Abstract
Overexpression of receptor tyrosine kinases (RTK), including members of the HER family, has prognostic and therapeutic significance in invasive esophagogastric carcinoma. RTK expression in premalignant gastroesophageal lesions has not been extensively explored. Formalin-fixed paraffin-embedded tissue samples of esophageal biopsy specimens from 73 patients with Barrett’s esophagus with either low-grade dysplasia (LGD) (n = 32) or high-grade dysplasia (HGD) (n = 59) were analyzed for HER1, HER2, HER3 and CMET expression by immunohistochemistry (IHC). Immunophenotype was correlated with histologic and clinical features. High-grade dysplasia (HGD) was associated with overexpression of HER1 (20.7% vs. 3.1%, p = 0.023), HER2 (5.3% vs. 0.0%, p = 0.187) and HER3 (47.4% vs. 9.4%, p<0.001) compared to low-grade dysplasia (LGD). There was a significant association of HER2 (20.0% vs. 2.1%, p = 0.022) and HER3 (80.0% vs. 40.4%, p = 0.023) overexpression in HGD lesions associated with foci of invasive carcinoma compared to those without invasive foci. Overexpression of CMET was observed in 42.9% of specimens, was increasingly observed with HGD compared to LGD (58.3% vs. 36.7%, p = 0.200), and was most often co-expressed with HER3 (62.5% of HER3-positive specimens vs. 38.2% of HER3-negative specimens, p = 0.212). In summary, HER3 is frequently overexpressed in high-grade dysplastic lesions of the gastroesophageal junction and may be a marker of invasive progression. These data provide rationale for targeting HER2 and HER3 pathways in an early disease setting to prevent disease progression.
Highlights
Barrett's esophagus (BE), or the presence of metaplastic columnar epithelium in the distal esophagus, predisposes to the development of esophageal adenocarcinoma (EAC) [1]
There were no significant differences between the low-grade dysplasia (LGD) and highgrade dysplasia (HGD) cohorts in the measured clinical and demographic variables (Table 1)
Similar trends were not observed in HER1-positive (p = 0.729) or HER2-positive (p = 1.0) specimens. This analysis of receptor tyrosine kinases (RTK) expression in dysplastic lesions of the gastroesophageal junction confirms that (1) human epidermal growth factor receptor (HER) family proteins are upregulated in Barrett’s esophagus with dysplasia; (2) the frequency of HER family overexpression is positively correlated with the degree of dysplasia; and (3) HER protein upregulation, HER2 and HER3, in dysplastic lesions is associated with an increased incidence of associated invasive cancer
Summary
Barrett's esophagus (BE), or the presence of metaplastic columnar epithelium in the distal esophagus, predisposes to the development of esophageal adenocarcinoma (EAC) [1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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