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.