Purpose: Refining the selection of HER2 positive metastatic gastric cancer patients candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 out of 20, 55%) as compared to sensitive (0% of 17) patients (p<0.001), and in HER2 IHC 2+ (7 out of 13, 53.8%) than 3+ (4 out of 24, 16.7%) tumors (p=0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free (5.2 versus 2.6 months, HR: 0.34 [95%CI: 0.07-0.48]; p=0.001) and overall survival (16.1 versus 7.6 months, HR: 0.38 [95%CI: 0.09-0.75], p=0.015). The predictive accuracy of AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in HER2-positive metastatic gastric cancer patients, and should be further validated with the aim of molecularly stratifying HER2 addicted cancers for the development of novel treatment strategies.
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