HER2overexpressing

HER2 overexpressing refers to tumors that express high levels of the human epidermal growth factor receptor 2 (HER2) on the cell surface. The HER2 protein is a receptor tyrosine kinase encoded by the ERBB2 gene, and its overexpression or gene amplification leads to increased signaling through pathways such as PI3K/AKT and MAPK, promoting cell growth and survival. This phenotype is most commonly associated with breast cancer but is also observed in gastric and other HER2-positive solid tumors.

Detection is typically performed on tumor tissue using immunohistochemistry (IHC) to assess protein expression and in situ hybridization (ISH, including FISH or CISH) to evaluate ERBB2 gene amplification. An IHC score of 3+ or confirmed amplification by ISH defines HER2 overexpression. Equivocal cases (IHC 2+) require confirmation by ISH and may be retested on a new sample.

In breast cancer, HER2 overexpression occurs in about 15-20% of cases and defines a distinct molecular subtype that influences prognosis and treatment. While historically linked to poorer outcomes, the advent of HER2-directed therapies has improved survival for many patients. HER2 testing also guides therapy in gastric and gastroesophageal junction cancers.

Therapies targeting HER2 include monoclonal antibodies such as trastuzumab and pertuzumab, antibody-drug conjugates like trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan, and small molecule tyrosine kinase inhibitors such as lapatinib and neratinib. Treatment often combines HER2 inhibitors with chemotherapy, depending on tumor type and stage.

Resistance and heterogeneity may limit response; mechanisms include receptor masking, truncated forms, downstream signaling alterations, and loss of downstream tumor suppressors. Ongoing research seeks to refine testing, overcome resistance, and expand the use of HER2-targeted therapy to additional tumor types.