Revisiting HER2 Targeting: Clinical and Translational Advances in Trastuzumab-Based Combination Therapy

HER2-positive breast cancer represents a biologically aggressive subtype characterised by overexpression or amplification of the human epidermal growth factor receptor-2 (HER2), which promotes tumour proliferation, metastasis, and poor clinical prognosis. The introduction of trastuzumab, a humanised monoclonal antibody targeting the extracellular domain of the HER2 receptor, has markedly improved survival outcomes and transformed the therapeutic landscape for patients with this disease. Nevertheless, intrinsic and acquired resistance to trastuzumab therapy remains a major clinical challenge, with a substantial proportion of patients demonstrating limited or transient responses to monotherapy. This systematic review evaluates emerging therapeutic strategies designed to enhance the clinical efficacy of trastuzumab through synergistic combination approaches. A structured literature search was conducted across major scientific databases to identify studies investigating trastuzumab-based combination therapies, including dual HER2 blockade with pertuzumab, antibody–drug conjugates such as ado-trastuzumab emtansine and trastuzumab deruxtecan, co-targeting strategies with epidermal growth factor receptor inhibitors such as nimotuzumab, and targeted nanotechnological platforms including trastuzumab-functionalized immunoliposomes and antibody–photosensitizer conjugates. The evidence indicates that these multimodal strategies improve therapeutic activity by inhibiting complementary signalling pathways, enhancing immune-mediated cytotoxicity, overcoming resistance mechanisms involving the PI3K/AKT/mTOR axis, and improving targeted drug delivery and tumour selectivity. Nanotechnology-based formulations further contribute by optimizing pharmacokinetics, reducing systemic toxicity, and enabling theranostic applications such as targeted imaging and photodynamic therapy. Collectively, these findings highlight the evolving paradigm of trastuzumab-based combination therapies as a central component of precision oncology in HER2-positive breast cancer. Continued translational and clinical investigations are required to refine patient selection, understand resistance mechanisms, and optimize therapeutic sequencing to achieve improved long-term outcomes for affected patients.