Erb-B2 receptor tyrosine kinase 2 with exon 20 insertion mutation (ERBB2 (HER2) exon 20 insertion)

Erb-B2 receptor tyrosine kinase 2 with exon 20 insertion mutation, commonly referred to as HER2 (ERBB2) exon 20 insertion, is a subset of activating mutations in the ERBB2 gene characterized by in-frame insertions in exon 20, frequently involving the α-C helix and adjacent loop region of the kinase domain[2]. These mutations lead to constitutive activation of the HER2 receptor, promoting oncogenic signaling independent of ligand binding. ERBB2 exon 20 insertions are detected in 1–4% of non-small cell lung cancers, most commonly as the Y772_A775dupYVMA variant, and are more frequent in non-smokers and female patients[1][2]. Unlike ERBB2 overexpression or gene amplification, exon 20 insertions act as direct oncogenic drivers and are associated with poor prognosis and distinct therapeutic vulnerabilities. Traditional HER2-targeted therapies for breast cancer (trastuzumab, lapatinib) are less effective, while antibody-drug conjugates (such as trastuzumab deruxtecan) and novel small-molecule inhibitors represent the most promising treatment approaches for these mutations in lung cancer[4][5]. Detection of ERBB2 exon 20 insertion mutations serves as both a diagnostic and predictive biomarker for therapy selection, and co-occurring tumor suppressor mutations such as TP53 are common[1][3]. Therapeutic development is ongoing, and adverse events (especially with antibody-drug conjugates and some kinase inhibitors) require careful management[4][5].

Other names

HER2 exon 20 insertionHER2 ex20insERBB2 ex20insHER2 exon20 mutantHuman epidermal growth factor receptor 2 exon 20 insertion

Inhibition of tyrosine kinase activity Antibody-dependent cellular cytotoxicity (for monoclonal antibodies) Delivery of cytotoxic payload (antibody-drug conjugates) Downregulation or internalization of HER2 receptor