older, remains an area of significant clinical uncertainty due to limited representation in clinical trials. Given the anticipated rise in the oldest-old population, real-world data are urgently needed to inform therapeutic strategies in this setting. This study aimed to evaluate the effectiveness and safety of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) in patients aged ≥ 80 years. Methods: We conducted a retrospective, multicenter analysis across seven Italian oncology centers. Eligible patients were aged 80 years or older and had initiated CDK4/6i therapy for HR+/HER2- metastatic breast cancer between January 2020 and May 2024. Data on demographics, comorbidities, frailty (G8 score), treatment regimens, and adverse events were collected. Primary endpoints included progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan–Meier method. Safety was assessed according to CTCAE v5.0 criteria. Results: A total of 39 patients were included. The median age was 83 years. Visceral metastases were present in 53.8% of cases, and 41.1% of patients were classified as frail (G8 ≤ 14). A reduced starting dose was adopted in 43.6% of patients. Median PFS was 13 months, and median OS was 15 months. Hematologic toxicities were the most frequent adverse events: neutropenia occurred in 62% of patients (grade ≥ 3 in 25%), and anemia in 13% (grade ≥ 3 in 6%). Non-hematologic toxicities included asthenia (16%), diarrhea (8%, mainly with abemaciclib), and elevated liver enzymes (24%). No cases of thrombocytopenia or QTc prolongation were observed. Temporary treatment interruptions were necessary in a substantial proportion of patients. Conclusions: In this real-world cohort of patients aged ≥ 80 years, CDK4/6 inhibitors combined with endocrine therapy demonstrated clinically meaningful outcomes with an acceptable safety profile. Individualized treatment approaches, including dose adjustments based on frailty and comorbidities, appear critical for optimizing outcomes. These findings support the feasibility of CDK4/6i-based therapy in the oldest-old population and highlight the need for prospective geriatric-focused studies.