Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with esophageal adenocarcinoma

Abstract

Purpose: There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC).

Patients and methods: HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS).

Results: Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023).

Conclusion: Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 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 determination of benefit from HER2-targeted therapy.

Fig 1.

Among patients with esophageal adenocarcinoma who underwent surgical resection with curative intent, the prognostic impact of (A and B) HER2 gene amplification in the overall cohort (N = 675) and (C and D) heterogeneous HER2 gene amplification in the subgroup of patients with HER2-amplified tumors (n = 117) is shown. Hazard ratios (HRs) were adjusted for tumor stage, grade, number of malignant nodes, and polysomy 17. Prognosis end points were disease-specific survival and overall survival.

Fig 2.

Among patients with esophageal adenocarcinoma who underwent surgical resection with curative intent, the prognostic impact of polysomy 17 is shown in the subgroup of patients with (A and B) HER2-amplified tumors (n = 117) and (C and D) HER2-nonamplified tumors (n = 558). Hazard ratios (HRs) were adjusted for tumor stage, grade, and number of malignant nodes. Prognosis end points were disease-specific survival and overall survival.

Fig A1.

Demonstration in resected surgical specimens of esophageal adenocarcinoma showing (A) heterogeneous and (B) nonheterogeneous HER2 gene amplification by fluorescence in situ hybridization with probes specific for HER2/neu (red) and chromosome 17 centromere (green). In panel A, a cluster of HER2-amplified cancer cells (arrowheads) is shown adjacent to HER2-nonamplified (arrows) cancer cells.