title: HER2 diagnostics in gastric cancer-guideline validation and development of standardized immunohistochemical testing.
abstract: Trastuzumab-based therapy has been shown to confer overall survival benefit in HER2-positive patients with advanced gastric cancer in a large multicentric trial (ToGA study). Subgroup analysis identified adenocarcinomas of the stomach and gastroesophageal (GE) junction with overexpression of HER2 according to immunohistochemistry (IHC) as potential responders. Due to recent approval of trastuzumab for HER2 positive metastatic gastric and GE-junction cancer in Europe (EMEA) HER2 diagnostics is now mandatory with IHC being the primary test followed by fluorescence in situ hybridization (FISH) in IHC2+ cases. However, in order to not miss patients potentially responding to targeted therapy determination of a HER2-positive status for gastric cancer required modification of scoring as had been proposed in a pre-ToGA study. To validate this new HER2 status testing procedure in terms of inter-laboratory and inter-observer consensus for IHC scoring a series of 547 gastric cancer tissue samples on a tissue microarray (TMA) was used. In the first step, 30 representative cores were used to identify specific IHC HER2 scoring issues among eight French and German laboratories, while in the second step the full set of 547 cores was used to determine IHC HER2 intensity and area score concordance between six German pathologists. Specific issues relating to discordance were identified and recommendations formulated which proved to be effective to reliably determine HER2 status in a prospective test series of 447 diagnostic gastric cancer specimens.
authors.affiliation: Targos Molecular Pathology GmbH und Pathologie Nordhessen, 34119 Kassel, Germany. rueschoff@patho-nordhessen.de
authors.forename: Josef
authors.initials: J
authors.lastname: Rüschoff
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baretton
authors.forename: Susanne
authors.initials: S
authors.lastname: Arbogast
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Geneviéve
authors.initials: G
authors.lastname: Monges
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Chenard
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Iris
authors.initials: I
authors.lastname: Nagelmeier
authors.forename: Werner
authors.initials: W
authors.lastname: Schlake
authors.forename: H
authors.initials: H
authors.lastname: Höfler
authors.forename: H H
authors.initials: HH
authors.lastname: Kreipe
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods / Q000592:standards*; D015588:Observer Variation; D017410:Practice Guidelines as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D015203:Reproducibility of Results; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics*; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases