Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study

Filippo Pietrantonio, Giovanni Fucà, Federica Morano, Annunziata Gloghini, Simona Corso, Giuseppe Aprile, Federica Perrone, Ferdinando De Vita, Elena Tamborini, Gianluca Tomasello, Ambra Vittoria Gualeni, Elena Ongaro, Adele Busico, Elisa Giommoni, Chiara Costanza Volpi, Maria Maddalena Laterza, Salvatore Corallo, Michele Prisciandaro, Maria Antista, Alessandro PellegrinelliLorenzo Castagnoli, Serenella M Pupa, Giancarlo Pruneri, Filippo de Braud, Silvia Giordano, Chiara Cremolini, Maria Di Bartolomeo

Research output: Contribution to journalArticle

Abstract

Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient 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 of 20, 55%) as compared with sensitive (0% of 17) patients (P < 0.001), and in HER2 IHC 2+ (7 of 13, 53.8%) than 3+ (4 of 24, 16.7%) tumors (P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07-0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09-0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the 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 patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082-9. ©2017 AACR.

Original languageEnglish
Pages (from-to)1082-1089
Number of pages8
JournalClinical Cancer Research
Volume24
Issue number5
DOIs
Publication statusPublished - Mar 1 2018

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    Pietrantonio, F., Fucà, G., Morano, F., Gloghini, A., Corso, S., Aprile, G., Perrone, F., De Vita, F., Tamborini, E., Tomasello, G., Gualeni, A. V., Ongaro, E., Busico, A., Giommoni, E., Volpi, C. C., Laterza, M. M., Corallo, S., Prisciandaro, M., Antista, M., ... Di Bartolomeo, M. (2018). Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study. Clinical Cancer Research, 24(5), 1082-1089. https://doi.org/10.1158/1078-0432.CCR-17-2781