Gastric (including gastroesophageal junction) adenocarcinoma ranks top three in global cancer mortality. Between 4–30% of patients have human epidermal growth factor receptor 2 (HER2) driven disease, and targeting HER2 receptor signalling improved prospects in metastatic setting. HER2 status is assessed by immunohistochemistry and in situ hybridisation. However, determination and interpretation of HER2 status remains challenging due to intra- and intertumoral heterogeneity and lack of data on the biological relevant cut-off. Currently, only trastuzumab is approved for treatment of HER2 amplified advanced gastric cancer. The strength of HER2 amplification at baseline and after progression should be integrated in future prospective randomised trials. HER2 loss occurs predominantly in cases with initial moderate immunostaining for HER2 and can lead to clinical resistance to trastuzumab. We review the use of liquid biopsies as an alternative to traditional tissue biopsies to overcome heterogeneity and to allow monitoring the dynamics of the plasma HER2 status. We believe that early detection of plasma HER2 loss can identify patients at risk for loss of response to anti-HER2 therapy. Based on a clinical case, we tried to define the implications and clinical relevance of HER2 positivity. We illustrate the usefulness of re-determination of the HER2 status in metastatic lesions after disease progression and provide the prospects of non-invasive testing.

(BELG J MED ONCOL 2019;13(4):135–141)