Severe Adverse Events in Neoadjuvant Therapy of Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Phase 3 Trials.

Neoadjuvant therapy (NAT) is standard treatment for triple-negative breast cancer (TNBC) but toxicity is a major concern. This study aimed to assess the incidence and risk of grade ≥ 3 adverse events (AEs) associated with NAT in nonmetastatic TNBC. We performed a systematic review and meta-analysis registered in PROSPERO (CRD42024562785). Four databases were searched for randomized controlled trials (RCTs) from 2010 to 2025 reporting grade ≥ 3 AEs in TNBC. Pooled prevalence and risk ratios (RRs) were estimated using random-effects models. Six RCTs including 3316 patients were analyzed. Neutropenia was the most common severe AE, with pooled prevalence of 33.5% for ICIs, 23.7% for PARP inhibitors, and 16.0% for platinum regimens. PARP inhibitors significantly increased neutropenia (RR 1.84) and anemia (RR 2.08), while thrombocytopenia risk was also higher (RR 3.56). ICIs were associated with more febrile neutropenia (14.9%) but without a significant risk increase. ALT elevation was more frequent with platinum regimens (6.4%). Fatal AEs were rare (<1%). NAT improves outcomes in TNBC but is associated with substantial severe toxicity. PARP inhibitors carry the greatest hematologic risks, ICIs add immune-related AEs, and platinum regimens showed the lowest AE burden. Biomarker-driven patient selection and vigilant monitoring are essential to optimize safety.