Zhao and Xia 1 wrote a comprehensive review regarding the role of HER2 aberrations in non–small-cell lung cancer (NSCLC). Although from their analysis, HER2 exon 20 mutations emerge as the most clearly actionable driver in NSCLC, the authors themselves pinpoint ambiguous functional roles of individual HER2 aberrations (ie, activating mutations, amplification, and overexpression), as well as their reciprocal associations. Therefore, HER2 biology may be different in lung cancer compared with breast or gastric cancers, possibly because of specific microenvironmental and tumor-host interactions.

As pointed out by the authors, a substantial heterogeneity exists in therapeutic approaches and clinical results of HER2-targeting strategies in this context. This is well exemplified by two clinical NSCLC cases harboring different HER2 alterations (HER2 mutation and all three HER2 aberrations—mutation, amplification, and protein overexpression, respectively) we discuss herein.