Radiation therapy combined with tyrosine kinase inhibitors in 826 patients with HER2-positive breast cancer brain metastases: a systematic review and network meta-analysis.

Brain metastases occur in up to 50% of patients with HER2-positive breast cancer, posing significant therapeutic challenges due to the limited penetration of systemic therapies across the blood-brain barrier and the constraints of radiation therapy (RT). While small-molecule tyrosine kinase inhibitors (TKIs) show promise for crossing the blood-brain barrier and local RT provides initial control, optimal combination strategies remain unclear. This study assesses the safety and efficacy of RT combined with TKIs for HER2-positive breast cancer brain metastases (BCBM), aiming to identify optimal strategies and synergistic benefits. A comprehensive search was conducted through February 12, 2025, for studies on HER2-positive BCBM patients treated with combined RT and TKI versus either alone. Pairwise meta-analyses were conducted using a random-effects model. Bayesian network meta-analysis (NMA) was conducted to integrate direct and indirect comparisons, addressing the lack of head-to-head trials. Eleven studies (2 RCTs, 9 retrospective; 826 patients) evaluated four treatment strategies: pyrotinib + RT, pyrotinib alone, RT alone, and lapatinib + RT. Pairwise meta-analyses showed pyrotinib + RT demonstrated a significantly superior overall response rate (ORR) compared to pyrotinib alone (OR = 3.10, 95% CI = 1.86-5.18) and improved intracranial progression-free survival (PFS) over pyrotinib alone (HR = 0.61, 95% CI = 0.38-0.99) and RT alone (HR = 0.33, 95% CI = 0.12-0.89). Lapatinib + RT was associated with significantly higher severe adverse events (SAEs) than RT alone (OR = 6.13, 95% CI = 2.17-17.27). Bayesian NMA further revealed pyrotinib + RT had superior ORR compared to lapatinib + RT (logOR = 2.18, 95% CI = 0.07-4.58). Ranking probabilities from the Bayesian NMA confirmed pyrotinib + RT as most effective for ORR (97.05%) and DCR (88.57%), with lapatinib + RT associated with the highest SAE risk (95.38%). Based on the available evidence, pyrotinib + RT may represent a promising therapeutic approach, associated with improved ORR and intracranial PFS compared to monotherapies and a favorable safety profile. In contrast, lapatinib + RT appeared to offer limited benefit and a higher risk of SAEs. Further randomized controlled trials are needed to validate these findings.