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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Stomach Neoplasms
Case-Control Studies
Biomarkers
Neoplasms
Confidence Intervals
Receptor Protein-Tyrosine Kinases
Phosphatidylinositol 3-Kinases
Trastuzumab
Research Design
Mutation
Survival

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Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients : the AMNESIA Case-Control Study. / Pietrantonio, Filippo; Fucà, Giovanni; Morano, Federica; Gloghini, Annunziata; Corso, Simona; Aprile, Giuseppe; Perrone, Federica; De Vita, Ferdinando; Tamborini, Elena; Tomasello, Gianluca; Gualeni, Ambra Vittoria; Ongaro, Elena; Busico, Adele; Giommoni, Elisa; Volpi, Chiara Costanza; Laterza, Maria Maddalena; Corallo, Salvatore; Prisciandaro, Michele; Antista, Maria; Pellegrinelli, Alessandro; Castagnoli, Lorenzo; Pupa, Serenella M; Pruneri, Giancarlo; de Braud, Filippo; Giordano, Silvia; Cremolini, Chiara; Di Bartolomeo, Maria.

In: Clinical Cancer Research, Vol. 24, No. 5, 01.03.2018, p. 1082-1089.

Research output: Contribution to journalArticle

Pietrantonio, Filippo ; Fucà, Giovanni ; Morano, Federica ; Gloghini, Annunziata ; Corso, Simona ; Aprile, Giuseppe ; Perrone, Federica ; De Vita, Ferdinando ; Tamborini, Elena ; Tomasello, Gianluca ; Gualeni, Ambra Vittoria ; Ongaro, Elena ; Busico, Adele ; Giommoni, Elisa ; Volpi, Chiara Costanza ; Laterza, Maria Maddalena ; Corallo, Salvatore ; Prisciandaro, Michele ; Antista, Maria ; Pellegrinelli, Alessandro ; Castagnoli, Lorenzo ; Pupa, Serenella M ; Pruneri, Giancarlo ; de Braud, Filippo ; Giordano, Silvia ; Cremolini, Chiara ; Di Bartolomeo, Maria. / Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients : the AMNESIA Case-Control Study. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 5. pp. 1082-1089.
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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. {\circledC}2017 AACR.",
author = "Filippo Pietrantonio and Giovanni Fuc{\`a} and Federica Morano and Annunziata Gloghini and Simona Corso and Giuseppe Aprile and Federica Perrone and {De Vita}, Ferdinando and Elena Tamborini and Gianluca Tomasello and Gualeni, {Ambra Vittoria} and Elena Ongaro and Adele Busico and Elisa Giommoni and Volpi, {Chiara Costanza} and Laterza, {Maria Maddalena} and Salvatore Corallo and Michele Prisciandaro and Maria Antista and Alessandro Pellegrinelli and Lorenzo Castagnoli and Pupa, {Serenella M} and Giancarlo Pruneri and {de Braud}, Filippo and Silvia Giordano and Chiara Cremolini and {Di Bartolomeo}, Maria",
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TY - JOUR

T1 - Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients

T2 - the AMNESIA Case-Control Study

AU - Pietrantonio, Filippo

AU - Fucà, 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

N1 - ©2017 American Association for Cancer Research.

PY - 2018/3/1

Y1 - 2018/3/1

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; 24(5); 1082-9. ©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; 24(5); 1082-9. ©2017 AACR.

U2 - 10.1158/1078-0432.CCR-17-2781

DO - 10.1158/1078-0432.CCR-17-2781

M3 - Article

C2 - 29208673

VL - 24

SP - 1082

EP - 1089

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -