MMAP-16 RISK OF RADIATION NECROSIS WITH CONCURRENT VS. NON-CONCURRENT ANTIBODY-DRUG CONJUGATES AND RADIOTHERAPY IN HER2-POSITIVE BREAST CANCER WITH BRAIN METASTASES: A META-ANALYSIS

Abstract Antibody-drug conjugates (ADCs) have transformed treatment in HER2-positive breast cancer (BC), particularly in patients with brain metastases (BM), due to agents like trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), both demonstrating intracranial efficacy. Radiotherapy (RT), especially stereotactic radiosurgery (SRS), remains a mainstay in BM management. However, combining ADCs with RT may increase the risk of symptomatic radiation necrosis (SRN), a potentially debilitating complication that can significantly impair neurological function and quality of life. This meta-analysis evaluates SRN outcomes in patients receiving concurrent (C-ADC) versus non-concurrent ADCs with RT (NC-ADC). A systematic search was conducted in January 2025 across PubMed, Cochrane Library, and major oncology conference proceedings (ASCO, SNO, ESMO, SABCS). Eligible studies included randomized controlled trials and cohort studies (CS) that reported SRN or related toxicity outcomes in HER2-positive BC patients with BM treated with either C-ADC or NC-ADC approaches. Pooled SRN proportions and risk ratios (RR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed using the I² statistic. Of 884 studies screened, 9 CS (N=421) met inclusion criteria. The median patient age was 56.3 years (IQR: 49.8–57). Prior intracranial RT was reported in 41.3%, with 19.3% receiving SRS and 19.6% undergoing whole-brain RT. Median time to C-ADC was 8.75 days (IQR: 8.0–18.0), and to NC-ADC was 273.5 days (IQR: 225.8–327.8). SRN occurred in 19.5% (95% CI: 9.2%–29.8%; I²=39.2%) of C-ADC patients versus 6.9% (95% CI: 2.5%–11.2%; I²=52.0%) in NC-ADC. C-ADC was associated with significantly increased SRN risk (RR=2.73, 95% CI: 1.45–5.11, P=0.002; I²=0.0%), with consistent findings across included studies. Concurrent ADC-RT treatment is linked to a significantly higher SRN risk. Careful patient selection and prospective studies are essential to optimize treatment sequencing strategies that balance efficacy with safety and minimize toxicity.