title: Serum HER2 as an adjunct to assess HER2 status for advanced gastric cancer: A prospective multicenter trial (SHERLOCK).
abstract: BACKGROUND
  Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer.
  
  
  METHODS
  We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated.
  
  
  RESULTS
  Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2.
  
  
  CONCLUSIONS
  Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.
authors.affiliation: a Department of Gastroenterology , Rheumatology and Clinical Immunology, Sapporo Medical University , Sapporo , Japan ;
authors.forename: Mayuko
authors.initials: M
authors.lastname: Saito
authors.affiliation: a Department of Gastroenterology , Rheumatology and Clinical Immunology, Sapporo Medical University , Sapporo , Japan ;
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: a Department of Gastroenterology , Rheumatology and Clinical Immunology, Sapporo Medical University , Sapporo , Japan ;
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Arimura
authors.affiliation: b Department of Gastroenterology , Muroran City General Hospital , Muroran , Japan ;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaneto
authors.affiliation: c Department of Medical Oncology , Keiyukai Sapporo Hospital , Sapporo , Japan ;
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okuda
authors.affiliation: d Center for Translational Research, The Institute of Medical Science, The University of Tokyo , Tokyo , Japan ;
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.affiliation: e Department of Gastroenterology , Sapporo-Kosei General Hospital , Sapporo , Japan ;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hagiwara
authors.affiliation: f Department of Gastroenterology , Kushiro City General Hospital , Kushiro , Japan ;
authors.forename: Kazuya
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: g Department of Gastroenterology , Otaru Municipal Hospital , Otaru , Japan ;
authors.forename: Takeya
authors.initials: T
authors.lastname: Adachi
authors.affiliation: g Department of Gastroenterology , Otaru Municipal Hospital , Otaru , Japan ;
authors.forename: Akira
authors.initials: A
authors.lastname: Goto
authors.affiliation: h Department of Gastroenterology , Obihiro Kyokai Hospital , Obihiro , Japan ;
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakachi
authors.affiliation: i Department of Gastroenterology , Hakodate Goryoukaku Hospital , Hakodate , Japan ;
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yawata
authors.affiliation: j Department of Hematology and Gastroenterology , Tenshi Hospital , Sapporo , Japan ;
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Yoshimoto
authors.affiliation: k Center for Gastroenterology, Teine Keijinkai Hospital , Sapporo , Japan ;
authors.forename: Tokuma
authors.initials: T
authors.lastname: Tanuma
authors.affiliation: l Division of Gastroenterology , Sapporo Shirakaba-dai Hospital , Sapporo , Japan ;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: m Division of Gastroenterology , Sapporo Satozuka Hospital , Sapporo , Japan ;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaoka
authors.affiliation: n Division of Gastroenterology , Saiseikai Otaru Hospital , Otaru , Japan ;
authors.forename: Tsunenori
authors.initials: T
authors.lastname: Mizukoshi
authors.affiliation: o Division of Gastroenterology , JR Sapporo Hospital , Sapporo , Japan ;
authors.forename: Mariko
authors.initials: M
authors.lastname: Kawayama
authors.affiliation: p Division of Gastroenterology & Hepatology , Keio University School of Medicine , Tokyo , Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hamamoto
authors.affiliation: a Department of Gastroenterology , Rheumatology and Clinical Immunology, Sapporo Medical University , Sapporo , Japan ;
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D015415:Biomarkers; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human