Gene copy number variation and protein over expression of EGFR and HER2 in distal extrahepatic cholangiocarcinoma

Abstract

EGFR and HER2 are among the most promising therapeutic targets in solid cancers. The expression status of EGFR and HER2 are associated with the prognosis, and with a number of clinicopathological factors, in many cancers. However, few studies have examined this association in distal extrahepatic cholangiocarcinoma (EHCC). Therefore, we investigated EGFR and HER2 protein expression and gene copy number variation (CNV) in distal EHCC. We also studied the association of these factors with clinicopathological parameters and prognosis. Immunostaining, using antibodies against EGFR and HER2, was performed on 84 cases of distal EHCC. All positive (3+) and equivocal (2+) EGFR and HER2 expression cases, together with randomly selected negative (1 + and 0) cases, were evaluated for EGFR and HER2CNV. Among distal EHCC samples, 6.0% (n = 5) were positive (3+) for EGFR expression and 6.0% (n = 5) were equivocal (2+). HER2 expression was positively identified in 2.4% of samples (n = 2), and was equivocal in 1.2% of samples (n = 1). All cases of positive EGFR expression showed amplification (n=1) or high polysomy (n = 4) involving the EGFR gene; three cases (60%) of equivocal EGFR expression showed high polysomy of the EGFRgene. All cases of positive or equivocal HER2 expression (n = 3, 3.6%) showed amplification of the HER2 gene. In univariate analysis, EGFR expression and CNV were associated with shorter cancer-specific overall survival (p = 0.003 and p = 0.018, respectively). Multivariate analysis also showed that EGFR CNV was a significant prognostic factor in distal EHCC (p = 0.015). Although further study is warranted, our findings suggest that EGFR expression and CNV are factors associated with poor prognosis, and that anticancer therapeutics against EGFR and HER2 receptors may be promising therapeutic options for patients with distal EHCC.