ERBB2 and cancer: Indeed, most HER2 mutations have been functionally annotated using ectopic expression in preclinical model, which cannot predict their oncogenic dependence when arising endogenously in cancer cells.34 The difficulty in assessing the clinical relevance of acquired HER2 mutations is all the more critical with the advent of liquid biopsies, which may identify large numbers of potentially actionable mutations present at low allele frequencies.