HER2-targeted PET/CT in breast cancer: a systematic review of lesion-level concordance with pathology

Purpose Human epidermal growth factor receptor 2 (HER2)-targeted PET/CT enables whole-body characterization of HER2 expression in breast cancer (BC). HER2 is a key biomarker used to guide treatment selection and known to exhibit spatial and temporal heterogeneity. This systematic review evaluated lesion-level concordance between HER2-targeted PET and pathology-defined HER2 expression. Materials and Methods PubMed, EMBASE, and Web of Science were searched through January 27, 2026, for clinical trials of HER2-targeted PET in BC reporting lesion-level findings with tissue verification by immunohistochemistry and/or in situ hybridization. Lesion-level sensitivity, specificity, and QUADAS-2 ratings were summarized descriptively. Results Ten reports comprising 195 lesions with paired PET-biopsy HER2 classification met inclusion criteria. Both affinity protein- and monoclonal antibody (mAb)-based tracers detected HER2-positive lesions. Sensitivity estimates were 75% [95% CI, 65–83%] for affinity protein-based tracers, and 100% [95% CI, 59–100%] for mAb-based tracers. Specificity for excluding HER2-positive disease was 79% (95% CI, 68–87%) for affinity protein-based tracers and was not estimable for mAb-based tracers. Most false-positive lesions were HER2-low rather than HER2-zero (≥86%). Conclusion HER2-targeted PET shows moderate-to-good lesion-level concordance with biopsy results, with uptake observed in both HER2-positive and HER2-low disease, whereas HER2-zero lesions are less consistently visualized. Although these findings support a continuum of HER2 expression and a potential complementary role in treatment selection, diagnostic performance estimates are constrained by small study populations, selective lesion verification, and heterogeneous imaging methodologies. Wider clinical adoption of HER2-targeted PET will depend on larger prospective studies with standardized protocols and clinically relevant endpoints.