Modulating the pace: systemic targeted therapy, brain metastasis velocity, and outcomes after Gamma Knife radiosurgery in breast cancer brain metastases

Purpose: Management of brain metastases from breast cancer (BMBC) is advancing with stereotactic radiosurgery (SRS) and systemic targeted therapies. However, the role of SRS in cases with a high intracranial lesion burden and the impact of systemic therapy on disease progression remain uncertain. Methods: We retrospectively analyzed 230 BMBC patients treated with Gamma Knife radiosurgery (GKRS) from 2014 to 2024. Data on lesion count, systemic therapy, and outcomes were collected. Patients were stratified by lesion number (≤ 4 vs. > 4) and brain metastasis velocity (BMV: <4, 4–13, > 13 new lesions/year). Survival and progression were assessed using Kaplan–Meier analysis, chi-square tests, and multivariable regression. Results: GKRS was effective and safe even for patients with > 4 lesions, showing no significant differences in survival (median OS: 65.0 vs. 63.0 months), retreatment rates, or adverse radiation effects compared to patients with fewer lesions. Similar results were observed for those with more than 10 and 20 lesions. Targeted systemic therapy reduced BMV (7.9 vs. 11.4 lesions/year, p = 0.047) and delayed retreatment but did not improve survival. Molecular subtype was significantly associated with the BMV group but not with BMV as a continuous variable. The observed survival exceeded predictions from older prognostic models. Higher BMV was associated with increased retreatment and shorter survival after GKRS. Conclusions: GKRS is safe and effective for BMBC patients with extensive intracranial disease. Systemic targeted therapies slow intracranial progression and delay retreatment. Subtype-specific metastatic velocity may guide risk-adjusted strategies, supporting a personalized approach that considers lesion burden, molecular subtype, and disease kinetics.