Abstract
BackgroundCholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy.MethodsIn this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer.ResultsWe identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival.ConclusionsThis study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.
Highlights
Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year
Dimerization activates the intrinsic tyrosine kinase domain leading to the induction of different downstream signaling cascades, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3kinase (PI3K)/protein kinase B (PKB or Akt) pathway which are essential for cellular proliferation and differentiation [9]
HER2 positivity in cholangiocarcinoma and correlation with clinicopathological criteria By application of both IHC and dc-ISH and strict adherence to the testing algorithm provided by Rüschoff et al [11] (Fig. 1), we only identified six CCA cases exhibiting HER2 gene amplification, corresponding to a low frequency of approximately 1.4%
Summary
Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. Acknowledged etiologies of CCA encompass parasitic infestation with liver flukes, cholelithiasis, diabetes, obesity, tobacco smoking, chronic viral hepatitis B and C, bile duct cystic disorders and primary sclerosing cholangitis (PSC) as the strongest and best-documented risk factor in the Western population [5] Integrating these associations, chronic inflammation and cholestasis seem to be key components of cholangiocarcinogenesis. Reflecting the geographic differences of CCA incidence, most of the studies on HER2 expression in CCA were conducted in Asia and South America Adding to this heterogeneity, data on HER2 positivity in the Western population is very limited with only a few studies being realized in Western countries [13,14,15,16,17,18,19,20,21] (Table 1). Due to the low CCA incidence rates in Western countries, these studies usually lack sufficient sample numbers, which is further aggravated by the fact that all different kinds of biliary tract cancer (BTC) are investigated as a whole, including gallbladder
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