title: HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?
abstract: Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as "high quality" (HQ) if IHC overexpression was defined as presence of moderate/strong staining or "low quality" (LQ) where "any" expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9-34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8-27.1 %) vs. 4.8 % (95 % CI 0-14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to "unselected" patients: 57.6 % (95 % CI 16.2-99 %) vs. 17.9 % (95 % CI 0.1-35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7-46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.|Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Galdy
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Lamarca
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.|Institute of Cancer Sciences, Department of Medical Oncology, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Mairéad G
authors.initials: MG
authors.lastname: McNamara
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hubner
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
authors.forename: Chiara A
authors.initials: CA
authors.lastname: Cella
authors.affiliation: Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.affiliation: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK. juan.valle@christie.nhs.uk.|Institute of Cancer Sciences, Department of Medical Oncology, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK. juan.valle@christie.nhs.uk.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
mesh_terms: D001661:Biliary Tract Neoplasms / Q000201:enzymology*; D006801:Humans; D053858:Metabolic Networks and Pathways; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: Biliary tract cancer; Cholangiocarcinoma; HER2 pathway; HER3 pathway; Meta-analysis; Systematic review