Dataset Information

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

ABSTRACT: BACKGROUND:Cholangiocarcinoma 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. METHODS:In 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. RESULTS:We 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. CONCLUSIONS:This 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.

SUBMITTER: Albrecht T

PROVIDER: S-EPMC6896712 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

Albrecht Thomas T Rausch Melina M Rössler Stephanie S Albrecht Michael M Braun Jana Dorothea JD Geissler Veronika V Mehrabi Arianeb A Vogel Monika Nadja MN Pathil-Warth Anita A Mechtersheimer Gunhild G Renner Marcus M Rupp Christian C Weiss Karl Heinz KH Busch Elena E Köhler Bruno B Springfeld Christoph C Schirmacher Peter P Goeppert Benjamin B

BMC cancer 20191205 1

<h4>Background</h4>Cholangiocarcinoma 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.<h4>Methods</h4>In this ...[more]

PMID: 31805897

Similar Datasets

Project description:Cholangiocarcinoma (CCA) caused by infection of the liver fluke Opisthorchis viverrini, (Ov) is the major public health problem in northeast Thailand. Following Ov infection the subsequent molecular changes can be associated by reactive oxygen species (ROS) induced chronic inflammation, advanced periductal fibrosis, and cholangiocarcinogenesis. Notably, resistance to an activation of cell death in prolonged oxidative stress conditions can occur but some damaged/mutated cells could survive and enable clonal expansion. Our study used a natural product, xanthohumol (XN), which is an anti-oxidant and anti-inflammatory compound, to examine whether it could prevent Ov-associated CCA carcinogenesis. We measured the effect of XN with or without praziquantel (PZ), an anti-helminthic treatment, on DNA damage, redox status change including iron accumulation and periductal fibrosis during CCA genesis induced by administration of Ov and N-dinitrosomethylamine (NDMA) in hamsters. Animals were randomly divided into four groups: group I, Ov infection and NDMA administration (ON); group II, Ov infection and NDMA administration and PZ treatment (ONP); the latter 2 groups were similar to group I and II, but group III received additional XN (XON) and group IV received XN plus PZ (XONP). The results showed that high 8-oxodG (a marker of DNA damage) was observed throughout cholangiocarcinogenesis. Moreover, increased expression of CD44v8-10 (a cell surface in regulation of the ROS defense system), whereas decreased expression of phospho-p38MAPK (a major ROS target), was found during the progression of the bile duct cell transformation. In addition, high accumulation of iron and expression of transferrin receptor-1 (TfR-1) in both malignant bile ducts and inflammatory cells were detected. Furthermore, fibrosis also increased with the highest level being on day 180. On the other hand, the groups of XN with or without PZ supplementations showed an effective reduction in all the markers examined, including fibrosis when compared with the ON group. In particular, the XONP group, in which a significant reduction DNA damage occurred, was also found to have iron accumulation and fibrosis compared to the other groups. Our results show that XN administered in combination with PZ could efficiently prevent CCA development and hence provide potential chemopreventive benefits in Ov-induced cholangiocarcinogenesis.

Project description:Background: HER2 antagonists have marked activity and are approved for the treatment of HER2 overexpressing breast and gastric cancers. Recent studies have shown that ERBB2 (HER2) gene amplification and overexpression may also be actionable in other tumor types. Inter- and intratumoral heterogeneity in HER2 status, however, poses a significant challenge in identifying patients that may benefit from HER2-targeted therapies. ERBB2 amplification as identified by circulating cell-free DNA (cfDNA), which circumvents tissue heterogeneity issues, is emerging as a robust biomarker predictive of response to anti-HER2 agents. Here, the prevalence and genomic landscape of ERBB2 alterations detectable by next-generation sequencing (NGS) of cfDNA was evaluated in a large cohort of Asian patients with advanced solid tumors. Methods: Results were queried for consecutive patients (n = 469) tested by a comprehensive 70/73-gene cfDNA NGS assay (Guardant360®) between November 2015 and June 2018. Patients with ERBB2 gene alterations including copy number amplifications (CNAs), single nucleotide variants (SNVs), and insertion-deletions (indels) were identified. Results: ERBB2 alterations were detected in 52 patients (11.1%); ERBB2 SNVs, CNAs, and indels were found in 27 (5.8%), 27 (5.8%), and 10 (2.1%) patients, respectively. ERBB2 amplification was most frequently identified in gastric (21.4%; 6/28), colorectal (11.1%; 5/45), lung (3.9%; 9/231), and breast (3.2%; 1/31) cancer patients. ERBB2 amplification was often mutually exclusive with other oncogenic alterations in gastric (83.3%; 5/6) and colorectal (60%; 3/5) cancer patients. ERBB2 copy number gains were also highest in gastric and colorectal cancers (median 4.8 and 6.6, respectively). We further report two cases of advanced gastric cancer patients, one treatment naïve, and the other having failed four lines of therapy, whose ERBB2 CNAs were identified by cfDNA and derived clinical benefit from HER2-based therapies. Conclusion: Our data indicate that ERBB2 amplification is a common event in solid tumors among Asian cancer patients. High ERBB2 incidence and copy number gains were observed in gastric and colorectal cancer patients, often in the absence of other oncogenic mutations, underscoring its likely role as the driver alteration in those settings. Finally, we show the potential of comprehensive cfDNA testing in identifying patients who are most likely to benefit from HER2-targeted therapies.

Dataset Information

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

Publications

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets