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.

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.

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%.

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.