Timing matters: radiation necrosis risk of antibody-drug conjugates (ADCs) combined with radiation therapy in breast cancer brain metastases: a systematic review and comparative meta-analysis.

Brain metastases are a significant challenge in advanced breast cancer. While antibody-drug conjugates (ADCs), including trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), and radiation therapy (RT) are increasingly utilized, concerns exist regarding the heightened risk of symptomatic radiation necrosis (RN) when these modalities are combined. This systematic review and meta-analysis aimed to quantify the incidence of symptomatic RN following RT with concurrent or sequential ADC therapy in breast cancer patients with brain metastases and to identify predictive factors. A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science through July 8th, 2025. Studies investigating symptomatic RN in breast cancer patients with brain metastases treated with RT and ADCs were included. The risk of bias was assessed using ROBINS-I. Meta-analysis using a random-effects model estimated pooled RN rates and odds ratios (ORs) for different ADC timing strategies (concurrent vs. non-concurrent administration) and comparisons between ADC-recipients and non-ADC control groups. Seven studies encompassing 444 patients with brain metastases were analyzed, of whom 223 (50%) received ADC therapy. The overall pooled symptomatic RN rate in ADC recipients was 20% (95% CI: 12–32%). Compared to radiation therapy alone, ADC administration significantly increased RN risk (OR 2.76, 95% CI: 1.19–6.37; P = 0.018). Treatment timing significantly influenced outcomes: concurrent ADC with RT was associated with higher symptomatic RN odds compared to non-concurrent administration (OR 3.44, 95% CI: 1.39–8.52; P = 0.008). Non-concurrent ADC administration showed no statistically significant increase in symptomatic RN risk versus non-ADC (OR 1.62, 95% CI: 0.23–11.41; P = 0.629). Meta-regression revealed a significant temporal trend, with newer studies reporting lower symptomatic RN rates. Combining ADCs with RT, particularly concurrently, significantly elevates the risk of symptomatic RN in breast cancer patients with brain metastases. These findings necessitate cautious clinical decision-making, potentially favoring sequential administration, and underscore the importance of personalized treatment planning to mitigate neurotoxicity.