Adverse prognostic impact of heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma (EAC).

Abstract

4009 Background: HER2 expression in upper digestive cancer is reported to be heterogeneous, which substantially affects interpretation of HER2 positivity in the clinic. Yet the frequency and prognostic impact of HER2 genetic heterogeneity and polysomy 17 (poly17) are unknown in EAC. Methods: HER2 amplification (fluorescence in situ hybridization) and protein expression were examined in untreated surgical EAC specimens (N = 661) at Mayo Clinic. HER2 genetic heterogeneity was defined per ASCO/CAP as amplification (HER2/CEP17 ratio ≥ 2) in 5-50% of cancer cells; poly17 refers to ≥ 3 copies of chromosome 17. Most tumors were T3-4 (68%) or lymph node (LN)-positive (73%). Cox models were used to assess disease-specific (DSS) and overall survival (OS). Results: HER2 amplification was detected in 117 of 661 EACs (18%), of which 20 (17%) showed HER2 heterogeneity. HER2 heterogeneous tumors had a significantly higher frequency of poly17 and high tumor grade. HER2 heterogeneity by amplification vs expression were correlated. Since heterogeneity was limited to HER2-amplified tumors, survival analysis was stratified by amplification status. In multivariable analysis, only HER2 heterogeneity and metastatic LN number were prognostic (Table). Conclusions: Among HER2 amplified EACs, 17% show HER2 heterogeneity, which is associated with increased poly17 and independently predicts 2-fold higher risk of cancer-specific death. Among HER2-nonamplified cases, poly17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and evaluation of benefit from HER2 targeted therapy. [Table: see text]