title: Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications.
abstract: BACKGROUND
  HER2 and topoisomerase 2 alpha (TOP2A) genomic status was previously reported to predict benefit from anthracyclines in breast cancer. We sought to define the prognostic impact and possible pitfalls related to these biomarkers in resectable gastroesophageal adenocarcinoma.
  
  
  METHODS
  HER2 and TOP2A gene amplification by fluorescent in situ hybridization and HER2 protein expression by immunohistochemistry (IHC) were assessed on whole tissue sections from 101 patients receiving peri- or postoperative epirubicin-based chemotherapy. In a subgroup of patients, at least two matched tumor blocks, originating either from surgical procedures (n = 88) or diagnostic biopsies (n = 32), were available for HER2 analyses by IHC.
  
  
  RESULTS
  Eighteen of 101 patients (17.8 %) were HER2 positive, whereas TOP2A was amplified in 4 of 84 patients (4.7 %). HER2 positivity was significantly associated with improved disease-free survival [HR = 0.47 (95 % CI 0.22-0.99), P = 0.046] and overall survival [HR = 0.33 (95 % CI 0.13-0.83), P < 0.018], independent of clinical-pathologic features. HER2 expression in matched tumor blocks from the same resection specimen was discordant in up to 11.8 % of pairs, while this rate increased up to 27.2 % when diagnostic biopsies and paired surgical samples were compared.
  
  
  CONCLUSIONS
  HER2 status is an independent prognostic biomarker in gastroesophageal adenocarcinomas receiving epirubicin-based chemotherapy. Compared to diagnostic biopsies, HER2 assessment in multiple resection specimens might lower the risk of sampling errors. These findings have several implications with respect to the optimal choice of the sample to be submitted to IHC testing of HER2.
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy. nic_personeni@hotmail.com.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. nic_personeni@hotmail.com.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0002-7995-272X
authors.initials: N
authors.lastname: Personeni
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Baretti
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozzarelli
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Spaggiari
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rubino
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Tronconi
authors.affiliation: Department of General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Fumagalli Romario
authors.affiliation: Department of General Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Ospedale San Raffaele, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rosati
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.|Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.|Humanitas University, Rozzano, Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni 56 Rozzano, 20089, Milan, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Rimassa
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D015251:Epirubicin; D000075223:Poly-ADP-Ribose Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C000618811:TOP2A protein, human
keywords: Epirubicin; FISH; Gastroesophageal; HER2; Heterogeneity; Immunohistochemistry; Topoisomerase 2 alpha