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

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, pro spective, 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 2þ (7 of 13,
53.8%) than 3þ (4 of 24, 16.7%) tumors (P ¼ 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 ¼ 0.001] and overall
survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09–0.75; P ¼
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.