Treatment Sequencing of CDK4/6 Inhibitors in Bone-Only Hormone Receptor-Positive Metastatic Breast Cancer: Multi-Center Real-World Data Revealing a Numerical Trend Favoring Later-Line Use

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy represent the gold standard in the first-line treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, the optimal timing of CDK4/6i initiation in patients with bone-only disease (BoD) remains a matter of clinical discussion. This multicenter retrospective study evaluated the impact of CDK4/6i treatment line (first-line vs. second-or-later-line) on progression-free survival (PFS) and overall survival (OS) in HR+/HER2− MBC patients with BoD. Methods: A total of 282 HR+/HER2− MBC patients with radiologically confirmed BoD treated across five tertiary academic centers were analyzed. All patients received bone-modifying agents (zoledronic acid or denosumab). Patients were categorized into Group 1 (first-line CDK4/6i, n = 193) and Group 2 (second-or-later-line CDK4/6i, n = 89). Baseline characteristics were recorded. Multivariable Cox proportional hazards models were adjusted for key clinicopathological variables. Results: The median PFS was 30.193 months in the first-line group and 19.253 months in the second/later-line group, with no statistically significant difference (p = 0.055). The median OS was 62.324 months in the first-line group and 72.00 months in the second/later-line group, which was significant in the univariate analysis (p = 0.036). However, this significance was not maintained in the multivariate analysis adjusting for potential confounders (p = 0.487). Except for strong ER positivity, baseline characteristics were balanced between groups. In the multivariate analysis, no clinical factor, including treatment line, independently and significantly impacted OS. Conclusions: In HR+/HER2− MBC patients with bone-only disease, first-line CDK4/6 inhibitor therapy demonstrates a trend toward superior PFS. After correcting for key observational biases, the later line of therapy does not independently alter OS. These findings reinforce that first-line CDK4/6 inhibitor plus endocrine therapy remains the definitive standard of care, and later-line initiation should be reserved solely for select clinical scenarios where first-line use was not feasible.