The emerging role of antibody-drug conjugates in breast cancer: a systematic review of clinical evidence

INTRODUCTION: Antibody-drug conjugates (ADCs) represent a transformative class of targeted anticancer agents that combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic pay­loads. Over the past decade, ADCs have fundamentally reshaped the treatment paradigm for breast cancer across all molecular subtypes, including human epidermal growth factor receptor 2 (HER2)-positive, tumors with low or ultralow HER2 receptor expression (HER2-low/ultralow, which do not constitute a distinct biological subtype but rather represent a therapeutically actionable classification), hormone receptor (HR)-positive/HER2-negative, and triple-negative breast cancer (TNBC). This systematic review aims to comprehensively evaluate the clinical evidence supporting the use of ADCs in breast cancer from 2016 to 2025. METHODS: A systematic literature search was conducted across PubMed, MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov for studies published between January 2016 and December 2025. Eligible studies included randomized controlled trials (RCTs), single-arm phase I–III trials, and systematic reviews/meta-analyses evaluating Food and Drug Administration (FDA) approved or investigational ADCs in breast cancer. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool for RCTs and the ROBINS-I tool for non-randomized studies. RESULTS: A total of 94 studies met the inclusion criteria, encompassing data from over 18,000 patients. Four ADCs have received FDA approval for breast cancer indications: trastuzumab emtansine (T-DM1), trastuzumab deruxte­can (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd). In HER2-positive metastatic breast cancer, T-DXd demonstrated superior progression-free survival (PFS) and overall survival (OS) compared with T-DM1 in the DESTINY-Breast03 trial median PFS 28.8 vs. 6.8 months; hazard ratio (HR) = 0.33. In HER2- -low disease, T-DXd significantly improved PFS (9.9 vs. 5.1 months; HR = 0.50) and OS (23.4 vs. 16.8 months; HR = 0.64) vs. chemotherapy in DESTINY-Breast04. For metastatic TNBC, SG demonstrated superior PFS (5.6 vs. 1.7 months; HR = 0.41) and OS (12.1 vs. 6.7 months; HR = 0.48) in the ASCENT trial. Dato-DXd showed improved PFS (6.9 vs. 4.9 months; HR = 0.63) in HR+/HER2− breast cancer in TROPION-Breast01. Each ADC class exhibits a distinct toxicity profile: interstitial lung disease (IDL)/pneumonitis is characteristic of DXd-containing agents, neutropenia and diarrhea predominate with SG, and stomatitis/ocular toxicity are notable with Dato-DXd. Evidence-based management strategies including proactive monitoring, prophylactic interventions, and structured dose modification protocols are discussed. CONCLUSIONS: ADCs have established a new standard of care across multiple breast cancer subtypes. The rec­ognition that tumors with low HER2 receptor expression can be effectively targeted by T-DXd (without reclassifying these tumors as a distinct biological subtype), the expansion of TROP2-targeted therapies, and the ongoing inves­tigation of novel targets and combination strategies underscore the rapidly evolving ADC landscape. The growing evidence for ADCs in the perioperative setting, including the established adjuvant role of T-DM1 and ongoing trials evaluating T-DXd and SG in early-stage disease, further broadens their therapeutic impact. Key challenges remain, including optimal sequencing, management of class-specific toxicities, identification of predictive biomarkers, and resistance mechanisms.