ERBB2 kinase domain mutations are seen in up to 4.3% of breast cancers. In vitro analyses demonstrated that L755S confer resistance to lapatinib and could potentially emerge as an acquired mutation during therapy. Another preclinical study has shown that L755S is sensitive to irreversible TKIs neratinib and canertinib. The predictive and prognostic as well as therapeutic implications of ERBB2 mutations need further elucidation.

ERBB2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. ERBB2 mutations have been reported in ~2-3% of lung adenocarcinomas. The majority of ERBB2 mutations are in-frame insertions in exon 20, which encodes part of the kinase domain; however, point mutations (L755S and G776C) have also been identified. Lung adenocarcinomas with ERBB2 mutations are mutually exclusive with EGFR, KRAS, ALK alterations and these variants are more frequent in patients who are never-smokers. Mutations in ERRB2 do not have an independent prognostic value in lung adenocarcinoma, according to a recent study. In vitro analyses have shown that ERBB2 L755P and L755S mutations are associated with constitutive kinase activation and resistance to lapatinib treatment. The predictive significance of ERBB2 mutations in lung adenocarcinomas needs further elucidation. Recommend correlation with other clinical and laboratory findings.