Abstract
Responses to palliative radiotherapy (RT) for metastatic lesions vary among patients, and molecular determinants of radiosensitivity remain unclear. This study investigated genomic features associated with local progression-free survival (LPFS) in metastatic breast cancer patients treated with palliative RT. Forty-four patients who underwent next-generation sequencing of 523 cancer-related genes were retrospectively analyzed. The biologically effective dose (BED) was calculated using an α/β ratio of 3 Gy, and local progression was defined as recurrence or progression within the irradiated field. A total of 60 metastatic lesions, predominantly in bone (68.3%), were evaluated. Higher BED (≥88 Gy) was significantly associated with longer LPFS (p = 0.011). Among 320 detected mutations mapped to 141 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the PI3K-Akt signaling pathway remained an independent predictor in multivariate analysis (p = 0.03). Subgroup analyses demonstrated that patients with Ras, PI3K-Akt, or FoxO pathway mutations derived greater LPFS benefit from high BED, whereas this advantage was confined to wild-type tumors for the PD-L1/PD-1 checkpoint and choline metabolism pathways. These findings suggest that pathway-specific molecular contexts modulate RT response and may inform individualized radiation dose strategies in metastatic breast cancer.