PTEN is a Predictive Biomarker of Trastuzumab Resistance and Prognostic Factor in HER2-overexpressing Gastroesophageal Adenocarcinoma

Introduction: Poor Trastuzumab (Tmab) response in human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is reported to be associated with loss of phosphatase and tensin homolog (PTEN) expression. Methods: In a multicenter, retrospective observational study, pathological samples of HER2-GEA patients receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. Primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The effect of PI3K pathway inhibitors on HER2-GEA cell lines were evaluated in in-vitro . Results: Among 145 HER2-GEA patients, 29 formed the PTEN-loss group and 116 the PTEN-positive group. In patients with target region, DCR was significantly lower in PTEN-loss than in PTEN-positive patients (67% and 87%, respectively, p=0.049). Multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR=1.63, p=0.035) and OS (HR=1.83, p=0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, while Tmab combined with PI3K/mTOR inhibitor NPV-BEZ235 suppressed the proliferation of PTEN knockdown cells which were resistant to Tmab alone. Conclusion: In HER2-GEA patients, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with PI3K/mTOR inhibitor would be an effective treatment option for HER2-GEA with PTEN loss.