HER3 Expression Is a Marker of Tumor Progression in Premalignant Lesions of the Gastroesophageal Junction

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.