Neoadjuvant antibody-drug conjugates for early-stage breast cancer: A systematic review and meta-analysis.

BACKGROUND: Pathologic complete response (pCR) is a key endpoint of neoadjuvant therapy in early-stage breast cancer (EBC), associated with improved survival, particularly in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. More recently, antibody-drug conjugates (ADCs), established in metastatic disease, are being evaluated in the neoadjuvant setting. DESIGN: We systematically searched for studies of EBC patients treated with neoadjuvant ADCs, alone or in combination. Meta-analyses were carried out using a random-effects model, with heterogeneity assessed via I² statistics and Cochran's Q test. RESULTS: Twenty-four studies were included, 22 (2,363 patients) contributed to the pCR analysis, predominantly phase I/II trials and two phase III studies. Nine ADCs targeting HER2, trophoblast cell surface antigen 2 (TROP2), LIV1 or human epidermal growth factor receptor 3 (HER3), and incorporating six distinct payload classes were identified. The pooled pCR rate was 38.34% (95% CI 29.36-47.72; I² = 92.8%), highest among hormone receptor (HR)-negative/HER2+ tumors (65.06%), followed by HR+/HER2+ (47.53%), TNBC (29.37%), and HR+/HER2- (2.94%) (p<0.0001). By target, pCR rates were 43.93% for HER2-directed ADCs, 41.41% for TROP2, 16.57% for LIV1, and 3% for HER3. Common all-grade adverse events (AEs) included nausea (64.52%), diarrhea (48.24%), alopecia (39.19%), alanine aminotransferase elevation (38.80%), aspartate aminotransferase elevation (34.87%), neutropenia (29.53%), vomiting (25.95%), and anemia (24.89%). Grade ≥3 AEs occurred in 25.06% of patients. CONCLUSION: Neoadjuvant ADC-based strategies yield clinically meaningful pCR rates in EBC, with the greatest benefit in HER2+ disease, supporting further investigation and biomarker-guided patient selection.