Abstract
Hypersensitivity reactions (HSRs) to anti-HER2 monoclonal antibodies may limit access to optimal therapy in HER2-positive breast cancer. HSRs have been reported with both intravenous pertuzumab/trastuzumab and the fixed-dose subcutaneous pertuzumab/trastuzumab formulation, including severe systemic reactions and anaphylaxis, although the overall incidence is low. We describe a patient with metastatic HER2-positive breast cancer who developed an immediate hypersensitivity reaction during intravenous pertuzumab administration followed by recurrent delayed cutaneous manifestations after anti-HER2 treatment and, subsequently, after subcutaneous PHESGO® administration. Diagnostic work-up revealed selective intradermal reactivity to pertuzumab, whereas trastuzumab remained consistently negative. A CFSE-based lymphocyte proliferation assay demonstrated increased CD3+ T-cell and CD19+ B-cell proliferation predominantly after stimulation with the combined pertuzumab/trastuzumab formulation. These findings, together with the clinical history, identified pertuzumab as the most likely culprit and were consistent with a mixed immediate/delayed hypersensitivity phenotype. A simplified 9-step subcutaneous desensitization protocol enabled administration of the full therapeutic dose of PHESGO® without breakthrough reactions and was successfully repeated in subsequent cycles. This case highlights the value of combining skin testing with functional cellular assays to improve immune characterization and supports the feasibility of simplified subcutaneous desensitization for fixed-dose anti-HER2 biologics.