HER2 loss in HER2-positive gastric or gastroesophageal cancer after trastuzumab therapy : Implication for further clinical research

Background: Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. Patients and Methods: In this study, we analysed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive (immunohistochemistry [IHC] 3+ or 2+ with in-situ hybridization [ISH] amplification) gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. Results: HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32% and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinico-pathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80% vs. 14%; p=0.008) and HER2 over-expression (63% vs. 14%; p=0.025). Conclusion: As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease. This article is protected by copyright. All rights reserved.