Repurposing HER2 IHC: Pan-HER2 and Low-HER2.

The recent clinical trials and regulatory approval of new antibody drug conjugates targeting HER2 protein (trastuzumab deruxtecan, T-DXd) has moved the bar in terms of therapy for breast cancer and other solid tumors. With new drugs and expanding indications comes a need for refined companion diagnostics. Pathologists are asked to adapt IHC and other assays (mutation testing, circulating tumor DNA) accordingly. This brings attention to lower HER2 expression levels in breast cancer ("low" and even "ultralow"), and a tumor agnostic approval for cancers with high HER2 expression (3+ according to gastric scoring). This new landscape raises many questions concerning HER2 immunohistochemistry assay comparability, applicability (sensitivity, limit of detection), readout reproducibility, and clinical reporting, among many others. With a myriad of clinical trials still underway, this will remain a rapidly evolving field.