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), includingEGFR/MET/KRAS/PI3K/PTENmutations andEGFR/MET/KRASamplifications. 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.
Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients : the AMNESIA Case-Control Study / F. Pietrantonio, G. Fucà, F. Morano, A. Gloghini, S. Corso, G. Aprile, F. Perrone, F. De Vita, E. Tamborini, G. Tomasello, A.V. Gualeni, E. Ongaro, A. Busico, E. Giommoni, C.C. Volpi, M.M. Laterza, S. Corallo, M. Prisciandaro, M. Antista, A. Pellegrinelli, L. Castagnoli, S.M. Pupa, G. Pruneri, F. de Braud, S. Giordano, C. Cremolini, M. Di Bartolomeo. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 24:5(2018 Mar 01), pp. 1082-1089.
|Titolo:||Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients : the AMNESIA Case-Control Study|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||1-mar-2018|
|Data ahead of print / Data di stampa:||5-dic-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1158/1078-0432.CCR-17-2781|
|Appare nelle tipologie:||01 - Articolo su periodico|