Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study.
Clin Cancer Res
; 24(5): 1082-1089, 2018 03 01.
Article
in En
| MEDLINE
| ID: mdl-29208673
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.ExperimentalDesign:
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach Neoplasms
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Biomarkers, Tumor
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Drug Resistance, Neoplasm
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Trastuzumab
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Antineoplastic Agents, Immunological
Type of study:
Clinical_trials
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Evaluation_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limits:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Clin Cancer Res
Journal subject:
NEOPLASIAS
Year:
2018
Document type:
Article
Affiliation country: