TY - JOUR
T1 - Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study.
AU - Pietrantonio, Filippo
AU - Fuca, Giovanni
AU - Morano, Federica
AU - Gloghini, Annunziata
AU - Corso, Simona
AU - Aprile, Giuseppe
AU - Perrone, Federica
AU - De Vita, Ferdinando
AU - Tamborini, Elena
AU - Tomasello, Gianluca
AU - Gualeni, Ambra Vittoria
AU - Ongaro, Elena
AU - Busico, Adele
AU - Giommoni, Elisa
AU - Volpi, Chiara Costanza
AU - Laterza, Maria Maddalena
AU - Corallo, Salvatore
AU - Prisciandaro, Michele
AU - Antista, Maria
AU - Pellegrinelli, Alessandro
AU - Castagnoli, Lorenzo
AU - Pupa, Serenella M.
AU - Pruneri, Giancarlo
AU - de Braud, Filippo
AU - Giordano, Silvia
AU - Cremolini, Chiara
AU - Di Bartolomeo, Maria
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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; 1-8. (c)2017 AACR.
AB - 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; 1-8. (c)2017 AACR.
M3 - Article
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
ER -