Personalized Medicine and Imaging Optimal Patient Selection for Trastuzumab Treatment in HER2-Positive Advanced Gastric Cancer

Purpose: Chemotherapy plus trastuzumab is standard of care for HER2-positive advanced gastric cancer (AGC). However, not all patients with HER2-positive AGC seem to benefit from trastuzumab. We evaluated the association between treatment outcomes with trastuzumab and HER2 status in patients with HER2positive AGC. Experimental Design: We enrolled 126 patients with HER2positive AGC treated with trastuzumab plus chemotherapy in a training cohort. HER2 IHC (N 1⁄4 126), HER2/CEP17 ratio (N 1⁄4 66), andHER2 gene copy number (GCN;N1⁄4 59) were analyzed, and the optimal values for discriminating overall survival (OS) were determined using receiver operating characteristic (ROC) curve analysis. We validated the findings from the training cohort using an independent validation cohort (N 1⁄4 72). Results: Patients with HER2 IHC 3þ showed significantly longer OS (29 vs. 15.3 months; P 1⁄4 0.025) than patients with IHC 2þ. An HER2/CEP17 ratio of 4.48 was the optimal cutoff for predicting longer OS (26.9 vs. 14.7 months; P 1⁄4 0.027). In subgroup analysis, treatment outcomes of patients with IHC 3þ were not influenced by the level of HER2 gene amplification. However, in patients with IHC 2þ, an HER2/ CEP17 ratio more than 3.69 and HER2 GCN more than 7.75 were positive predictive factors for better outcomes with trastuzumab-based chemotherapy. These findings were confirmed in both the validation cohort and the combined cohort. Conclusions:HER2 IHC status,HER2/CEP17 ratio, and HER2 GCN were correlated with clinical outcomes of trastuzumabbased treatment in HER2-positive AGC. Clinical outcomes of patients with IHC 2þ were strongly dependent on the HER2/CEP17 ratio and HER2 GCN. Clin Cancer Res; 21(11); 2520–9.